Long-term Outcomes of Patients With Recurrent Ovarian Cancer Treated With a Polyvalent Vaccine With Bevacizumab Combination

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Kahn, Govind Ragupathi, Qin C. Zhou, Alexia Iasonos, Sara Kravetz, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1347080/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background: To characterize the safety, immunogenicity, and outcomes of patients with high-grade serous ovarian cancer (HGSOC) in second or greater remission treated with a polyvalent antigen-KLH plus OPT-821 vaccine construct and bevacizumab. Methods: Patients with recurrent HGSOC were treated with the vaccine plus bevacizumab at our institution from 01/05/2011-03/20/2012. Follow-up continued until 03/2021. Blood/urine samples were collected. “Responders” had an immunogenic response to > 3 antigens; “non-responders” to < 2 antigens. Results: Twenty-one patients were treated on study. One developed a dose limiting-toxicity (grade 4 fever). Two (10%) experienced bevacizumab-related grade 3 hypertension. Thirteen (68%) and 16 (84%) of 19 responded to ≥3 and ≥2 antigens, respectively (Globo-H, GM2, TF cluster Tn, MUC-1). Four of 21 patients were alive >5 years post-treatment. Responders and non-responders had a median PFS of 4.9 months (95% CI: 2.8-8.1) and 5.0 months (95% CI: 0.7-cannot estimate), respectively; median OS was 30.7 months (95% CI: 16.9-52.0) and 34.2 months (95% CI: 12.8-cannot estimate), respectively. On two-time point analysis (baseline, week 17), increased IL-8 exhibited improved PFS (HR as 10-unit increase, 0.43; p=0.04); increased PDGF exhibited worse OS (HR as 10-unit increase, 1.01; p = 0.02). Conclusions: This is the longest follow-up of vaccine administration with bevacizumab among patients with ovarian cancer. The vaccine was well tolerated with bevacizumab. Response was not associated with improved survival. On two-time point analysis, increased IL-8 was associated with significant improvement in PFS; increased PDGF with significantly worse OS. For all time point measurements, cytokine levels were not significantly associated with survival. Trial registration: NCT01223235 vaccine ovarian cancer cytokines immunotherapy bevacizumab remission Figures Figure 1 Introduction Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy due to its typically late stage at presentation and high predilection for metastases and recurrence [1]. Aberrant immunologic responses have been shown to contribute to the invasion and progression of EOC [2]. Greater than 80% of women diagnosed with EOC will relapse following primary treatment [3]. Many patients will have some degree of response to subsequent chemotherapy. Subsequent remissions are of progressively shorter duration, however, until chemotherapy resistance generally develops. This is believed to have a correlation with host immune responses and tumor genomic factors [4, 5]. Because of this, the immune environment remains a key target for therapies in both the maintenance and recurrent settings. The mechanisms to explain the vast differences in downstream ovarian cancer recurrence outcomes among patients with similar histology remains unknown, however, and requires further evaluation. Previous studies have demonstrated the presence of antitumoral T cells in the ovarian cancer microenvironment [6, 7]. We previously completed a phase I safety and immunogenicity study of the polyvalent vaccine-KLH conjugate [GM2, Globo-H, Le y , Tn-MUC1, Tn(c), STn(c) and TF(c)] plus immunological adjuvant QS-21 in patients with epithelial ovarian, fallopian tube, or peritoneal cancer in a first, second, or later complete clinical remission [8]. We subsequently conducted a follow-up phase II randomized, double-blind trial of a polyvalent vaccine-KLH conjugate + OPT-821 versus OPT-821 alone (Gynecologic Oncology Group [GOG]255) [9]. The results from GOG255 demonstrated that vaccine immunotherapy with the addition of an adjuvant was well tolerated, with mild toxicity largely confined to injection site reactions, and greater immunogenicity (compared to vaccine alone) against five of the antigens contained in the vaccine (Globo-H, GM2, MUC1-TN, MUC1, and TF). However, there were no differences in progression-free survival (PFS) or overall survival (OS) between vaccine-KLH conjugate plus OPT-821 versus OPT-821 alone [9]. GOG255 results were published with a median follow-up of 34 months; a later analysis performed in 2018 had a median follow-up of 60 months [9]. The efficacy of anti-angiogenic agents in the treatment of ovarian cancer has also been demonstrated [10, 11]. The AURELIA study (NCT00976911) showed that the addition of bevacizumab to chemotherapy in platinum-resistant ovarian cancer increased the median PFS from 3.4 to 6.7 months [12]. The combination compared with chemotherapy alone also resulted in increased response rates and improved quality of life. In addition to modulation of the tumor vasculature, vascular endothelial growth factor (VEGF) has been shown to suppress dendritic cell maturation and alter antigen presentation. It also exhibits a host of other influences on immune activity, providing a rationale for combining anti-VEGF therapy with vaccination as a source of immune stimulation [13]. The future direction of ovarian cancer immunotherapies will require the detection of specific biomarkers to predict the effectiveness of different treatment combinations while also minimizing toxicities [14]. The goal of this study is to evaluate both the short-term and delayed immunologic responses, as well as clinical outcomes, in patients with recurrent EOC after receiving a polyvalent vaccine and bevacizumab combination. Materials And Methods This study was approved by the Institutional Review Board at Memorial Sloan Kettering Cancer Center (MSK). Eligibility Criteria Eligible patients had histologically documented EOC arising in the ovary, fallopian tube, or peritoneum, with stage II-IV disease at diagnosis after second or subsequent clinical remission. Primary treatment must have included cytoreductive surgery and a platinum-based chemotherapy regimen. Eligible patients had relapsed at least once, had completed chemotherapy and/or surgery, and were deemed suitable to enter a period of observation. Patients could have asymptomatic residual measurable disease on computed tomography (CT) scan or be in complete clinical remission. Complete clinical remission was defined as serum CA-125 < 35 IU/mL, negative physical examination, and no evidence of disease on CT of the abdomen and pelvis. Patients had to be longer than 4 weeks out from completion of prior cytotoxic chemotherapy. Other requirements included Karnofsky Performance Status (KPS) ≥70; adequate organ function, defined as absolute neutrophil count ≥1000 cells/mm 3 ; platelets ≥100,000 cells/mm 3 ; serum creatinine ≤1.5 times the institutional upper limits of normal; and total bilirubin, AST and alkaline phosphatase ≤2.5 times the institutional upper limits of normal. Patients were ineligible if they were of child-bearing potential, had a known autoimmune disease or immune deficiency, a known allergy to seafood, history of myocardial infarction within 6 months, untreated brain metastasis, uncontrolled hypertension, or other standard contraindications to receiving bevacizumab therapy. Treatment Plan The administered polyvalent vaccine contained GM2 (30 µg, equivalent to antigen concentration in GM2-KLH conjugate), Globo-H (30 µg), Tn-MUC1 (3 µg) and TF(c) (3 µg), individually conjugated to KLH (600 μg) and mixed with adjuvant OPT-821 (100 µg) in 1.0 mL normal saline as the diluent. The vaccine was administered in 1cc total volume subcutaneously at weeks 1, 2, 3, 7, 11, and 17. Bevacizumab was given via intravenous infusion at 7.5 mg/kg over 20-30 minutes once every 2 weeks, beginning on day 1 of week 1 through week 11, and once every 3 weeks thereafter. Bevacizumab could be continued until disease progression or toxicity. Vaccine Preparation The antigen conjugation method and administration protocol was previously referenced in GOG255 [9]. The IND was held by MSK. The following antigens were conjugated to KLH (carrier protein) mixed with OPT-821 adjuvant: Tn glycosylated MUC-1 (Tn-MUC1) was synthesized by Pepceuticals Ltd (Leicester, UK). The Globo-H hexasaccharide-KLH was synthesized and conjugated under good manufacturing practices (GMP) by Optimer Pharmaceuticals Inc. (San Diego, CA). GM2: Ganglioside GM2 was extracted by Matreya Inc. (Philadelphia, PA). It was conjugated to KLH by Althea Technologies (San Diego, CA). TF(c): TF cluster was synthesized by the MSK Organic Synthesis Core. Tn-MUC1-KLH, TF(c)-KLH conjugates were prepared by the MSK Clinical Grade Production (CGP) facility under GMP. OPT-821 is an immunological adjuvant obtained from Optimer Pharmaceuticals Inc. (San Diego, CA). Vaccines and OPT-821 were vialed and released for clinical use by the CGP Core facility. Dose Adjustment Dose reduction or delay of vaccine was not permitted. Delays in bevacizumab were permitted in the event of toxicity, with a maximum allowable treatment interruption of 8 weeks. There was no dose reduction of bevacizumab. Toxicity was evaluated according to the National Cancer Institute CTCAE scale version 4 [15]. Patients were to be removed from the study for a vaccine-related dose-limiting toxicity (DLT), defined as grade ≥2 allergic reaction, grade ≥2 autoimmune reaction, grade ≥3 hematologic or non-hematologic toxicity including fever, or grade ≥3 injection site reaction. Any patient with grade 2 or greater toxicity was followed with appropriate studies until results returned to baseline. Patients were removed from the study for progression of disease , as defined by RECIST [16] . Evaluation During Study Pretreatment evaluation included a complete medical history, physical and radiologic examination (CT), vital signs, KPS assessment, and clinical laboratory tests, including hematologic, biochemistry, CA-125, and immunologic testing. Patients had repeat complete blood count (CBC) and comprehensive biochemistry panel at regular intervals, and at the off-study visit. Urine protein was obtained and followed at regular intervals. CT imaging was performed every 3 months while on study, or sooner to evaluate patients if signs or symptoms, blood tests, or physical examination suggested progression of disease. Serologic IgM and IgG antibody responses were measured by ELISA against each antigen at baseline and week 7. The correlative multiplex panels were measured at weeks 1, 17, and off-study. Antibody Response Against Vaccine Antigens The IgM and IgG antibody responses were measured by ELISA in duplicate against each antigen as described earlier [8]. The criteria for immunogenicity used was based on that of the individual pilot trials: patients must have had IgM/IgG titer >1:40 or an eightfold increase in prevailing antibody titer if present at baseline. These criteria were based on our previous studies [8]. The antibody titer was defined as the highest serum dilution showing an absorbance of ≥0.1 optical density (a measurement of percent transmission). ”Responders” were defined as patients with an immunogenic response to ≥3 antigens; ”Non-Responders” were defined as patients with an immunogenic response to ≤2 antigens. Multiplex Assays A multiplex angiogenesis assay panel was performed to include monoclonal antibodies specific for interleukin-8 (IL-8), VEGF, platelet-derived growth factor (PDGF), and fibroblast growth factor-basic (FGF-basic). Statistical Considerations The primary endpoint of this pilot trial was safety; the secondary endpoint was to measure patient immunogenicity following administration of the polyvalent vaccine in combination with bevacizumab. No clinically significant systemic toxicity was associated with administration of similar vaccines. Twenty-one patients would be accrued, and if >8 of 21 patients met the criteria for immunogenicity (described above) for three or more antigens, the study would be considered positive [17]. This calculation assumes that the probability of immune response under the null hypothesis (i.e., no activity) is 0.2 versus the alternative hypothesis (i.e., target response probability) of 0.5. Type I and Type II errors were set to 0.1. In prior trials, antibodies were generally present by the completion of the fourth vaccination (week 7). PFS was measured from the start of vaccine therapy until progression, and OS was measured from the start of vaccine therapy until death or last follow-up (for only one patient). The associations between cytokine measurements between baseline and week 17 or at different time points, and the PFS/OS, were analyzed using time-dependent Cox proportion hazard (PH) models. The PFS/OS by antibody response versus non-response for the five vaccine antigens, as well as the responder versus non-responder evaluation, was analyzed using landmark analyses with landmark time as months (chosen by the longest interval post vaccination antibody IgG/IgM titers). Antibodies against the individual antigens were studied by ELISA. All p-values are two-sided, with statistical significance evaluated at the 0.05 alpha level. Ninety-five percent confidence intervals (95% CI) for all parameters of interest were calculated to assess the precision of the obtained estimates. All analyses were performed with the use of R statistical software version 4.1.1 (R Foundation for Statistical Computing, Vienna, Austria). Results Patient Characteristics Twenty-one patients with recurrent high-grade serous ovarian carcinoma were enrolled on the study between 01/05/2011 and 03/20/2012. All 21 patients were included in the safety analysis. Follow-up for survival was continued until 03/2021. Patient characteristics are described in Table 1 . Patients had a median age of 56 years (range, 49-70 years). Twenty tumors were adnexal in origin, and one was of peritoneal origin. All patients had KPS ranging from 90-100%. The majority of patients (71%) were in complete remission at study entry. Patients were relatively heavily pretreated—38% were in a third, 38% in a fourth, and 14% in a fifth remission. Three patients had a deleterious BRCA mutation (2 BRCA1 , 1 BRCA2 ). One patient was found to have a TSC2 mutation post-treatment. The median number of systemic treatment regimens administered to patients after this vaccine study was five (range, 0-7). Total systemic treatments after vaccine therapy included platinum-based chemotherapy (23/92, 25%), taxane-based chemotherapy (18/92, 20%), bevacizumab (14/92, 15%), gemcitabine (13/92, 14%), liposomal doxorubicin (12/92, 13%) and poly-adenosine ribose phosphorylase (PARP) inhibitors (8/92, 9%). Thirty-two percent of regimens were combination therapies (30/92, 32%) (Table 2). Adverse Events One patient experienced a dose-limiting toxicity—a grade 4 fever (40.1°C for 48 h)—following vaccination. Two patients (10%) developed grade 3 hypertension related to bevacizumab; one of these patients had uncontrolled hypertension despite pharmaceutical management and was removed from the study 7 months after the start date due to excessive toxicity. One patient developed grade 3 hyperglycemia, not attributed to the vaccine or bevacizumab. Otherwise, side effects were self-limited; mild fatigue, fever, myalgia, and localized injection site reactions were the most common. Table 3 depicts the maximum toxicity for treatment-related events with vaccine and bevacizumab. No clinically relevant hematologic abnormalities were noted. There was no clinical or laboratory evidence of autoimmunity. The vaccine was well tolerated overall. Immune Response The predefined definition of immunogenicity to the vaccine was met in 13 of 19 evaluable patients with response to at least 3 of the 5 vaccine antigens ( Table 4) , and in 16 of 19 patients with response to at least 2 antigens. Two patients were excluded from the immunogenicity analysis due to a lack of post-intervention antibody results. Twelve of 19 patients exhibited an antibody response for GM2; 15/19 for Globo-H; 1/19 for Tn; 12/19 for TF; and 14/19 for MUC1. There was no significant difference between antigen antibody response and cytokine level when segregating by immune responders for each antigen. Survival Outcomes The median PFS for the overall cohort was 6.0 months (95% CI: 2.5-7.1 months). The median OS for the overall cohort was 34.6 months (95% CI: 20.1-53). The 5-year OS rate was 23.8% (8.7-43.1%). Among the 4 patients who were alive beyond 5 years, 2 had BRCA- associated ovarian cancer (50%). There was no median follow-up time for the cohort, as all patients on trial were followed until their death; one patient who was still alive at her last follow-up date was followed for 112.5 months. Survival Outcomes by Antibody Response Responders and non-responders had a median PFS of 4.9 months (95% CI: 2.8-8.1) and 5.0 months (95% CI 0.7-cannot estimate), respectively, and 6-month PFS rates of 30.8% (95% CI: 9.5-55.4%) and 16.7% (95% CI: 0.8-51.7%), respectively (Table 5). Responders and non-responders had a median OS of 30.7 months (95% CI: 16.9-52.0) and 34.2 months (95% CI: 12.8-cannot estimate), respectively, and 5-year OS rates of 15.4% (95% CI: 2.5-38.8%) and 16.7% (95% CI: 0.8-51.7%), respectively (Figure 1). The median OS for patients with a response to GM2 was 29.1 months, compared with 35.3 months for those without a response (p=0.327). The median OS for patients with a Globo-H response was 35.3 months, compared with 31.9 months for those without a response (p=0.38). The median OS for patients with a Tn response was 33.1 months, compared with 33.0 months for those without a response (p=0.793). The median OS for patients with a TF response was 30.6 months, compared with 42.6 months for those without a response (p=0.156). The median OS for patients with a MUC-1 response was 38.9 months, compared with 30.6 months for those without a response (p=0.94). Survival Outcomes by Cytokine Measurement When comparing two time point measurements (baseline and week 17), increased IL-8 levels had a moderately significant association with improved PFS (HR as 10-unit increase: 0.43; 95% CI: 0.19-0.97; p=0.04). Increased levels of PDGF had a moderately significant association with worse OS (HR as 10-unit increase: 1.01; p=0.02). When considering all time point measurements (baseline until progression for PFS or baseline until last measurements for OS), cytokine levels were not significantly associated with survival outcomes ( Table 5 ). Discussion This study includes the longest prospective follow-up of patients with ovarian cancer who have received vaccine immunotherapy. It is also the first study to report on the safety of polyvalent antigen-KLH plus OPT-821 vaccine construct administered in combination with bevacizumab. The rate of immunogenicity was qualitatively similar to that seen in our prior study, which did not include the addition of bevacizumab. In the current study, 68% and 84% of patients responded to ≥3 and ≥2 antigens, respectively, compared with 89% and 89%, respectively in our prior phase I trial without bevacizumab [8]. Given the potential immune-modulating effects of bevacizumab and the GOG255 study (NCT00857545), which evaluated the vaccine in settings where bevacizumab may have been used, it was necessary to ascertain whether there would be toxicity-related adverse effects due to the addition of bevacizumab. No additional toxicities were observed in this study. Measured cytokines in the multiplex assay likewise showed no changes between baseline and week 17, or when values were considered at each time point until progression of disease or last follow-up. The median PFS from the start of preceding chemotherapy was 13 months (95% CI: 10-20 months), within the reported range of progression in this population, in patients receiving maintenance bevacizumab therapy in the platinum-sensitive setting, as seen in the OCEANS study [18]. Four patients (19%) were alive more than 5 years after the study intervention; and 3 (14%) were alive after more than 6 years. One patient treated on study in second remission was still alive at her most recent follow-up, 9 years after the start of the trial. Patients with an antibody response against Globo-H compared to those without a response had a median OS of 35.3 versus 31.9 months, respectively; patients with response against MUC-1 compared to those without had an OS of 38.9 versus 30.6 months, respectively. These findings were not significant, which could be attributed to the small sample size. We did not identify predictors of survival. Although we observed antibody responses to the vaccine antigens, we were not able to conclude that such responses induced protective immune responses. Unfortunately, our correlative studies did not include T-cell response profiling. Ovarian cancer is a notoriously aggressive malignancy in part due to its tumor microenvironment and interaction with host immunity. Previous studies have suggested that FGF and FGF-1 play a crucial role in the progression of ovarian cancer. A 2017 study by Sun et al. found that FGF increased cellular proliferation, migration, and invasion while also regulating protein kinase pathways, resulting in epithelial-to-mesenchymal transition [1]. Similarly, PDGF has also been implicated in the progression of ovarian cancer cells. Matei et al. conducted one of the first studies to demonstrate a strong correlation between PDGF expression and VEGF in EOC; in PDGFR-expressing immortalized ovarian cancer cells, PDGF stimulated the expression of VEGF in association with the PI3K/Akt pathway [19]. IL-8 has also been shown to be elevated in ovarian cyst fluid, ascites, serum, and tumor tissue in ovarian cancer. Wang et al. demonstrated that IL-8 secretion by ovarian cancer cells increases proliferation through alteration of Cyclin D1/B1 proteins and invasion, angiogenic potential, adhesion, and invasion by correlating with MMP-2/MMP-9 activity and expression [20]. Globo-H, a glycosphingolipid of the globo series and a sugar terminus mimicking the antigen H determinant, has also been associated with EOC stem cells, angiogenesis, and an immunosuppressor through Notch signaling [21]. Lastly, microbial glycans, TF and Tn, which are widely expressed in adenocarcinomas, have been shown to likely play a role in self versus altered-self immunoreactivity [22]. Given these previous findings, antibodies against different cancer-associated antigens are desired targets when generating therapeutic cancer vaccines. The current study has several limitations. This was a small sample size of 21 women diagnosed with recurrent EOC. It is not possible to ascertain whether individuals with BRCA mutations had prolonged survival due to immunoreactivity following the vaccine or disease characteristics secondary to their BRCA mutation status. While our study evaluated associations and trend levels, causality cannot be determined. Since the inception of this study utilizing antibodies as the primary effectors, the field of immune modulation has continued to expand with the use of checkpoint inhibitors, as well as a variety of other agents, such as OX40 and ICOS. In addition, the evidence base suggesting synergy between bevacizumab and other immunomodulators continues to grow [13]. Given the putative mechanisms of bevacizumab with respect to the immune response, further study with vaccines or other mechanisms prompting T-cell effector proliferation or an integrated response (rather than antibodies alone, as seen in the vaccination here) is critical. This study includes the longest reported follow-up of patients with ovarian cancer undergoing vaccine therapy. Bevacizumab and polyvalent-KLH vaccine can be safely administered together, with retention of vaccine immunogenicity. Increased levels of IL-8 were associated with a moderately significant improvement in PFS; increased levels of PDGF were associated with a moderately significant improvement in OS. When considering all time point measurements, cytokine levels were not significantly associated with survival outcomes. Declarations Acknowledgements : Dr. O’Cearbhaill acknowledges mentorship from Prof. Garry Duffy from the National University of Ireland, Galway. Funding : This clinical study, the Clinical Grade Production and Organic Synthesis Core facility, data analysis were funded in part by the National Cancer Institute (P30 CA008748 and P01 CA190174-01A1). Bevacizumab was supplied by Genentech Inc. Disclosures/Conflicts of Interest: C.A. reports personal fees from Tesaro, personal fees from Immunogen, grants and personal fees from Clovis, grants from Genentech, grants from AbbVie, grants from Astra Zeneca, grants from Astra Zeneca, personal fees from Eisai/Merck, personal fees from Mersana Therapeutics, personal fees from Roche/Genentech, personal fees from Abbvie, personal fees from AstraZeneca/Merck, personal fees from Repare, outside the submitted work. M.L.H. reports other from Sanofi, other from GSK, personal fees from Research to Practice, personal fees from Up to Date, other from Bayer, personal fees from GOG Foundation, personal fees from Tesaro, personal fees from Lilly Oncology, personal fees from Merck, personal fees from Janssen, outside the submitted work. A.I. reports personal fees from Mylan, outside the submitted work. V.M. reports grants from Eisai, grants from Merck, grants from Takeda, from ArQule, grants from Karyopharm, grants from AstraZeneca, grants from Lilly, other from Clovis, other from Novasris, other from GSK, other from ITEOS, outside the submitted work. R.E.O. reports personal fees from Tesaro/GSK, personal fees from Regeneron, personal fees from Seattle Genetics, other from AstraZeneca Pharmaceuticals, personal fees from Fresenius Kabi, personal fees from Gynecologic Oncology Foundation, personal fees from Bayer, personal fees from Curio, advisor for Carina Biotech outside the submitted work; and Non-compensated steering committee member for the PRIMA, Moonstone (Tesaro/GSK), ARTISTRY7 (Arkemes) and DUO-O (AstraZeneca) studies. Her institute receives funding for clinical research from Bayer/Celgene/Juno, Tesaro/GSK, Ludwig Cancer Institute, Abbvie/StemCentrx, Merck, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Sellas Therapeutics, Genentech, Kite Pharma, Gynecologic Oncology Foundation. References 1. Sun Y, Fan X, Zhang Q, Shi X, Xu G, Zou C. 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Aghajanian, C., et al., OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol, 2012. 30 (17): p. 2039-45. 19. Matei D, Kelich S, Cao L, Menning N, Emerson RE, Rao J, Jeng MH, Sledge GW. PDGF BB induces VEGF secretion in ovarian cancer. Cancer Biol Ther. 2007 Dec;6(12). 20. Wang Y, Xu RC, Zhang XL, Niu XL, Qu Y, Li LZ, Meng XY. Interleukin-8 secretion by ovarian cancer cells increases anchorage-independent growth, proliferation, angiogenic potential, adhesion and invasion. Cytokine. 2012 Jul;59(1):145-55. 21. Pochechueva, T., Alam, S., Schötzau, A. et al. Naturally occurring anti-glycan antibodies binding to Globo H-expressing cells identify ovarian cancer patients. J Ovarian Res 10, 8 (2017). 22. Smorodin EP, Sergeyev BL. The level of IgG antibodies reactive to TF, Tn and alpha-Gal polyacrylamide-glycoconjugates in breast cancer patients: relation to survival. Exp Oncol. 2016 Jun;38(2):117-21. Tables Table 1: Baseline patient demographics (N=21) Variable No. of Patients Age, median (range), years 56 (49-70) FIGO stage at diagnosis ≤II 1 (4.8%) III 14 (67%) IV 6 (29%) Cancer type Ovarian 18 (86%) Primary peritoneal 1 (4.8%) Fallopian tube 2 (9.5%) Karnofsky Performance Status, median (range) 90 (90-100) Remission at Start of Study Second 2 (9.5%) Third 8 (38%) Fourth 8 (38%) Fifth 3 (14%) Complete 15 (71%) Partial 6 (29%) Platinum sensitivity status Platinum sensitive 18 (86%) Platinum resistant 3 (14%) Penultimate treatment prior to vaccine* Platinum 10 (48%) Taxane 3 (14%) Gemcitabine 8 (38%) Bevacizumab 4 (19%) Cyclophosphamide 1 (4.8%) Pegylated liposomal doxorubicin 5 (24%) Pemetrexed 1 (4.8%) Topotecan 1 (4.8%) Histologic subtype High-grade serous carcinoma 21(100%) Germline mutation status Wild type 18 (85.7%) BRCA1 variant 2 (9.5%) BRCA2 variant 1 (4.8%) FIGO, International Federation of Gynecology and Obstetrics *Given in combination for select patients Table 2: Patient outcomes following vaccine therapy Patient Subsequent systemic regimens following vaccine OS from diagnosis (months) OS from trial (months) 1 4 97 53 2 0 119 14 3 5 135 59 4 6 131 112 5 7 122 52 6 6 85 27 7 5 131 88 8 7 62 20 9 5 109 73 10 7 127 52 11 6 72 29 12 5 26 34 13 1 56 18 14 1 60 32 15 2 52 32 16 3 36 15 17 7 59 36 18 2 31 9 19 4 80 43 20 7 85 62 21 2 37 19 OS, overall survival Table 3: Patients per maximum toxicity grade for treatment-related adverse events with vaccine and bevacizumab (N=21) Treatment-Related Adverse Events Grade 2 n (%) Grade 3 n (%) Grade 4 n (%) Leukopenia 2 (9.5%) 0 0 Anemia 1 (4.8%) 0 0 Hyperglycemia 0 1 (4.8%) 0 Amylase 2 (9.5%) 0 0 Bilirubin 1 (4.8%) 0 0 Fever 2 (9.5%) 0 1 (4.8%) Hypertension 0 2 (9.5%) 0 Diarrhea 1 (4.8%) 0 0 Nausea/anorexia 1 (4.8%) 0 0 Injection site reaction 3 (14%) 0 0 Headache 1 (4.8%) 0 0 Epistaxis/nasal congestion 1 (4.8%) 0 0 Table 4: Time-dependent analysis for immunology response and response summary Time-dependent analysis for immunology response (includes either IgM or IgG) HR (95%CI) Cox PH p-value Response* No. of patients Non-response* No. of patients GM2 0.96 (0.37 - 2.45) 0.925 12 7 Globo-H 0.69 (0.23 - 2.03) 0.496 15 4 Tn 0.78 (0.10 - 6.06) 0.816 1 18 TF 2.33 (0.80 - 6.79) 0.123 12 7 MUC-1 0.89 (0.33 - 2.39) 0.816 14 5 Response summary No. of patients Response to 5 vaccine antigens 0 (0%) Response to 4 vaccine antigens 6 (32%) Response to 3 vaccine antigens 7 (37%) Response to 2 vaccine antigens 3 (16%) Response to 1 vaccine antigen 3 (16%) *(N=19, 2 patients removed given lack of serologic testing) ** Cytokines include Globo-H, GM2, MUC1-TN, MUC-1, and TF). Table 5. Overall survival and progression-free survival by antibody response status and time-dependent cytokine measurements Overall survival by antibody response status Variable n Deaths Median OS 5-Year OS Rate HR p-value Non- Responder 6 5 34.2 (95% CI: 12.8-NE) 16.7% (95% CI: 0.8-51.7%) 1.0 0.62 Responder 13 13 30.7 (95% CI: 16.9-52) 15.4% (95% CI: 2.5-38.8%) 1.31 (95% CI: 0.46-3.70) Progression-free survival by antibody response status Variable n Progression Median PFS 6-Month PFS Rate HR p-value Non-Responder 6 6 5.0 (95% CI: 0.7-NE) 16.7% (95% CI: 0.8-51.7%) 1.0 0.84 Responder 13 13 4.9 (95% CI: 2.8-8.1) 30.8% (95% CI: 9.5-55.4%) 0.9 (95% CI: 0.34-2.43) Overall survival by time-dependent cytokine measurements Variable Comparing Baseline and Week 17 All Cytokine Values HR (in 10 unit) (95% CI) Cox PH p-value HR (in 10 unit) (95% CI) Cox PH p-value FGFb 0.99 (0.92-1.07) 0.782 1.01 (0.96-1.07) 0.687 IL_8 0.62 (0.27-1.38) 0.24 1.02 (0.89-1.17) 0.782 PDGF-BB 1.01 (1-1.02) 0.02 1 (1-1.01) 0.1 VEGF 1.02 (0.97-1.08) 0.479 1.01 (0.98-1.05) 0.413 Progression-free survival by time-dependent cytokine measurements Variable Comparing Baseline and Week 17 All Cytokine Values HR (in 10 unit) (95% CI) Cox PH p-value HR (in 10 unit) (95% CI) Cox PH p-value FGFb 0.98 (0.91-1.05) 0.581 0.98 (0.92-1.05) 0.522 IL-8 0.43 (0.19-0.97) 0.043 0.66 (0.32-1.38) 0.272 PDGF-BB 1.00 (0.99-1.01) 0.814 0.99 (0.98-1.01) 0.836 VEGF 0.99 (0.95-1.03) 0.795 0.98 (0.94-1.03) 0.562 OS, overall survival; PFS, progression-free survival; NE, not estimable p-value was obtained by applying permutation log-rank test with 5000 permutation times OS was measured from the start of study intervention until date of death or last follow-up Additional Declarations Competing interest reported. Disclosures/Conflicts of Interest: C.A. reports personal fees from Tesaro, personal fees from Immunogen, grants and personal fees from Clovis, grants from Genentech, grants from AbbVie, grants from Astra Zeneca, grants from Astra Zeneca, personal fees from Eisai/Merck, personal fees from Mersana Therapeutics, personal fees from Roche/Genentech, personal fees from Abbvie, personal fees from AstraZeneca/Merck, personal fees from Repare, outside the submitted work. M.L.H. reports other from Sanofi, other from GSK, personal fees from Research to Practice, personal fees from Up to Date, other from Bayer, personal fees from GOG Foundation, personal fees from Tesaro, personal fees from Lilly Oncology, personal fees from Merck, personal fees from Janssen, outside the submitted work. A.I. reports personal fees from Mylan, outside the submitted work. V.M. reports grants from Eisai, grants from Merck, grants from Takeda, from ArQule, grants from Karyopharm, grants from AstraZeneca, grants from Lilly, other from Clovis, other from Novasris, other from GSK, other from ITEOS, outside the submitted work. R.E.O. reports personal fees from Tesaro/GSK, personal fees from Regeneron, personal fees from Seattle Genetics, other from AstraZeneca Pharmaceuticals, personal fees from Fresenius Kabi, personal fees from Gynecologic Oncology Foundation, personal fees from Bayer, personal fees from Curio, advisor for Carina Biotech outside the submitted work; and Non-compensated steering committee member for the PRIMA, Moonstone (Tesaro/GSK), ARTISTRY7 (Arkemes) and DUO-O (AstraZeneca) studies. Her institute receives funding for clinical research from Bayer/Celgene/Juno, Tesaro/GSK, Ludwig Cancer Institute, Abbvie/StemCentrx, Merck, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Sellas Therapeutics, Genentech, Kite Pharma, Gynecologic Oncology Foundation. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 05 Apr, 2022 Reviews received at journal 17 Mar, 2022 Reviewers agreed at journal 28 Feb, 2022 Reviewers invited by journal 16 Feb, 2022 Editor assigned by journal 16 Feb, 2022 Submission checks completed at journal 16 Feb, 2022 First submitted to journal 10 Feb, 2022 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1347080","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":84223074,"identity":"bdf2a9b1-d162-4198-8937-060b5010cfa1","order_by":0,"name":"Ryan M. Kahn","email":"","orcid":"","institution":"Memorial Sloan Kettering Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ryan","middleName":"M.","lastName":"Kahn","suffix":""},{"id":84223075,"identity":"aabd7a80-578c-4dc6-89ec-8cc5210ebd9a","order_by":1,"name":"Govind Ragupathi","email":"","orcid":"","institution":"Memorial Sloan Kettering Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Govind","middleName":"","lastName":"Ragupathi","suffix":""},{"id":84223076,"identity":"2ede72e5-612f-4980-af58-08c0b0c437ee","order_by":2,"name":"Qin C. Zhou","email":"","orcid":"","institution":"Memorial Sloan Kettering Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Qin","middleName":"C.","lastName":"Zhou","suffix":""},{"id":84223077,"identity":"8f62c155-4a93-4440-8064-0c0a493e856c","order_by":3,"name":"Alexia Iasonos","email":"","orcid":"","institution":"Memorial Sloan Kettering Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alexia","middleName":"","lastName":"Iasonos","suffix":""},{"id":84223078,"identity":"ff03d268-9af3-4c96-820e-37d2ee0544d3","order_by":4,"name":"Sara Kravetz","email":"","orcid":"","institution":"Memorial Sloan Kettering Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sara","middleName":"","lastName":"Kravetz","suffix":""},{"id":84223081,"identity":"7a527e76-5996-4f17-8c7a-d3a7c5e9a721","order_by":5,"name":"Martee L. Hensley","email":"","orcid":"","institution":"Memorial Sloan Kettering Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Martee","middleName":"L.","lastName":"Hensley","suffix":""},{"id":84223084,"identity":"08bf0667-d39d-4ecf-ade5-c50faa20a3ce","order_by":6,"name":"Jason Konner","email":"","orcid":"","institution":"Memorial Sloan Kettering Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jason","middleName":"","lastName":"Konner","suffix":""},{"id":84223085,"identity":"6761e990-c12b-4804-9c25-f1525c926aae","order_by":7,"name":"Vicky Makker","email":"","orcid":"","institution":"Memorial Sloan Kettering Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Vicky","middleName":"","lastName":"Makker","suffix":""},{"id":84223087,"identity":"a17344b2-0376-40f2-bc20-cbfbab651177","order_by":8,"name":"William P. Tew","email":"","orcid":"","institution":"Memorial Sloan Kettering Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"William","middleName":"P.","lastName":"Tew","suffix":""},{"id":84223088,"identity":"25f894e7-ec6d-4d21-9f24-226d57e15cb3","order_by":9,"name":"Carol Aghajanian","email":"","orcid":"","institution":"Memorial Sloan Kettering Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Carol","middleName":"","lastName":"Aghajanian","suffix":""},{"id":84223089,"identity":"47bd1e2c-3741-4f13-8626-a05a0d79a0ed","order_by":10,"name":"Paul J. Sabbatini","email":"","orcid":"","institution":"Memorial Sloan Kettering Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Paul","middleName":"J.","lastName":"Sabbatini","suffix":""},{"id":84223090,"identity":"816c5970-3c7d-4554-9185-fc5bfccfe5d2","order_by":11,"name":"Roisin E. O’Cearbhaill","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxUlEQVRIiWNgGAWjYLACxoYDDPwMDMwkapFsIFmLwQFitfCzHz74uXLHnXzja8cfG/yoYZAz71+AX4tkT1qy5Nkzzyy33c4xTuw5xmAsc+MBfi0GN3gMJBvbDhuY3c5hPszYwJA4Q+IAIS38n3+CtBjPTn9MrBYeNrAtBtIJxslgLfwNBP1iZtl45rCBBNAvhj3HJIwlJPDrAIXY45uNOw4b8AMdJvGjxkZOgp+Aw9AB0AqJBNK0gCwm0ZZRMApGwSgY9gAATUdFKkNOidMAAAAASUVORK5CYII=","orcid":"","institution":"Memorial Sloan Kettering Cancer Center","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Roisin","middleName":"E.","lastName":"O’Cearbhaill","suffix":""}],"badges":[],"createdAt":"2022-02-10 15:44:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1347080/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1347080/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":18436929,"identity":"0036e954-7c56-4315-9a51-3ff523c4b0eb","added_by":"auto","created_at":"2022-02-21 14:57:57","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":153610,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOverall (A) and progression-free (B) survival curves by responder status\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-1347080/v1/1f371ef7fb3261e66a4a3361.png"},{"id":18436930,"identity":"68443e82-5165-4129-9747-984ef80b0929","added_by":"auto","created_at":"2022-02-21 14:58:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":893331,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1347080/v1/54e0713d-4151-46fc-94ad-07f9e8caaeaa.pdf"}],"financialInterests":"Competing interest reported. Disclosures/Conflicts of Interest: C.A. reports personal fees from Tesaro, personal fees from Immunogen, grants and personal fees from Clovis, grants from Genentech, grants from AbbVie, grants from Astra Zeneca, grants from Astra Zeneca, personal fees from Eisai/Merck, personal fees from Mersana Therapeutics, personal fees from Roche/Genentech, personal fees from Abbvie, personal fees from AstraZeneca/Merck, personal fees from Repare, outside the submitted work. M.L.H. reports other from Sanofi, other from GSK, personal fees from Research to Practice, personal fees from Up to Date, other from Bayer, personal fees from GOG Foundation, personal fees from Tesaro, personal fees from Lilly Oncology, personal fees from Merck, personal fees from Janssen, outside the submitted work. A.I. reports personal fees from Mylan, outside the submitted work. V.M. reports grants from Eisai, grants from Merck, grants from Takeda, from ArQule, grants from Karyopharm, grants from AstraZeneca, grants from Lilly, other from Clovis, other from Novasris, other from GSK, other from ITEOS, outside the submitted work. R.E.O. reports personal fees from Tesaro/GSK, personal fees from Regeneron, personal fees from Seattle Genetics, other from AstraZeneca Pharmaceuticals, personal fees from Fresenius Kabi, personal fees from Gynecologic Oncology Foundation, personal fees from Bayer, personal fees from Curio, advisor for Carina Biotech outside the submitted work; and Non-compensated steering committee member for the PRIMA, Moonstone (Tesaro/GSK), ARTISTRY7 (Arkemes) and DUO-O (AstraZeneca) studies. Her institute receives funding for clinical research from Bayer/Celgene/Juno, Tesaro/GSK, Ludwig Cancer Institute, Abbvie/StemCentrx, Merck, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Sellas Therapeutics, Genentech, Kite Pharma, Gynecologic Oncology Foundation.","formattedTitle":"\u003cp\u003eLong-term Outcomes of Patients With Recurrent Ovarian Cancer Treated With a Polyvalent Vaccine With Bevacizumab Combination\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEpithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy due to its typically late stage at presentation and high predilection for metastases and recurrence [1]. Aberrant immunologic responses have been shown to contribute to the invasion and progression of EOC [2]. Greater than 80% of women diagnosed with EOC will relapse following primary treatment [3]. Many patients will have some degree of response to subsequent chemotherapy. Subsequent remissions are of progressively shorter duration, however, until chemotherapy resistance generally develops. This is believed to have a correlation with host immune responses and tumor genomic factors [4, 5]. Because of this, the immune environment remains a key target for therapies in both the maintenance and recurrent settings. The mechanisms to explain the vast differences in downstream ovarian cancer recurrence outcomes among patients with similar histology remains unknown, however, and requires further evaluation.\u003c/p\u003e\n\u003cp\u003ePrevious studies have demonstrated the presence of antitumoral T cells in the ovarian cancer microenvironment [6, 7]. We previously completed a phase I safety and immunogenicity study of the polyvalent vaccine-KLH conjugate [GM2, Globo-H, Le\u003csup\u003ey\u003c/sup\u003e, Tn-MUC1, Tn(c), STn(c) and TF(c)] plus immunological adjuvant QS-21 in patients with epithelial ovarian, fallopian tube, or peritoneal cancer in a first, second, or later complete clinical remission [8]. We subsequently conducted a follow-up phase II randomized, double-blind trial of a polyvalent vaccine-KLH conjugate + OPT-821 versus OPT-821 alone (Gynecologic Oncology Group [GOG]255) [9]. The results from GOG255 demonstrated that vaccine immunotherapy with the addition of an adjuvant was well tolerated, with mild toxicity largely confined to injection site reactions, and greater immunogenicity (compared to vaccine alone) against five of the antigens contained in the vaccine (Globo-H, GM2, MUC1-TN, MUC1, and TF). However, there were no differences in progression-free survival (PFS) or overall survival (OS) between vaccine-KLH conjugate plus OPT-821 versus OPT-821 alone [9]. GOG255 results were published with a median follow-up of 34 months; a later analysis performed in 2018 had a median follow-up of 60 months [9].\u003c/p\u003e\n\u003cp\u003eThe efficacy of anti-angiogenic agents in the treatment of ovarian cancer has also been demonstrated [10, 11]. The AURELIA study (NCT00976911) showed that the addition of bevacizumab to chemotherapy in platinum-resistant ovarian cancer increased the median PFS from 3.4 to 6.7 months [12]. The combination compared with chemotherapy alone also resulted in increased response rates and improved quality of life. In addition to modulation of the tumor vasculature, vascular endothelial growth factor (VEGF) has been shown to suppress dendritic cell maturation and alter antigen presentation. It also exhibits a host of other influences on immune activity, providing a rationale for combining anti-VEGF therapy with vaccination as a source of immune stimulation [13].\u003c/p\u003e\n\u003cp\u003eThe future direction of ovarian cancer immunotherapies will require the detection of specific biomarkers to predict the effectiveness of different treatment combinations while also minimizing toxicities [14]. The goal of this study is to evaluate both the short-term and delayed immunologic responses, as well as clinical outcomes, in patients with recurrent EOC after receiving a polyvalent vaccine and bevacizumab combination.\u003c/p\u003e"},{"header":"Materials And Methods ","content":"\u003cp\u003eThis study was approved by the Institutional Review Board at Memorial Sloan Kettering Cancer Center (MSK).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEligibility Criteria\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eEligible patients had histologically documented EOC arising in the ovary, fallopian tube, or peritoneum, with stage II-IV disease at diagnosis after second or subsequent clinical remission. Primary treatment must have included cytoreductive surgery and a platinum-based chemotherapy regimen. Eligible patients had relapsed at least once, had completed chemotherapy and/or surgery, and were deemed suitable to enter a period of observation. Patients could have asymptomatic residual measurable disease on computed tomography (CT) scan or be in complete clinical remission. Complete clinical remission was defined as serum CA-125 \u003cu\u003e\u0026lt;\u003c/u\u003e35 IU/mL, negative physical examination, and no evidence of disease on CT of the abdomen and pelvis. Patients had to be longer than 4 weeks out from completion of prior cytotoxic chemotherapy. Other requirements included Karnofsky Performance Status (KPS) \u0026ge;70; adequate organ function, defined as absolute neutrophil count \u0026ge;1000 cells/mm\u003csup\u003e3\u003c/sup\u003e; platelets \u0026ge;100,000 cells/mm\u003csup\u003e3\u003c/sup\u003e; serum creatinine \u0026le;1.5 times the institutional upper limits of normal; and total bilirubin, AST and alkaline phosphatase \u0026le;2.5 times the institutional upper limits of normal. Patients were ineligible if they were of child-bearing potential, had a known autoimmune disease or immune deficiency, a known allergy to seafood, history of myocardial infarction within 6 months, untreated brain metastasis, uncontrolled hypertension, or other standard contraindications to receiving bevacizumab therapy. \u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTreatment Plan\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe administered polyvalent vaccine contained GM2 (30 \u0026micro;g, equivalent to antigen concentration in GM2-KLH conjugate), Globo-H (30 \u0026micro;g), Tn-MUC1 (3 \u0026micro;g) and TF(c) (3 \u0026micro;g), individually conjugated to KLH (600 \u0026mu;g)\u003cstrong\u003e \u003c/strong\u003eand mixed with adjuvant OPT-821 (100 \u0026micro;g) in 1.0 mL normal saline as the diluent. The vaccine was administered in 1cc total volume subcutaneously at weeks 1, 2, 3, 7, 11, and 17. Bevacizumab was given via intravenous infusion at 7.5 mg/kg over 20-30 minutes once every 2 weeks, beginning on day 1 of week 1 through week 11, and once every 3 weeks thereafter. Bevacizumab could be continued until disease progression or toxicity. \u003c/p\u003e\n\u003cp\u003e\u003cem\u003eVaccine Preparation\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe antigen conjugation method and administration protocol was previously referenced in GOG255 [9]. The IND was held by MSK. The following antigens were conjugated to KLH (carrier protein) mixed with OPT-821 adjuvant: Tn glycosylated MUC-1\u003cstrong\u003e \u003c/strong\u003e(Tn-MUC1) was synthesized by Pepceuticals Ltd (Leicester, UK). The Globo-H hexasaccharide-KLH was synthesized and conjugated under good manufacturing practices (GMP) by Optimer Pharmaceuticals Inc. (San Diego, CA). GM2:\u003cstrong\u003e \u003c/strong\u003eGanglioside GM2 was extracted by Matreya Inc. (Philadelphia, PA). It was conjugated to KLH by Althea Technologies (San Diego, CA). TF(c): TF cluster was synthesized by the MSK Organic Synthesis Core. Tn-MUC1-KLH, TF(c)-KLH conjugates were prepared by the MSK Clinical Grade Production (CGP) facility under GMP. OPT-821 is an immunological adjuvant obtained from Optimer Pharmaceuticals Inc. (San Diego, CA). Vaccines and OPT-821 were vialed and released for clinical use by the CGP Core facility. \u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDose Adjustment\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eDose reduction or delay of vaccine was not permitted. Delays in bevacizumab were permitted in the event of toxicity, with a maximum allowable treatment interruption of 8 weeks. There was no dose reduction of bevacizumab. Toxicity was evaluated according to the National Cancer Institute CTCAE scale version 4 [15]. Patients were to be removed from the study for a vaccine-related dose-limiting toxicity (DLT), defined as grade \u0026ge;2 allergic reaction, grade \u0026ge;2 autoimmune reaction, grade \u0026ge;3 hematologic or non-hematologic toxicity including fever, or grade \u0026ge;3 injection site reaction. Any patient with grade 2 or greater toxicity was followed with appropriate studies until results returned to baseline. Patients were removed from the study for progression of disease\u003cem\u003e, as defined by RECIST\u003c/em\u003e \u003cem\u003e[16]\u003c/em\u003e\u003cem\u003e.\u003c/em\u003e \u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEvaluation During Study\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePretreatment evaluation included a complete medical history, physical and radiologic examination (CT), vital signs, KPS assessment, and clinical laboratory tests, including hematologic, biochemistry, CA-125, and immunologic testing. Patients had repeat complete blood count (CBC) and comprehensive biochemistry panel at regular intervals, and at the off-study visit. Urine protein was obtained and followed at regular intervals. CT imaging was performed every 3 months while on study, or sooner to evaluate patients if signs or symptoms, blood tests, or physical examination suggested progression of disease. Serologic IgM and IgG antibody responses were measured by ELISA against each antigen at baseline and week 7. The correlative multiplex panels were measured at weeks 1, 17, and off-study. \u003c/p\u003e\n\u003cp\u003eAntibody Response Against Vaccine Antigens\u003c/p\u003e\n\u003cp\u003eThe IgM and IgG antibody responses were measured by ELISA in duplicate against each antigen as described earlier [8]. The criteria for immunogenicity used was based on that of the individual pilot trials: patients must have had IgM/IgG titer \u0026gt;1:40 or an eightfold increase in prevailing antibody titer if present at baseline. These criteria were based on our previous studies [8]. The antibody titer was defined as the highest serum dilution showing an absorbance of \u0026ge;0.1 optical density (a measurement of percent transmission). \u0026rdquo;Responders\u0026rdquo; were defined as patients with an immunogenic response to \u0026ge;3 antigens; \u0026rdquo;Non-Responders\u0026rdquo; were defined as patients with an immunogenic response to \u0026le;2 antigens. \u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMultiplex Assays\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eA multiplex angiogenesis assay panel was performed to include monoclonal antibodies specific for interleukin-8 (IL-8), VEGF, platelet-derived growth factor (PDGF), and fibroblast growth factor-basic (FGF-basic). \u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical Considerations\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoint of this pilot trial was safety; the secondary endpoint was to measure patient immunogenicity following administration of the polyvalent vaccine in combination with bevacizumab. No clinically significant systemic toxicity was associated with administration of similar vaccines. Twenty-one patients would be accrued, and if \u0026gt;8 of 21 patients met the criteria for immunogenicity (described above) for three or more antigens, the study would be considered positive [17]. This calculation assumes that the probability of immune response under the null hypothesis (i.e., no activity) is 0.2 versus the alternative hypothesis (i.e., target response probability) of 0.5. Type I and Type II errors were set to 0.1. In prior trials, antibodies were generally present by the completion of the fourth vaccination (week 7).\u003c/p\u003e\n\u003cp\u003ePFS was measured from the start of vaccine therapy until progression, and OS was measured from the start of vaccine therapy until death or last follow-up (for only one patient). The associations between cytokine measurements between baseline and week 17 or at different time points, and the PFS/OS, were analyzed using time-dependent Cox proportion hazard (PH) models. The PFS/OS by antibody response versus non-response for the five vaccine antigens, as well as the responder versus non-responder evaluation, was analyzed using landmark analyses with landmark time as months (chosen by the longest interval post vaccination antibody IgG/IgM titers). \u003c/p\u003e\n\u003cp\u003eAntibodies against the individual antigens were studied by ELISA. All p-values are two-sided, with statistical significance evaluated at the 0.05 alpha level. Ninety-five percent confidence intervals (95% CI) for all parameters of interest were calculated to assess the precision of the obtained estimates. All analyses were performed with the use of R statistical software version 4.1.1 (R Foundation for Statistical Computing, Vienna, Austria).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003ePatient Characteristics \u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eTwenty-one patients with recurrent high-grade serous ovarian carcinoma were enrolled on the study between 01/05/2011 and 03/20/2012. All 21 patients were included in the safety analysis. Follow-up for survival was continued until 03/2021. Patient characteristics are described in \u003cstrong\u003eTable 1\u003c/strong\u003e. Patients had a median age of 56 years (range, 49-70 years). Twenty tumors were adnexal in origin, and one was of peritoneal origin. All patients had KPS ranging from 90-100%. The majority of patients (71%) were in complete remission at study entry. Patients were relatively heavily pretreated\u0026mdash;38% were in a third, 38% in a fourth, and 14% in a fifth remission. Three patients had a deleterious \u003cem\u003eBRCA\u003c/em\u003e mutation (2 \u003cem\u003eBRCA1\u003c/em\u003e, 1 \u003cem\u003eBRCA2\u003c/em\u003e). One patient was found to have a \u003cem\u003eTSC2\u003c/em\u003e mutation post-treatment. The median number of systemic treatment regimens administered to patients after this vaccine study was five (range, 0-7). Total systemic treatments after vaccine therapy included platinum-based chemotherapy (23/92, 25%), taxane-based chemotherapy (18/92, 20%), bevacizumab (14/92, 15%), gemcitabine (13/92, 14%), liposomal doxorubicin (12/92, 13%) and poly-adenosine ribose phosphorylase (PARP) inhibitors (8/92, 9%). Thirty-two percent of regimens were combination therapies (30/92, 32%) \u003cstrong\u003e(Table 2).\u003c/strong\u003e \u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAdverse Events\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eOne patient experienced a dose-limiting toxicity\u0026mdash;a grade 4 fever (40.1\u0026deg;C for 48 h)\u0026mdash;following vaccination. Two patients (10%) developed grade 3 hypertension related to bevacizumab; one of these patients had uncontrolled hypertension despite pharmaceutical management and was removed from the study 7 months after the start date due to excessive toxicity. One patient developed grade 3 hyperglycemia, not attributed to the vaccine or bevacizumab. Otherwise, side effects were self-limited; mild fatigue, fever, myalgia, and localized injection site reactions were the most common. \u003cstrong\u003eTable 3\u003c/strong\u003e depicts the maximum toxicity for treatment-related events with vaccine and bevacizumab. No clinically relevant hematologic abnormalities were noted. There was no clinical or laboratory evidence of autoimmunity. The vaccine was well tolerated overall. \u003c/p\u003e\n\u003cp\u003e\u003cem\u003eImmune Response\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe predefined definition of immunogenicity to the vaccine was met in 13 of 19 evaluable patients with response to at least 3 of the 5 vaccine antigens (\u003cstrong\u003eTable 4)\u003c/strong\u003e, and in 16 of 19 patients with response to at least 2 antigens. Two patients were excluded from the immunogenicity analysis due to a lack of post-intervention antibody results. Twelve of 19 patients exhibited an antibody response for GM2; 15/19 for Globo-H; 1/19 for Tn; 12/19 for TF; and 14/19 for MUC1. There was no significant difference between antigen antibody response and cytokine level when segregating by immune responders for each antigen. \u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSurvival Outcomes\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe median PFS for the overall cohort was 6.0 months (95% CI: 2.5-7.1 months). The median OS for the overall cohort was 34.6 months (95% CI: 20.1-53). The 5-year OS rate was 23.8% (8.7-43.1%). Among the 4 patients who were alive beyond 5 years, 2 had \u003cem\u003eBRCA-\u003c/em\u003eassociated ovarian cancer (50%). There was no median follow-up time for the cohort, as all patients on trial were followed until their death; one patient who was still alive at her last follow-up date was followed for 112.5 months. \u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSurvival Outcomes by Antibody Response\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eResponders and non-responders had a median PFS of 4.9 months (95% CI: 2.8-8.1) and 5.0 months (95% CI 0.7-cannot estimate), respectively, and 6-month PFS rates of 30.8% (95% CI: 9.5-55.4%) and 16.7% (95% CI: 0.8-51.7%), respectively \u003cstrong\u003e(Table 5).\u003c/strong\u003e Responders and non-responders had\u003cs\u003e \u003c/s\u003ea\u003cs\u003e \u003c/s\u003emedian OS of 30.7 months (95% CI: 16.9-52.0) and 34.2 months (95% CI: 12.8-cannot estimate), respectively, and 5-year OS rates of 15.4% (95% CI: 2.5-38.8%) and 16.7% (95% CI: 0.8-51.7%), respectively \u003cstrong\u003e(Figure 1).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median OS for patients with a response to GM2 was 29.1 months, compared with 35.3 months for those without a response (p=0.327). The median OS for patients with a Globo-H response was 35.3 months, compared with 31.9 months for those without a response (p=0.38). The median OS for patients with a Tn response was 33.1 months, compared with 33.0 months for those without a response (p=0.793). The median OS for patients with a TF response was 30.6 months, compared with 42.6 months for those without a response (p=0.156). The median OS for patients with a MUC-1 response was 38.9 months, compared with 30.6 months for those without a response (p=0.94). \u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSurvival Outcomes by Cytokine Measurement\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWhen comparing two time point measurements (baseline and week 17), increased IL-8 levels had a moderately significant association with improved PFS (HR as 10-unit increase: 0.43; 95% CI: 0.19-0.97; p=0.04). Increased levels of PDGF had a moderately significant association with worse OS (HR as 10-unit increase: 1.01; p=0.02). When considering all time point measurements (baseline until progression for PFS or baseline until last measurements for OS), cytokine levels were not significantly associated with survival outcomes (\u003cstrong\u003eTable 5\u003c/strong\u003e).\u003c/p\u003e"},{"header":"Discussion ","content":"\u003cp\u003eThis study includes the longest prospective follow-up of patients with ovarian cancer who have received vaccine immunotherapy. It is also the first study to report on the safety of polyvalent antigen-KLH plus OPT-821 vaccine construct administered in combination with bevacizumab. The rate of immunogenicity was qualitatively similar to that seen in our prior study, which did not include the addition of bevacizumab. In the current study, 68% and 84% of patients responded to \u0026ge;3 and \u0026ge;2 antigens, respectively, compared with 89% and 89%, respectively in our prior phase I trial without bevacizumab [8]. Given the potential immune-modulating effects of bevacizumab and the GOG255 study (NCT00857545), which evaluated the vaccine in settings where bevacizumab may have been used, it was necessary to ascertain whether there would be toxicity-related adverse effects due to the addition of bevacizumab. No additional toxicities were observed in this study. Measured cytokines in the multiplex assay likewise showed no changes between baseline and week 17, or when values were considered at each time point until progression of disease or last follow-up. The median PFS from the start of preceding chemotherapy was 13 months (95% CI: 10-20 months), within the reported range of progression in this population, in patients receiving maintenance bevacizumab therapy in the platinum-sensitive setting, as seen in the OCEANS study [18].\u003c/p\u003e\n\u003cp\u003eFour patients (19%) were alive more than 5 years after the study intervention; and 3 (14%) were alive after more than 6 years. One patient treated on study in second remission was still alive at her most recent follow-up, 9 years after the start of the trial. Patients with an antibody response against Globo-H compared to those without a response had a median OS of 35.3 versus 31.9 months, respectively; patients with response against MUC-1 compared to those without had an OS of 38.9 versus 30.6 months, respectively. These findings were not significant, which could be attributed to the small sample size. We did not identify predictors of survival. Although we observed antibody responses to the vaccine antigens, we were not able to conclude that such responses induced protective immune responses. Unfortunately, our correlative studies did not include T-cell response profiling. \u003c/p\u003e\n\u003cp\u003eOvarian cancer is a notoriously aggressive malignancy in part due to its tumor microenvironment and interaction with host immunity. Previous studies have suggested that FGF and FGF-1 play a crucial role in the progression of ovarian cancer. A 2017 study by Sun et al. found that FGF increased cellular proliferation, migration, and invasion while also regulating protein kinase pathways, resulting in epithelial-to-mesenchymal transition [1]. Similarly, PDGF has also been implicated in the progression of ovarian cancer cells. Matei et al. conducted one of the first studies to demonstrate a strong correlation between PDGF expression and VEGF in EOC; in PDGFR-expressing immortalized ovarian cancer cells, PDGF stimulated the expression of VEGF in association with the PI3K/Akt pathway [19]. IL-8 has also been shown to be elevated in ovarian cyst fluid, ascites, serum, and tumor tissue in ovarian cancer. Wang et al. demonstrated that IL-8 secretion by ovarian cancer cells increases proliferation through alteration of Cyclin D1/B1 proteins and invasion, angiogenic potential, adhesion, and invasion by correlating with MMP-2/MMP-9 activity and expression [20]. Globo-H, a glycosphingolipid of the globo series and a sugar terminus mimicking the antigen H determinant, has also been associated with EOC stem cells, angiogenesis, and an immunosuppressor through Notch signaling [21]. Lastly, microbial glycans, TF and Tn, which are widely expressed in adenocarcinomas, have been shown to likely play a role in self versus altered-self immunoreactivity [22]. Given these previous findings, antibodies against different cancer-associated antigens are desired targets when generating therapeutic cancer vaccines.\u003c/p\u003e\n\u003cp\u003eThe current study has several limitations. This was a small sample size of 21 women diagnosed with recurrent EOC. It is not possible to ascertain whether individuals with \u003cem\u003eBRCA\u003c/em\u003e mutations had prolonged survival due to immunoreactivity following the vaccine or disease characteristics secondary to their BRCA mutation status. While our study evaluated associations and trend levels, causality cannot be determined.\u003c/p\u003e\n\u003cp\u003eSince the inception of this study utilizing antibodies as the primary effectors, the field of immune modulation has continued to expand with the use of checkpoint inhibitors, as well as a variety of other agents, such as OX40 and ICOS. In addition, the evidence base suggesting synergy between bevacizumab and other immunomodulators continues to grow [13]. Given the putative mechanisms of bevacizumab with respect to the immune response, further study with vaccines or other mechanisms prompting T-cell effector proliferation or an integrated response (rather than antibodies alone, as seen in the vaccination here) is critical. \u003c/p\u003e\n\u003cp\u003eThis study includes the longest reported follow-up of patients with ovarian cancer undergoing vaccine therapy. Bevacizumab and polyvalent-KLH vaccine can be safely administered together, with retention of vaccine immunogenicity. Increased levels of IL-8 were associated with a moderately significant improvement in PFS; increased levels of PDGF were associated with a moderately significant improvement in OS. When considering all time point measurements, cytokine levels were not significantly associated with survival outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: Dr. O\u0026rsquo;Cearbhaill acknowledges mentorship from Prof. Garry Duffy from the National University of Ireland, Galway. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: This clinical study, the Clinical Grade Production and Organic Synthesis Core facility, data analysis were funded in part by the National Cancer Institute (P30 CA008748 and P01 CA190174-01A1). Bevacizumab was supplied by Genentech Inc. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosures/Conflicts of Interest: C.A.\u003c/strong\u003e reports personal fees from Tesaro, personal fees from Immunogen, grants and personal fees from Clovis, grants from Genentech, grants from AbbVie, grants from Astra Zeneca, grants from Astra Zeneca, personal fees from Eisai/Merck, personal fees from Mersana Therapeutics, personal fees from Roche/Genentech, personal fees from Abbvie, personal fees from AstraZeneca/Merck, personal fees from Repare, outside the submitted work. \u003cstrong\u003eM.L.H.\u003c/strong\u003e reports other from Sanofi, other from GSK, personal fees from Research to Practice, personal fees from Up to Date, other from Bayer, personal fees from GOG Foundation, personal fees from Tesaro, personal fees from Lilly Oncology, personal fees from Merck, personal fees from Janssen, outside the submitted work. \u003cstrong\u003eA.I.\u003c/strong\u003e reports personal fees from Mylan, outside the submitted work. \u003cstrong\u003eV.M.\u003c/strong\u003e reports grants from Eisai, grants from Merck, grants from Takeda, from ArQule, grants from Karyopharm, grants from AstraZeneca, grants from Lilly, other from Clovis, other from Novasris, other from GSK, other from ITEOS, outside the submitted work. \u003cstrong\u003eR.E.O.\u003c/strong\u003e reports personal fees from Tesaro/GSK, personal fees from Regeneron, personal fees from Seattle Genetics, other from AstraZeneca Pharmaceuticals, personal fees from Fresenius Kabi, personal fees from Gynecologic Oncology Foundation, personal fees from Bayer, personal fees from Curio, advisor for Carina Biotech outside the submitted work; and Non-compensated steering committee member for the PRIMA, Moonstone (Tesaro/GSK), ARTISTRY7 (Arkemes) and DUO-O (AstraZeneca) studies. Her institute receives funding for clinical research from Bayer/Celgene/Juno, Tesaro/GSK, Ludwig Cancer Institute, Abbvie/StemCentrx, Merck, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Sellas Therapeutics, Genentech, Kite Pharma, Gynecologic Oncology Foundation.\u003c/p\u003e"},{"header":"References","content":"\u003cp\u003e1. Sun Y, Fan X, Zhang Q, Shi X, Xu G, Zou C. Cancer-associated fibroblasts secrete FGF-1 to promote ovarian proliferation, migration, and invasion through the activation of FGF-1/FGFR4 signaling. Tumour Biol. 2017 Jul;39(7).\u003c/p\u003e\n\u003cp\u003e2. Li, S., et al., Cancer immunotherapy via targeted TGF-\u0026beta; signalling blockade in T(H) cells. Nature, 2020. \u003cstrong\u003e587\u003c/strong\u003e(7832): p. 121-125.\u003c/p\u003e\n\u003cp\u003e3. Dood, R.L., et al., Defining Survivorship Trajectories Across Patients With Solid Tumors: An Evidence-Based Approach. JAMA Oncology, 2018. \u003cstrong\u003e4\u003c/strong\u003e(11): p. 1519-1526.\u003c/p\u003e\n\u003cp\u003e4. Markman, M., et al., Duration of Response to Second-Line, Platinum-Based Chemotherapy for Ovarian Cancer: Implications for Patient Management and Clinical Trial Design. J Clin Oncol, 2004. \u003cstrong\u003e22\u003c/strong\u003e(15): p. 3120-3125.\u003c/p\u003e\n\u003cp\u003e5. Anderson, K.S., et al., p53 autoantibodies as potential detection and prognostic biomarkers in serous ovarian cancer. Cancer epidemiology, biomarkers \u0026amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2010. \u003cstrong\u003e19\u003c/strong\u003e(3): p. 859-868.\u003c/p\u003e\n\u003cp\u003e6. Zhang, L., et al., Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med, 2003. \u003cstrong\u003e348\u003c/strong\u003e(3): p. 203-13.\u003c/p\u003e\n\u003cp\u003e7. Coukos G, Tanyi J, Kandalaft LE. Opportunities in immunotherapy of ovarian cancer. Ann Oncol. 2016 Apr;27 Suppl 1(Suppl 1):i11-i15. .\u003c/p\u003e\n\u003cp\u003e8. Sabbatini, P.J., et al., Pilot study of a heptavalent vaccine-keyhole limpet hemocyanin conjugate plus QS21 in patients with epithelial ovarian, fallopian tube, or peritoneal cancer. Clin Cancer Res, 2007. \u003cstrong\u003e13\u003c/strong\u003e(14): p. 4170-7.\u003c/p\u003e\n\u003cp\u003e9. O\u0026apos;Cearbhaill RE, Deng W, Chen LM, Lucci JA 3rd, Behbakht K, Spirtos NM, Muller CY, Benigno BB, Powell MA, Berry E, Tewari KS, Hanjani P, Lankes HA, Aghajanian C, Sabbatini PJ. A phase II randomized, double-blind trial of a polyvalent Vaccine-KLH conjugate (NSC 748933 IND# 14384) + OPT-821 versus OPT-821 in patients with epithelial ovarian, fallopian tube, or peritoneal cancer who are in second or third complete remission: An NRG Oncology/GOG study. Gynecol Oncol. 2019 Dec;155(3):393-399.\u003c/p\u003e\n\u003cp\u003e10. Burger, R.A., et al., Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study. J Clin Oncol, 2007. \u003cstrong\u003e25\u003c/strong\u003e(33): p. 5165-71.\u003c/p\u003e\n\u003cp\u003e11. Garcia, A.A., et al., Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol, 2008. \u003cstrong\u003e26\u003c/strong\u003e(1): p. 76-82.\u003c/p\u003e\n\u003cp\u003e12. Pujade-Lauraine, E., et al., Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol, 2014. \u003cstrong\u003e32\u003c/strong\u003e(13): p. 1302-8.\u003c/p\u003e\n\u003cp\u003e13. Li, Y.L., H. Zhao, and X.B. Ren, Relationship of VEGF/VEGFR with immune and cancer cells: staggering or forward? Cancer Biol Med, 2016. \u003cstrong\u003e13\u003c/strong\u003e(2): p. 206-14.\u003c/p\u003e\n\u003cp\u003e14. Odunsi K. Immunotherapy in ovarian cancer. Ann Oncol. 2017 Nov 1;28(suppl_8):viii1-viii7. doi: 10.1093/annonc/mdx444.\u003c/p\u003e\n\u003cp\u003e15. Institute, N.C., Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. U.S. Department of Health and Human Services, 2009.\u003c/p\u003e\n\u003cp\u003e16. Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer, 2009. \u003cstrong\u003e45\u003c/strong\u003e(2): p. 228-47.\u003c/p\u003e\n\u003cp\u003e17. Yao, T.J., C.B. Begg, and P.O. Livingston, Optimal sample size for a series of pilot trials of new agents. Biometrics, 1996. \u003cstrong\u003e52\u003c/strong\u003e(3): p. 992-1001.\u003c/p\u003e\n\u003cp\u003e18. Aghajanian, C., et al., OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol, 2012. \u003cstrong\u003e30\u003c/strong\u003e(17): p. 2039-45.\u003c/p\u003e\n\u003cp\u003e19. Matei D, Kelich S, Cao L, Menning N, Emerson RE, Rao J, Jeng MH, Sledge GW. PDGF BB induces VEGF secretion in ovarian cancer. Cancer Biol Ther. 2007 Dec;6(12).\u003c/p\u003e\n\u003cp\u003e20. Wang Y, Xu RC, Zhang XL, Niu XL, Qu Y, Li LZ, Meng XY. Interleukin-8 secretion by ovarian cancer cells increases anchorage-independent growth, proliferation, angiogenic potential, adhesion and invasion. Cytokine. 2012 Jul;59(1):145-55.\u003c/p\u003e\n\u003cp\u003e21. Pochechueva, T., Alam, S., Sch\u0026ouml;tzau, A. et al. Naturally occurring anti-glycan antibodies binding to Globo H-expressing cells identify ovarian cancer patients. J Ovarian Res 10, 8 (2017).\u003c/p\u003e\n\u003cp\u003e22. Smorodin EP, Sergeyev BL. The level of IgG antibodies reactive to TF, Tn and alpha-Gal polyacrylamide-glycoconjugates in breast cancer patients: relation to survival. Exp Oncol. 2016 Jun;38(2):117-21.\u003c/p\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1: Baseline patient demographics (N=21)\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo. of Patients\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge, median (range), years\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e56 (49-70)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003eFIGO stage at diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026le;II\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e\u0026nbsp; 1 (4.8%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; III\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e14 (67%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; IV\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e\u0026nbsp; 6 (29%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCancer type\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Ovarian\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e18 (86%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Primary peritoneal\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e\u0026nbsp;1 (4.8%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Fallopian tube\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e\u0026nbsp;2 (9.5%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003eKarnofsky Performance Status, median (range)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e90 (90-100)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003eRemission at Start of Study\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Second\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e\u0026nbsp;2 (9.5%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Third\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e\u0026nbsp;8 (38%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Fourth\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e\u0026nbsp;8 (38%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Fifth\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e\u0026nbsp;3 (14%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Complete\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e15 (71%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Partial\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e\u0026nbsp; 6 (29%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlatinum sensitivity status\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Platinum sensitive\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e18 (86%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Platinum resistant\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e3 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePenultimate treatment prior to vaccine*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Platinum\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e10 (48%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Taxane\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e3 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Gemcitabine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e8 (38%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Bevacizumab\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e4 (19%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Cyclophosphamide\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Pegylated liposomal doxorubicin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e5 (24%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Pemetrexed\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Topotecan\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistologic subtype\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; High-grade serous carcinoma\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e21(100%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"53.858024691358025%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGermline mutation status\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"46.141975308641975%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"52.77777777777778%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Wild type\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"47.22222222222222%\"\u003e\n \u003cp\u003e18 (85.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"52.77777777777778%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; BRCA1\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;variant\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"47.22222222222222%\"\u003e\n \u003cp\u003e2 (9.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"52.77777777777778%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; BRCA2\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;variant\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"47.22222222222222%\"\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eFIGO, International Federation of Gynecology and Obstetrics\u003c/p\u003e\n\u003cp\u003e*Given in combination for select patients\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eTable 2: Patient outcomes following vaccine therapy\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.13978494623656%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.72043010752688%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSubsequent systemic regimens following vaccine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.032258064516128%\"\u003e\n \u003cp\u003e\u003cstrong\u003eOS from diagnosis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(months)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"30.107526881720432%\"\u003e\n \u003cp\u003e\u003cstrong\u003eOS from trial\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(months)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.13978494623656%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.72043010752688%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.032258064516128%\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"30.107526881720432%\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.13978494623656%\"\u003e\n \u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.72043010752688%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.032258064516128%\"\u003e\n \u003cp\u003e119\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"30.107526881720432%\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.13978494623656%\"\u003e\n \u003cp\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.72043010752688%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.032258064516128%\"\u003e\n \u003cp\u003e135\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"30.107526881720432%\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.13978494623656%\"\u003e\n \u003cp\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.72043010752688%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.032258064516128%\"\u003e\n \u003cp\u003e131\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"30.107526881720432%\"\u003e\n \u003cp\u003e112\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.13978494623656%\"\u003e\n \u003cp\u003e\u003cstrong\u003e5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.72043010752688%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.032258064516128%\"\u003e\n \u003cp\u003e122\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"30.107526881720432%\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.13978494623656%\"\u003e\n \u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.72043010752688%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.032258064516128%\"\u003e\n \u003cp\u003e85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"30.107526881720432%\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.13978494623656%\"\u003e\n \u003cp\u003e\u003cstrong\u003e7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.72043010752688%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.032258064516128%\"\u003e\n \u003cp\u003e131\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"30.107526881720432%\"\u003e\n \u003cp\u003e88\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.13978494623656%\"\u003e\n \u003cp\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.72043010752688%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.032258064516128%\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"30.107526881720432%\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.13978494623656%\"\u003e\n \u003cp\u003e\u003cstrong\u003e9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.72043010752688%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.032258064516128%\"\u003e\n \u003cp\u003e109\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"30.107526881720432%\"\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.13978494623656%\"\u003e\n \u003cp\u003e\u003cstrong\u003e10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.72043010752688%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.032258064516128%\"\u003e\n \u003cp\u003e127\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"30.107526881720432%\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.13978494623656%\"\u003e\n \u003cp\u003e\u003cstrong\u003e11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.72043010752688%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.032258064516128%\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"30.107526881720432%\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.13978494623656%\"\u003e\n \u003cp\u003e\u003cstrong\u003e12\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.72043010752688%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.032258064516128%\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"30.107526881720432%\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.13978494623656%\"\u003e\n \u003cp\u003e\u003cstrong\u003e13\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.72043010752688%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.032258064516128%\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"30.107526881720432%\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.13978494623656%\"\u003e\n \u003cp\u003e\u003cstrong\u003e14\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.72043010752688%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.032258064516128%\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"30.107526881720432%\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.13978494623656%\"\u003e\n \u003cp\u003e\u003cstrong\u003e15\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.72043010752688%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.032258064516128%\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"30.107526881720432%\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.13978494623656%\"\u003e\n \u003cp\u003e\u003cstrong\u003e16\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.72043010752688%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.032258064516128%\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"30.107526881720432%\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.13978494623656%\"\u003e\n \u003cp\u003e\u003cstrong\u003e17\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.72043010752688%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.032258064516128%\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"30.107526881720432%\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.13978494623656%\"\u003e\n \u003cp\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.72043010752688%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.032258064516128%\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"30.107526881720432%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.13978494623656%\"\u003e\n \u003cp\u003e\u003cstrong\u003e19\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.72043010752688%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.032258064516128%\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"30.107526881720432%\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.13978494623656%\"\u003e\n \u003cp\u003e\u003cstrong\u003e20\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.72043010752688%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.032258064516128%\"\u003e\n \u003cp\u003e85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"30.107526881720432%\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.13978494623656%\"\u003e\n \u003cp\u003e\u003cstrong\u003e21\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.72043010752688%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"29.032258064516128%\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"30.107526881720432%\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eOS, overall survival\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3: Patients per maximum toxicity grade for treatment-related adverse events with vaccine and bevacizumab (N=21)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"41.82098765432099%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment-Related Adverse Events\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.51851851851852%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 2\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003en (%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.660493827160494%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 3\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003en (%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 4\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003en (%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"41.82098765432099%\"\u003e\n \u003cp\u003e\u003cstrong\u003eLeukopenia\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.51851851851852%\"\u003e\n \u003cp\u003e\u0026nbsp;2 (9.5%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.660493827160494%\"\u003e\n \u003cp\u003e\u0026nbsp;0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e\u0026nbsp;0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"41.82098765432099%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnemia\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.51851851851852%\"\u003e\n \u003cp\u003e\u0026nbsp;1 (4.8%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.660493827160494%\"\u003e\n \u003cp\u003e\u0026nbsp;0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e\u0026nbsp;0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"41.82098765432099%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHyperglycemia\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.51851851851852%\"\u003e\n \u003cp\u003e\u0026nbsp;0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.660493827160494%\"\u003e\n \u003cp\u003e\u0026nbsp;1 (4.8%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e\u0026nbsp;0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"41.82098765432099%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAmylase\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.51851851851852%\"\u003e\n \u003cp\u003e\u0026nbsp;2 (9.5%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.660493827160494%\"\u003e\n \u003cp\u003e\u0026nbsp;0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e\u0026nbsp;0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"41.82098765432099%\"\u003e\n \u003cp\u003e\u003cstrong\u003eBilirubin\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.51851851851852%\"\u003e\n \u003cp\u003e\u0026nbsp;1 (4.8%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.660493827160494%\"\u003e\n \u003cp\u003e\u0026nbsp;0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e\u0026nbsp;0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"41.82098765432099%\"\u003e\n \u003cp\u003e\u003cstrong\u003eFever\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.51851851851852%\"\u003e\n \u003cp\u003e\u0026nbsp;2 (9.5%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.660493827160494%\"\u003e\n \u003cp\u003e\u0026nbsp;0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e\u0026nbsp;1 (4.8%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"41.82098765432099%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHypertension\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.51851851851852%\"\u003e\n \u003cp\u003e\u0026nbsp;0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.660493827160494%\"\u003e\n \u003cp\u003e\u0026nbsp;2 (9.5%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e\u0026nbsp;0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"41.82098765432099%\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiarrhea\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.51851851851852%\"\u003e\n \u003cp\u003e\u0026nbsp;1 (4.8%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.660493827160494%\"\u003e\n \u003cp\u003e\u0026nbsp;0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e\u0026nbsp;0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"41.82098765432099%\"\u003e\n \u003cp\u003e\u003cstrong\u003eNausea/anorexia\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.51851851851852%\"\u003e\n \u003cp\u003e\u0026nbsp;1 (4.8%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.660493827160494%\"\u003e\n \u003cp\u003e\u0026nbsp;0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e\u0026nbsp;0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"41.82098765432099%\"\u003e\n \u003cp\u003e\u003cstrong\u003eInjection site reaction\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.51851851851852%\"\u003e\n \u003cp\u003e\u0026nbsp;3 (14%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.660493827160494%\"\u003e\n \u003cp\u003e\u0026nbsp;0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e\u0026nbsp;0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"41.82098765432099%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHeadache\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.51851851851852%\"\u003e\n \u003cp\u003e\u0026nbsp;1 (4.8%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.660493827160494%\"\u003e\n \u003cp\u003e\u0026nbsp;0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e\u0026nbsp;0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"41.82098765432099%\"\u003e\n \u003cp\u003e\u003cstrong\u003eEpistaxis/nasal congestion\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.51851851851852%\"\u003e\n \u003cp\u003e\u0026nbsp;1 (4.8%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.660493827160494%\"\u003e\n \u003cp\u003e\u0026nbsp;0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e\u0026nbsp;0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4: Time-dependent analysis for immunology response and response summary\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTime-dependent analysis for immunology response (includes either IgM or IgG)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8.9903%;\" valign=\"top\" width=\"7.506053268765133%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.4703%;\" valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR (95%CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1176%;\" valign=\"top\" width=\"5.084745762711864%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Cox PH p-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.0968%;\" valign=\"top\" width=\"8.232445520581114%\"\u003e\n \u003cp\u003e\u003cstrong\u003eResponse*\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNo. of patients\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.0664%;\" valign=\"top\" width=\"33.65617433414044%\"\u003e\n \u003cp\u003e\u003cstrong\u003eNon-response*\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNo. of patients\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8.9903%;\" valign=\"top\" width=\"7.506053268765133%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGM2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.4703%;\" valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003e0.96 (0.37 - 2.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1176%;\" valign=\"top\" width=\"5.084745762711864%\"\u003e\n \u003cp\u003e0.925\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.0968%;\" valign=\"top\" width=\"8.232445520581114%\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.0664%;\" valign=\"top\" width=\"33.65617433414044%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8.9903%;\" valign=\"top\" width=\"7.506053268765133%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGlobo-H\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.4703%;\" valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003e0.69 (0.23 - 2.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1176%;\" valign=\"top\" width=\"5.084745762711864%\"\u003e\n \u003cp\u003e0.496\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.0968%;\" valign=\"top\" width=\"8.232445520581114%\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.0664%;\" valign=\"top\" width=\"33.65617433414044%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8.9903%;\" valign=\"top\" width=\"7.506053268765133%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTn\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.4703%;\" valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003e0.78 (0.10 - 6.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1176%;\" valign=\"top\" width=\"5.084745762711864%\"\u003e\n \u003cp\u003e0.816\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.0968%;\" valign=\"top\" width=\"8.232445520581114%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.0664%;\" valign=\"top\" width=\"33.65617433414044%\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8.9903%;\" valign=\"top\" width=\"7.506053268765133%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTF\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.4703%;\" valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003e2.33 (0.80 - 6.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1176%;\" valign=\"top\" width=\"5.084745762711864%\"\u003e\n \u003cp\u003e0.123\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.0968%;\" valign=\"top\" width=\"8.232445520581114%\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.0664%;\" valign=\"top\" width=\"33.65617433414044%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8.9903%;\" valign=\"top\" width=\"7.506053268765133%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMUC-1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.4703%;\" valign=\"top\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003e0.89 (0.33 - 2.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1176%;\" valign=\"top\" width=\"5.084745762711864%\"\u003e\n \u003cp\u003e0.816\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.0968%;\" valign=\"top\" width=\"8.232445520581114%\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.0664%;\" valign=\"top\" width=\"33.65617433414044%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 29.4606%;\" valign=\"top\" width=\"35.55291319857313%\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eResponse summary\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1176%;\" valign=\"top\" width=\"4.9940546967895365%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 34.1632%;\" valign=\"top\" width=\"41.26040428061831%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8.9903%;\" valign=\"top\" width=\"7.045454545454546%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 20.4703%;\" valign=\"top\" width=\"26.818181818181817%\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo. of patients\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1176%;\" valign=\"top\" width=\"4.7727272727272725%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 45.6432%;\" width=\"61.36363636363637%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8.9903%;\" valign=\"top\" width=\"7.045454545454546%\"\u003e\n \u003cp\u003e\u003cstrong\u003eResponse to 5 vaccine antigens\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.4703%;\" valign=\"top\" width=\"26.818181818181817%\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1176%;\" valign=\"top\" width=\"4.7727272727272725%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 45.6432%;\" width=\"61.36363636363637%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8.9903%;\" valign=\"top\" width=\"7.045454545454546%\"\u003e\n \u003cp\u003e\u003cstrong\u003eResponse to 4 vaccine antigens\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.4703%;\" valign=\"top\" width=\"26.818181818181817%\"\u003e\n \u003cp\u003e6 (32%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1176%;\" valign=\"top\" width=\"4.7727272727272725%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 45.6432%;\" width=\"61.36363636363637%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8.9903%;\" valign=\"top\" width=\"7.045454545454546%\"\u003e\n \u003cp\u003e\u003cstrong\u003eResponse to 3 vaccine antigens\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.4703%;\" valign=\"top\" width=\"26.818181818181817%\"\u003e\n \u003cp\u003e7 (37%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1176%;\" valign=\"top\" width=\"4.7727272727272725%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 45.6432%;\" width=\"61.36363636363637%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8.9903%;\" valign=\"top\" width=\"7.045454545454546%\"\u003e\n \u003cp\u003e\u003cstrong\u003eResponse to 2 vaccine antigens\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.4703%;\" valign=\"top\" width=\"26.818181818181817%\"\u003e\n \u003cp\u003e3 (16%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1176%;\" valign=\"top\" width=\"4.7727272727272725%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 45.6432%;\" width=\"61.36363636363637%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8.9903%;\" valign=\"top\" width=\"7.045454545454546%\"\u003e\n \u003cp\u003e\u003cstrong\u003eResponse to 1 vaccine antigen\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20.4703%;\" valign=\"top\" width=\"26.818181818181817%\"\u003e\n \u003cp\u003e3 (16%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1176%;\" valign=\"top\" width=\"4.7727272727272725%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 45.6432%;\" width=\"61.36363636363637%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*(N=19, 2 patients removed given lack of serologic testing)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e** Cytokines include Globo-H, GM2, MUC1-TN, MUC-1, and TF).\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5. Overall survival and progression-free survival by antibody response status and time-dependent cytokine measurements\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOverall survival by antibody response status\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellpadding=\"0\" cellspacing=\"0\" width=\"101%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDeaths\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian OS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e5-Year OS Rate\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eNon- Responder\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e34.2 (95% CI: 12.8-NE)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e16.7% (95% CI: 0.8-51.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eResponder\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e30.7 (95% CI: 16.9-52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e15.4% (95% CI: 2.5-38.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e1.31 (95% CI: 0.46-3.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eProgression-free survival by antibody response status\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellpadding=\"0\" cellspacing=\"0\" width=\"109%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eProgression\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eMedian PFS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e6-Month PFS Rate\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eHR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eNon-Responder\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5.0 (95% CI: 0.7-NE)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e16.7% (95% CI: 0.8-51.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.84\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eResponder\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.9 (95% CI: 2.8-8.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e30.8% (95% CI: 9.5-55.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.9 (95% CI: 0.34-2.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eOverall survival by time-dependent cytokine measurements\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellpadding=\"0\" cellspacing=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 9.9293%;\" valign=\"top\" width=\"14.245810055865922%\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 21.8444%;\" valign=\"top\" width=\"41.899441340782126%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Comparing Baseline and Week 17\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 19.8585%;\" valign=\"top\" width=\"38.687150837988824%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAll Cytokine Values\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 9.9293%;\" valign=\"top\" width=\"14.285714285714286%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 12.5109%;\" valign=\"top\" width=\"23.80952380952381%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR (in 10 unit) (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.3335%;\" valign=\"top\" width=\"18.067226890756302%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCox PH p-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.8158%;\" valign=\"top\" width=\"22.829131652661065%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR (in 10 unit) (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.0427%;\" valign=\"top\" width=\"15.826330532212886%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCox PH p-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 9.9293%;\" valign=\"top\" width=\"14.285714285714286%\"\u003e\n \u003cp\u003e\u003cstrong\u003eFGFb\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 12.5109%;\" valign=\"top\" width=\"23.80952380952381%\"\u003e\n \u003cp\u003e0.99 (0.92-1.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.3335%;\" valign=\"top\" width=\"18.067226890756302%\"\u003e\n \u003cp\u003e0.782\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.8158%;\" valign=\"top\" width=\"22.829131652661065%\"\u003e\n \u003cp\u003e1.01 (0.96-1.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.0427%;\" valign=\"top\" width=\"15.826330532212886%\"\u003e\n \u003cp\u003e0.687\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 9.9293%;\" valign=\"top\" width=\"14.285714285714286%\"\u003e\n \u003cp\u003e\u003cstrong\u003eIL_8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 12.5109%;\" valign=\"top\" width=\"23.80952380952381%\"\u003e\n \u003cp\u003e0.62 (0.27-1.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.3335%;\" valign=\"top\" width=\"18.067226890756302%\"\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.8158%;\" valign=\"top\" width=\"22.829131652661065%\"\u003e\n \u003cp\u003e1.02 (0.89-1.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.0427%;\" valign=\"top\" width=\"15.826330532212886%\"\u003e\n \u003cp\u003e0.782\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 9.9293%;\" valign=\"top\" width=\"14.285714285714286%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePDGF-BB\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 12.5109%;\" valign=\"top\" width=\"23.80952380952381%\"\u003e\n \u003cp\u003e1.01 (1-1.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.3335%;\" valign=\"top\" width=\"18.067226890756302%\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.8158%;\" valign=\"top\" width=\"22.829131652661065%\"\u003e\n \u003cp\u003e1 (1-1.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.0427%;\" valign=\"top\" width=\"15.826330532212886%\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 9.9293%;\" valign=\"top\" width=\"14.285714285714286%\"\u003e\n \u003cp\u003e\u003cstrong\u003eVEGF\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 12.5109%;\" valign=\"top\" width=\"23.80952380952381%\"\u003e\n \u003cp\u003e1.02 (0.97-1.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.3335%;\" valign=\"top\" width=\"18.067226890756302%\"\u003e\n \u003cp\u003e0.479\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.8158%;\" valign=\"top\" width=\"22.829131652661065%\"\u003e\n \u003cp\u003e1.01 (0.98-1.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.0427%;\" valign=\"top\" width=\"15.826330532212886%\"\u003e\n \u003cp\u003e0.413\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eProgression-free survival by time-dependent cytokine measurements\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellpadding=\"0\" cellspacing=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15.104895104895105%\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"41.11888111888112%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Comparing Baseline and Week 17\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"43.77622377622377%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAll Cytokine Values\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15.083798882681565%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR (in 10 unit) (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.06145251396648%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCox PH p-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"26.11731843575419%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR (in 10 unit) (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.737430167597765%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCox PH p-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15.083798882681565%\"\u003e\n \u003cp\u003e\u003cstrong\u003eFGFb\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"25%\"\u003e\n \u003cp\u003e0.98 (0.91-1.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"16.06145251396648%\"\u003e\n \u003cp\u003e0.581\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"26.11731843575419%\"\u003e\n \u003cp\u003e0.98 (0.92-1.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"17.737430167597765%\"\u003e\n \u003cp\u003e0.522\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15.083798882681565%\"\u003e\n \u003cp\u003e\u003cstrong\u003eIL-8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"25%\"\u003e\n \u003cp\u003e0.43 (0.19-0.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"16.06145251396648%\"\u003e\n \u003cp\u003e0.043\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"26.11731843575419%\"\u003e\n \u003cp\u003e0.66 (0.32-1.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"17.737430167597765%\"\u003e\n \u003cp\u003e0.272\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15.083798882681565%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePDGF-BB\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"25%\"\u003e\n \u003cp\u003e1.00 (0.99-1.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"16.06145251396648%\"\u003e\n \u003cp\u003e0.814\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"26.11731843575419%\"\u003e\n \u003cp\u003e0.99 (0.98-1.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"17.737430167597765%\"\u003e\n \u003cp\u003e0.836\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15.083798882681565%\"\u003e\n \u003cp\u003e\u003cstrong\u003eVEGF\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"25%\"\u003e\n \u003cp\u003e0.99 (0.95-1.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"16.06145251396648%\"\u003e\n \u003cp\u003e0.795\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"26.11731843575419%\"\u003e\n \u003cp\u003e0.98 (0.94-1.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"17.737430167597765%\"\u003e\n \u003cp\u003e0.562\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eOS, overall survival; PFS, progression-free survival; NE, not estimable\u003c/p\u003e\n\u003cp\u003ep-value was obtained by applying permutation log-rank test with 5000 permutation times \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOS was measured from the start of study intervention until date of death or last follow-up\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cancer-immunology-immunotherapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ciim","sideBox":"Learn more about [Cancer Immunology, Immunotherapy](http://link.springer.com/journal/262)","snPcode":"262","submissionUrl":"https://submission.nature.com/new-submission/262/3","title":"Cancer Immunology, Immunotherapy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"vaccine, ovarian cancer, cytokines, immunotherapy, bevacizumab, remission ","lastPublishedDoi":"10.21203/rs.3.rs-1347080/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1347080/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eTo characterize the safety, immunogenicity, and outcomes of patients with high-grade serous ovarian cancer (HGSOC) in second or greater remission treated with a polyvalent antigen-KLH plus OPT-821 vaccine construct and bevacizumab.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003ePatients with recurrent HGSOC were treated with the vaccine plus bevacizumab at our institution from 01/05/2011-03/20/2012. Follow-up continued until 03/2021. Blood/urine samples were collected. “Responders” had an immunogenic response to \u003cu\u003e\u0026gt;\u003c/u\u003e3 antigens; “non-responders” to \u003cu\u003e\u0026lt;\u003c/u\u003e2 antigens.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eTwenty-one patients were treated on study.\u003cstrong\u003e \u003c/strong\u003eOne developed a dose limiting-toxicity (grade 4 fever). Two (10%) experienced bevacizumab-related grade 3 hypertension. Thirteen (68%) and 16 (84%) of 19 responded to ≥3 and ≥2 antigens, respectively (Globo-H, GM2, TF cluster Tn, MUC-1). \u0026nbsp;Four of 21 patients were alive \u0026gt;5 years post-treatment. Responders and non-responders had a median PFS of 4.9 months (95% CI: 2.8-8.1) and 5.0 months (95% CI: 0.7-cannot estimate), respectively; median OS was 30.7 months (95% CI: 16.9-52.0) and 34.2 months (95% CI: 12.8-cannot estimate), respectively. On two-time point analysis (baseline, week 17), increased IL-8 exhibited improved PFS (HR as 10-unit increase, 0.43; p=0.04); increased PDGF exhibited worse OS (HR as 10-unit increase, 1.01; p = 0.02).\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eThis is the longest follow-up of vaccine administration with bevacizumab among patients with ovarian cancer.\u003cstrong\u003e \u003c/strong\u003eThe vaccine was well tolerated with bevacizumab. Response was not associated with improved survival. On two-time point analysis, increased IL-8 was associated with significant improvement in PFS; increased PDGF with significantly worse OS. For all time point measurements, cytokine levels were not significantly associated with survival.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eTrial registration: \u003c/strong\u003eNCT01223235\u003c/p\u003e","manuscriptTitle":"Long-term Outcomes of Patients With Recurrent Ovarian Cancer Treated With a Polyvalent Vaccine With Bevacizumab Combination","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-02-21 14:57:55","doi":"10.21203/rs.3.rs-1347080/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2022-04-05T19:57:11+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2022-03-17T15:26:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"097728c3-0262-4e40-990b-c628fd1ced2d","date":"2022-02-28T15:42:41+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-02-16T23:29:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-02-16T23:23:48+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2022-02-16T09:04:38+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cancer Immunology, Immunotherapy","date":"2022-02-10T15:29:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cancer-immunology-immunotherapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ciim","sideBox":"Learn more about [Cancer Immunology, Immunotherapy](http://link.springer.com/journal/262)","snPcode":"262","submissionUrl":"https://submission.nature.com/new-submission/262/3","title":"Cancer Immunology, Immunotherapy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"b4ae2c4b-0dc7-45a3-927e-60f8093523ad","owner":[],"postedDate":"February 21st, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2022-05-17T20:14:09+00:00","versionOfRecord":[],"versionCreatedAt":"2022-02-21 14:57:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1347080","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1347080","identity":"rs-1347080","version":["v1"]},"buildId":"re_ckhLnmML6MCF96OHNJ","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}