Autologous Cytokine-Induced Killer (CIK) Cell Immunotherapy plus Sintilimab and Chemotherapy in Advanced Non‒Small-Cell Lung Cancer: 3-Year Outcomes From the Phase Ib CCICC-002a Study

Autologous Cytokine-Induced Killer (CIK) Cell Immunotherapy plus Sintilimab and Chemotherapy in Advanced Non‒Small-Cell Lung Cancer: 3-Year Outcomes From the Phase Ib CCICC-002a Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Autologous Cytokine-Induced Killer (CIK) Cell Immunotherapy plus Sintilimab and Chemotherapy in Advanced Non‒Small-Cell Lung Cancer: 3-Year Outcomes From the Phase Ib CCICC-002a Study Weihong Zhang, Yanping Chen, Li Zhou, Yanjuan Xiong, Fan Yang, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6139702/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract We present 3-year results from the CCICC-002a study (ClinicalTrials.gov number: NCT03987867). Autologous CIK cells immunotherapy plus Sintilimab and chemotherapy demonstrated favorable tolerability and encouraging efficacy in previously untreated, advanced NSCLC patients. The CCICC-002a study enrolled 33 patients (34 patients were enrolled at the first analysis, 1 patient was excluded by EGFR mutation in the secondary biopsy). The media follow-up was 40.5 months (range, 38.0 to 43.0 months). By the cut-off date of October 31, 2023, 17 patients had died. Estimated 3-year OS rates was 54.4%; median OS was 37.4 months (95% CI, 27.6–37.4 months). In subgroups, median OS was 27.6 months (95% CI, 13.4–36.5 months) in squamous NSCLC and not reached (95% CI, 29.9 months -not reached) in non-squamous NSCLC, respectively. Estimated 3-year PFS rates were 33.8% and median PFS was 18.1 months (95% CI, 10.1–24.0 months) in all patients; median PFS was 17.0 months (95% CI, 5.0–24.0 months) in squamous NSCLC and 23.5 months (95% CI, 5.7 months -not reached) in non-squamous NSCLC. Median response duration was 19.9 months (95% CI, 10.5–26.2); 24.2% of patients were ongoing at data cut-off; the longest response was ongoing at 51.7 months. Treatment-related AEs (TRAEs) occurred in 97% of patients and resulted in study discontinuation in 6.1%; 66.7% experienced grade 3/4 TRAE. This long-term analysis of CCICC-002a represents the longest follow-up for CIK to date and confirms the durable antitumor activity and tolerability of CIK cells therapy in combination with Sintilimab plus chemotherapy in advanced NSCLC. NSCLC Cytokine-Induced Killer Cell Sintilimab Chemotherapy Safety Efficacy Figures Figure 1 Figure 2 Figure 3 Introduction Immunotherapies targeting programmed cell death-1 (PD-1) and its ligand (PD-L1), administered in combination with established chemotherapies, have transformed the first-line treatment of metastatic non–small-cell lung cancer (NSCLC) [1–4]. However, the success of anti-PD-1 therapy across a wide range of lung cancer, only a subset of patients received the long-term benefit from the treatment [5]. Cytokine-induced killer (CIK) cells are heterogeneous, major histocompatibility complex (MHC)-unrestricted T lymphocytes. In our previously clinical trials, the primary analysis of the CCICC-002a study demonstrated significantly improved the objective response rate (ORR) by the treatment of autologous CIK cells immunotherapy in combination with Sintilimab plus chemotherapy, and the safety of the treatment was well tolerable. The treatment of autologous CIK cells immunotherapy in combination with Sintilimab plus chemotherapy showed the ORR and DCR were 81.8% (95% CI, 64.5%-93.0%) and 100.0% (95% CI, 89.4%-100.0%), respectively. Here We report efficacy outcomes and safety from CCICC-002a with an approximately 3-year follow-up. Methods Patients and Study Design This study was a single-center, open-label, phase 1b trial (CCICC-002a ClinicalTrials.gov number, NCT03987867), approved by the State Food and Drug Administration of China (2006L01023), the National Key Technologies R&D Program of China (2018YFC1313400) and the Ethical Committee of Cancer Hospital of Tianjin Medical University, according to the guidelines of the Declaration of Helsinki. Informed consent was obtained from all subjects. Patients who were eligible for enrollment had to meet the following criteria: age between 18 and 75 years, pathologically confirmed stage IIIB/IIIC/IV squamous or non-squamous NSCLC without EGFR/ALK/ROS1 mutations (according to the eighth edition of the Cancer Staging Manual of the American Joint Committee on Cancer) [6], not suitable for concomitant chemoradiotherapy, receiving no previous systemic therapy for advanced disease, an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 [7], at least one measurable lesion according to version 1.1 of the Response Evaluation Criteria in Solid Tumors (RECIST) [8], and expected survival duration of ≥ 3 months. Patients were excluded if they had symptomatic central nervous system metastases, had immune deficiency or autoimmune diseases, had severe allergic disorder, had a history of noninfectious pneumonitis, had other malignancies, had received more than 30 Gy of radiotherapy to the lung in the previous 6 months, had uncontrollable medical condition, or were receiving systemic immunosuppressive treatment. Full eligibility criteria are listed in the trial protocol. Study Design and Treatment The study design for the CCICC-002 NSCLC cohorts has been reported previously [9]. Patients received Sintilimab (200mg, d1), carboplatin (area under the concentration-time curve, 5mg per milliliter per minute, d1), pemetrexed (for non-squamous patient, 500mg per square meter, d1) or paclitaxel (for squamous patient, 135mg per square meter, d1), and autologous CIK cells (total count ≥ 1×10 10 , d13), administered intravenously every 3 weeks for 4 cycles. Then, non-squamous patients received Sintilimab (200mg, d1) plus pemetrexed (500mg per square meter, d1), and squamous patients received Sintilimab (200mg, d1) every 3 weeks as maintenance therapy until radiographic progression, unacceptable toxic effects, investigator decision, patient withdrawal of consent, or two years, whichever occurred first (Figure S2). CIK Cells Preparation CIK cells were prepared as described in our previous studies [10-12]. Brief description of CIK cells preparation was showed in Figure S3. Endpoints and Assessments The first efficacy endpoint was objective response rate (ORR) according to RECIST version 1.1. ORR was defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR). Imaging was performed every 6 weeks in the first 1 years, every 2 months for 3 years, and every 6 months thereafter. Another primary endpoint was investigator-assessed safety. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. 18 F-FDG PET/CT was used at the baseline and the best effect to detect residual tumor activity. The evaluation of complete metabolic response (CMR) was based on the Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) 1.0 [13]. The secondary endpoints were DOR, PFS, OS. PFS was the time from the initial treatment until the date of disease progression or the date of death from any cause, whichever occurred first; and OS was the time from the initial treatment until the date of death from any cause. Survival was assessed every 2 months after the discontinuation of therapy. DCR was the proportion of patients with a best overall response of CR, PR, and stable disease (SD). Tumor biopsy samples were obtained from 31 patients and pleural fluid sediment samples were obtained from another 2 patients before treatment initiation. We did not detect the PD-L1 expression, CD8 + tumor infiltrating lymphocyte (TIL), and other tumor biomarkers in pleural fluid sediment specimens. PD-L1 expression was assessed by means of the PD-L1 immunohistochemistry (IHC) 22C3 pharmDx assay (Agilent) in formalin-fixed tumor samples obtained before the treatment. Expression was categorized according to the tumor proportion score (TPS) (i.e., the percentage of tumor cells with membranous PD-L1 staining). Statistical Analysis Efficacy and safety analyses included patients who received one or more treatment. We estimated ORR and its 95% CI using the binomial exact method. We estimated PFS, OS and DOR using the Kaplan-Meier method. Median follow-up was calculated as the time from first treatment to data cutoff for all patients. Patients without a progression event were censored at the date of the last non-PD assessment. DOR was based on investigator assessment. Analyses were performed using a data cut-off date of October 31, 2023. Results Patients and Treatment A total of 33 patients (19 squamous patients and 14 non-squamous patients) were enrolled between May 17, 2019, and January 15, 2021. Baseline demographic and clinical characteristics are listed in Table 1. As of the data cutoff-October 31, 2023 median follow-up was 40.5 months (range, 38.0 to 43.0 months). Median treatment duration was 9.4 months (range, 0.8 to 39.0 months). 1 patient was still receiving treatment, 1 patient lost, and 15 patients were still alive at the time of analysis. Seven patients [2 (10.5%) of 19 squamous patients and 5 (35.7%) of 14 non-squamous patients] received 2 or more years of treatment with Sintilimab (Figure S1). Efficacy At data cut-off, nine patients continue response to the treatment. Twenty - three patients [15 (78.9%) of 19 squamous patients, 8 (57.1%) of 14 non-squamous patients] experienced PD or died, and 1 patient lost. Median PFS was 18.1 months (95% CI, 10.1 to 24.0 months) for all patients (Figs 1A). The Kaplan-Meier estimate of PFS at 3 years was 33.8% among all patients. And seventeen patients [12 (63.2%) of 19 squamous patients and 5 (35.7%) of 14 non-squamous patients] had dead. Median OS was 37.4 months (95% CI, 26.6 to 37.4 months) for all patients (Figs 1B). The Kaplan-Meier estimate of OS at 3 years was 54.5% among all patients. Among all 33 treated patients, 7 (21.2%) achieved CR/CMR, 20 (60.6%) achieved PR, and 6 (18.2%) achieved SD, for the DCR of 100% (Table 2; Fig 1C). In total, 15 (45.5%) patients experienced a DCR of PD. Median time to response was 1.5 months (95% CI, range:0.7 to 6.5 months), and median duration of response was 19.9 months (95% CI, range, 10.5 to 26.2 months). Of those who achieved CR/CMR, median time to response was 1.5 months (95% CI, range, 1.4 to 2.8 months), and median duration of response was NR (95% CI, range: range: NR to NR months). Response was ongoing in 71.4% (n = 5) of patients who achieved CR/CMR (n = 7). In subgroup analysis, a trend for improvement in PFS and OS was observed for non-squamous patients versus squamous patients, this was not statistically significant (HR, 0.53; 95% CI, 0.22 to 1.27; P = 0.165; Fig 2A). The median PFS was 23.5 months (95% CI, 10.1 to 23.5) versus 17 (95% CI, 4.9 to 24) with non-squamous patients versus squamous patients, respectively. The median OS was NR (95% CI, NR to NR) versus 27.6 (95% CI, 13.4 to 36.5) months with non-squamous patients versus squamous patients, respectively (Fig 2B). PD-L1 expression level has exhibited a positive correlation with tumor response in previous studies of ICIs monotherapies [14, 15]. Fifteen PD-L1 positive samples (48.4%) and sixteen PD-L1 negative samples (51.6%) were identified in the study. Among patients with PD-L1 TPS of 1% or greater (PD-L1-positive patients), median PFS and median OS were NR and NR (95% CI, NR to NR months; 95% CI, NR to NR months) and the 3-year PFS rate and OS rare were 60.0% and 73.3%, respectively. Among the patients with PD-L1 TPS of less than 1% (PD-L1-negative patients), median PFS was 10.1 months (95% CI, 4.9 to 19.2 months) (Fig 3A); median OS was 26.6 months (95% CI, 15.6 to 37.4 months) and the 3year OS rate was 37.5%. PD-L1-positive patients had a statistically significant PFS [HR, 0.25; 95% CI, 0.10 to 0.61; P = 0.001] and OS [HR, 0.36; 95% CI, 0.13 to 0.95; P = 0.044] advantage compared with PD-L1-negative patients (Fig 3B). Additional clinical characters analyzed for correlation with clinical efficacy included age, sex, smoking, ECOG PS and tumor metastatic stage. Among the subgroups, patients with ECOG PS < 1 had a longer PFS, and a longer OS than the rest of the patients (P = 0.005, P = 0.033, respectively) (Fig 3C; Fig 3D). Safety The treatment-related adverse events (TRAEs) were reported in 32 (93.0%) patients (Table 3). Grade 3 or greater TRAEs occurred in 22 (66.7%) patients. Grade 3 or greater TRAEs of more than 5% included neutropenia (60.6%), fatigue (51.5%), nausea (63.6%), leukopenia (69.7%), thrombocytopenia (30.3%), hypothyroidism (33.3%), and pneumonia (15.2%). Immune-related adverse events (irAEs) occurred in 15 (45.5%) patients (Table 3). Grade 3 or greater irAEs occurred in 4 (12.1%) patients. Grade 3 or greater irAEs included pneumonia (5.9%), cardiomyopathy (2.9%), dysphagia (2.9%), rash (2.9%), and cough (2.9%). The only grade 5 immune mediated AEs to occur in 1 patient was pneumonitis (2.9%) after 2 cycles of treatment (Table 3). Discussion In a review of the literature, we found that, to date, this trial has been the first study of CIK cells immunotherapy combination with PD-1 inhibitor plus chemotherapy in lung cancer. Three-year outcomes from our study represent the longest follow-up of patients with advanced/metastatic NSCLC who received CIK cells immunotherapy combination with PD-1 inhibitor plus chemotherapy. Overall, it is clear that these outcomes represent a clinically meaningful improvement over the 3-year OS rate and PFS rate with immunotherapies for the treatment of advanced/metastatic NSCLC. Together with the results from ORIENT-11 [16] and ORIENT-12 [9], the data from CCICC-002 suggests that introducing CIK as a first-line therapy may have a favorable long-term effect on outcomes. For squamous NSCLC, the median PFS was 17.0 month and the median OS was 27.6 month. Whereas, in keynote189 China study [17, 18], the median PFS was 8.3 month and the median OS was 29.9 months, respectively. However, among the 13 advanced squamous cell carcinoma patients who experienced disease progression, 4 refused to accept second-line or supportive treatment in which all patients died within 3 months after progression. The median OS was 7.1 months in the 4 patients. This may be the reason for the prolonged PFS (17.0 months), but PFS is not converted into OS in squamous patients. Meanwhile in the 14 non-squamous patients, 7 patients developed into disease progression who all received second line treatment, and 3 are all alive. The median OS and the median PFS were NR. And OS are consistent with PFS. To our knowledge, the survival benefit associated with the anti-PD-1 combination therapy was related to PD-L1 expression. In this study, higher PD-L1 expression was associated with longer OS and PFS. patients with PD-L1 TPS of 1% or greater, median PFS and median OS were NR. Among the seven patients achieved CR/CMR, one developed into disease progression. Among the three patients with brain metastasis at baseline, one achieved CR, one achieved CMR and one achieved PR. The observed intracranial and systemic responses were comparable, indicating that the regimen had synergistic effects in the brain. This finding was consistent with the Phase 1b Study of Sintilimab Plus Anlotinib [19] and the KEYNOTE-189 posthoc analysis. The TRAEs were 93.0%, grade 3 or greater TRAEs were 66.7%, and one patient (2.9%) died from grade 5 immune-related pneumonia. The ORR was 81.8%, DCR was 100.0%, median DOR was 19.9 months, median PFS was 18.1 months, and median OS was 37.4 months. These results showed that CIK cells combined with PD-1 inhibitor and chemotherapy had good tolerance and encouraging efficacy in advanced NSCLC. In conclusion, autologous CIK cells immunotherapy in combination with Sintilimab plus chemotherapy continued to demonstrate prolonged survival and durable antitumor activity after 3 years of follow-up, with manageable toxicity, in patients with previously untreated advanced/metastatic NSCLC without EGFR/ALK alterations. These results continue to support the combination of first line autologous CIK cells immunotherapy in combination with Sintilimab plus chemotherapy as an important care for these patients. Abbreviations CIK: Cytokine-induced killer; CR: complete response; CMR: complete metabolic response; ECOG: Eastern Cooperative Oncology Group; irAEs: Immune-related adverse events; IHC: immunohistochemistry; MHC: major histocompatibility complex; NSCLC: non–small-cell lung cancer; ORR: objective response rate; PD-1: programmed cell death-1; PR: partial response; RECIST: Response Evaluation Criteria in Solid Tumors; SD: stable disease; TRAEs: Treatment-related AEs; TPS: tumor proportion score; TIL: tumor infiltrating lymphocyte Declarations Authors’ contributions Weihong Zhang, Yanping Chen, Li Zhou: Conceptualization, Investigation, Formal analysis, Data curation, Writing – original draft; Yanjuan Xiong, Fan Yang, Meng Shen, Shuzhan Li, Jiali Zhang, Weijiao Du, Zhenzhen Hui, Xiao Tian, Ying Han, Yang Wang, Shunju Pang, Baozhu Ren, Xinwei Zhang, Shui Cao: Validation, Investigation, Data curation, Writing – original draft; Runmei Li: Validation, Investigation, Data curation, Writing – review & editing, Supervision, Project administration. Liang Liu, Xiubao Ren: Conceptualization, Methodology, Writing – review & editing, Supervision, Project administration. Competing interests All authors reported no potential conflicts of interest. Availability of data and material Data are available on reasonable request. Ethics approval and consent to participate This study was approved by the State Food and Drug Administration of China (2006L01023), the National Key Technologies R&D Program of China (2018YFC1313400) and the Ethical Committee of Cancer Hospital of Tianjin Medical University (no. Ey2022004), according to the guidelines of the Declaration of Helsinki. Informed consent was obtained from all subjects. Funding This study is funded by National Natural Science Foundation of China (U20A20375, 82372779, 82303196, 82373279, 82373283, 82103001), Tianjin Science and Technology Commission project (No. 21JCQNJC01430) and Tianjin Key Medical Discipline (Specialty) Construction Project (No. TJYXZDXK-009A). 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Characteristic N = 33 Age, years Median 62.5 Range 40-73 Gender, n (%) Male 29 (87.9) Female 4 (12.1) ECOG PS, n (%) 0 13 (39.4) 1 19 (57.6) 2 1 (3.0) Smoking history, n (%) Current/former 28 (84.8) Never 5 (15.2) Histology, n (%) Squamous 19 (57.6) Non-squamous 14 (42.4) Stage at diagnosis, n (%) IIIB/IIIC 6 (18.2) IV 27 (81.8) Sites of metastasis, n (%) Liver 6 (18.2) Brain 3 (9.1) Bone 3 (9.1) Other 21 (63.6) PD-L1 subgroups, n (%) TPS ≥ 1% 15 (45.5) TPS＜1% 16 (48.5) Unknown 2 (6.0) Abbreviations: ECOG, Eastern Cooperative Oncology Group; PS, performance status score; PD-L1, programmed death ligand-1; TPS, tumor proportion score, the percentage of tumor cells with membranous programmed cell death protein ligand-1 staining. Table 2. Summary of Response in The Phase IB Study. Variable ITT (N=33) SQ (N=19) NSQ (N=14) ORR, n (%) 27 (81.8) 14 (73.7) 13 (92.9) 95% CI 64.5-93.0 48.8-90.9 66.1-99.8 DCR, n (%) 33 (100) 19 (100) 14 (100) 95% CI 89.4-100.0 82.4-100.0 76.8-100.0 CR, n (%) 2 (6.1) 0 (0) 2 (14.3) CMR, n (%) 5 (15.2) 3 (15.8) 2 (14.3) PR, n (%) 20 (60.6) 11 (57.9) 9 (64.3) SD, n (%) 6 (18.2) 5 (26.3) 1 (7.1) Median time to response, months (range) 1.5 (0.7-6.5) 1.5 (0.7-6.5) 1.7 (1.4-3.8) Median DOR, months 95% CI 19.9 (10.5-26.2) 17.9 (6.6-26.2) 19.9 (2.8-22.0) Abbreviations: ITT, intention to treat analysis; SQ, squamous; NSQ, non-squamous; ORR, objective response rate; CI, confidence interval; DCR, disease control rate; CR, complete response; CMR, complete metabolic response; PR, partial response; SD, stable disease; DOR, duration of response; NR, not reached; NA, not available. Table 3. Adverse Events in The Phase IB Study. Treatment-Related Adverse Events Any Grade Grade 3, 4, or 5 number of patients (%) Any event 31 (93.0) 22 (66.7) Event leading to discontinuation of 2 (6.1) 2 (6.1) all treatment Discontinuation of Sintilimab 4 (12.1) 4 (12.1) Discontinuation of CIK cells 2 (6.1) 2 (6.1) Discontinuation of Chemotherapy 3 (9.1) 3 (9.1) Event leading to death 1 (3.0) 1 (3.0) Anemia 23 (69.7) 1 (3.0) Neutropenia 20 (60.6) 8 (24.2) Leukopenia 23 (69.7) 3 (9.1) Thrombocytopenia 10 (30.3) 2 (6.1) Nausea 21 (63.6) 3 (9.1) Alanine aminotransferase increased 7 (21.2) 1 (3.0) Aspartate aminotransferase increased 4 (12.1) 1 (3.0) Hypoalbuminemia 13 (39.4) 0 (0) Fatigue 17 (51.5) 7 (21.2) Rash 4 (12.1) 1 (3.0) Cough 10 (30.3) 1 (3.0) Pneumonia 5 (15.2) 2 (6.1) Hypothyroidism 11 (33.3) 0 Adrenal insufficiency 3 (9.1) 0 Cardiomyopathy 1 (3.0) 1 (3.0) Mucostitis oral 1 (3.0) 1 (3.0) Dysphagia 1 (3.0) 1 (3.0) hyperparathyroidism 1 (3.0) 0 Immune-Related Adverse Event Any Grade Grade 3, 4, or 5 number of patients (%) Any event 15 (45.5) 4 (12.1) Event leading to death 1 (3.0) 1 (3.0) Hypothyroidism 11 (33.3) 0 Pneumonia 5 (14.7) 2 (5.9) Rash 4 (11.8) 1 (2.9) Adrenal insufficiency 3 (8.8) 0 Cough 2 (5.9) 1 (2.9) Cardiomyopathy 1 (2.9) 1 (2.9) Dysphagia 1 (2.9) 1 (2.9) hyperparathyroidism 1 (3.0) 0 Abbreviations: CIK, cytokine-induced killer. Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterials.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 06 Mar, 2025 Editor assigned by journal 04 Mar, 2025 Submission checks completed at journal 04 Mar, 2025 First submitted to journal 02 Mar, 2025 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 Our Team In Review Editorial Policies Advisory Board 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-6139702","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":423872824,"identity":"e71ba72c-8a43-4e9c-acd4-c6386886a5d0","order_by":0,"name":"Weihong Zhang","email":"","orcid":"","institution":"Tianjin Medical University Cancer Institute and Hospital","correspondingAuthor":false,"prefix":"","firstName":"Weihong","middleName":"","lastName":"Zhang","suffix":""},{"id":423872826,"identity":"d6f87ebd-26a6-48f6-b7a4-f07f1113a332","order_by":1,"name":"Yanping Chen","email":"","orcid":"","institution":"Tianjin Medical University Cancer 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Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyklEQVRIiWNgGAWjYBACPmYGxgMJQAY/AwOIOkBYCxszUBlIrWQb0VpgygyOgfnEaGHnMTjwoOaO3eb7DU8389TcYeBv704g4DCgloRjz5K3HWNIu81z7BmDxJmzG4jQwnY42QykhbfhMIOBRC4xWv4dTjZuI0lLYtthOwM24rWwFRxI7DucIHEsIe3mnGOHeQj6hZ//8MaHP74dtudvPpN2403NYTn+9l78WmAgsYGBJwHE4CFKOQjYMzCwHyBa9SgYBaNgFIwsAADFjEvMLNPMRwAAAABJRU5ErkJggg==","orcid":"","institution":"Tianjin Medical University Cancer Institute and Hospital","correspondingAuthor":true,"prefix":"","firstName":"Liang","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2025-03-02 13:38:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6139702/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6139702/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":78238655,"identity":"e4f504c5-2bfc-4780-b300-fe5296dc5c78","added_by":"auto","created_at":"2025-03-11 08:47:29","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":422752,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Progression-free survival, (B) overall survival and (C) Exposure and duration of response in all patients by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. per RECIST version 1.1. PFS: progression-free survival; OS: overall survival; TPS: the tumor proportion score, the percentage of tumor cells with membranous programmed cell death protein ligand-1 staining; CR: complete response; CMR: complete metabolic response; PR: partial response; SD: stable disease; PD: progressive disease; EOT: end of treatment; All: all patients (N = 33).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6139702/v1/09bcbcc8427eb6ea7909d01a.png"},{"id":78238649,"identity":"d2f931e7-32f5-4da7-8bcb-1fe89962ed5e","added_by":"auto","created_at":"2025-03-11 08:47:27","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":656258,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Progression-free survival and (B) overall survival in squamous patients and non-squamous patients by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. SQ, squamous patients (N = 19); non-SQ: non-squamous patients (N = 14); CI: conffdence interval; NA: not available.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6139702/v1/f5ff9e38037a34e0454b2d33.png"},{"id":78238662,"identity":"ae7126dd-f7cc-407d-bbf5-c2ca4bf1dde3","added_by":"auto","created_at":"2025-03-11 08:47:37","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":399177,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Median PFS and (B) Median OS in PD-L1-positive patients and PD-L1-negative patients, (C) Median PFS and (D) Median OS in ECOG=0 patients and ECOG=1 patients. ECOG: Eastern Cooperative Oncology Group; TPS: the tumor proportion score, the percentage of tumor cells with membranous programmed cell death protein ligand-1 staining.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6139702/v1/845adf2a99fc31018897bebb.png"},{"id":78240322,"identity":"8e07336a-42bd-4dbf-9f8f-8ecba4fddd5d","added_by":"auto","created_at":"2025-03-11 08:55:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2197611,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6139702/v1/8e205646-5c4f-4276-8670-93036ace262f.pdf"},{"id":78238656,"identity":"3a7b2e99-4b1d-45b4-8439-7ec78043ce12","added_by":"auto","created_at":"2025-03-11 08:47:30","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":885146,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-6139702/v1/b5268e6fa023ed88a7b860ad.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Autologous Cytokine-Induced Killer (CIK) Cell Immunotherapy plus Sintilimab and Chemotherapy in Advanced Non‒Small-Cell Lung Cancer: 3-Year Outcomes From the Phase Ib CCICC-002a Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eImmunotherapies targeting programmed cell death-1 (PD-1) and its ligand (PD-L1), administered in combination with established chemotherapies, have transformed the first-line treatment of metastatic non\u0026ndash;small-cell lung cancer (NSCLC) [1\u0026ndash;4]. However, the success of anti-PD-1 therapy across a wide range of lung cancer, only a subset of patients received the long-term benefit from the treatment [5].\u003c/p\u003e \u003cp\u003eCytokine-induced killer (CIK) cells are heterogeneous, major histocompatibility complex (MHC)-unrestricted T lymphocytes. In our previously clinical trials, the primary analysis of the CCICC-002a study demonstrated significantly improved the objective response rate (ORR) by the treatment of autologous CIK cells immunotherapy in combination with Sintilimab plus chemotherapy, and the safety of the treatment was well tolerable. The treatment of autologous CIK cells immunotherapy in combination with Sintilimab plus chemotherapy showed the ORR and DCR were 81.8% (95% CI, 64.5%-93.0%) and 100.0% (95% CI, 89.4%-100.0%), respectively. Here We report efficacy outcomes and safety from CCICC-002a with an approximately 3-year follow-up.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003ePatients\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;and Study Design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was a single-center, open-label, phase 1b trial (CCICC-002a ClinicalTrials.gov number, NCT03987867), approved by the State Food and Drug Administration of China (2006L01023), the National Key Technologies R\u0026amp;D Program of China (2018YFC1313400) and the Ethical Committee of Cancer Hospital of Tianjin Medical University, according to the guidelines of the Declaration of Helsinki. Informed consent was obtained from all subjects. Patients who were eligible for enrollment had to meet the following criteria: age between 18 and 75 years, pathologically confirmed stage IIIB/IIIC/IV squamous or non-squamous NSCLC without EGFR/ALK/ROS1 mutations (according to the eighth edition of the Cancer Staging Manual of the American Joint Committee on Cancer) [6], not suitable for concomitant chemoradiotherapy, receiving no previous systemic therapy for advanced disease, an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 [7], at least one measurable lesion according to version 1.1 of the Response Evaluation Criteria in Solid Tumors (RECIST) [8], and expected survival duration of \u0026ge; 3 months. Patients were excluded if they had symptomatic central nervous system metastases, had immune deficiency or autoimmune diseases, had severe allergic disorder, had a history of noninfectious pneumonitis, had other malignancies, had received more than 30 Gy of radiotherapy to the lung in the previous 6 months, had uncontrollable medical condition, or were receiving systemic immunosuppressive treatment. Full eligibility criteria are listed in the trial protocol.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Design and Treatment\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study design for the CCICC-002 NSCLC cohorts has been reported previously [9]. Patients received Sintilimab (200mg, d1), carboplatin (area under the concentration-time curve, 5mg per milliliter per minute, d1), pemetrexed (for non-squamous patient, 500mg per square meter, d1) or paclitaxel (for squamous patient, 135mg per square meter, d1), and autologous CIK cells (total count \u0026ge; 1\u0026times;10\u003csup\u003e10\u003c/sup\u003e, d13), administered intravenously every 3 weeks for 4 cycles. Then, non-squamous patients received Sintilimab (200mg, d1) plus pemetrexed (500mg per square meter, d1), and squamous patients received Sintilimab (200mg, d1) every 3 weeks as maintenance therapy until radiographic progression, unacceptable toxic effects, investigator decision, patient withdrawal of consent, or two years, whichever occurred first (Figure S2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCIK Cells Preparation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCIK cells were prepared as described in our previous studies [10-12]. Brief description of CIK cells preparation was showed in Figure S3.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEndpoints and Assessments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe first efficacy endpoint was objective response rate (ORR) according to RECIST version 1.1. ORR was defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR). Imaging was performed every 6 weeks in the first 1 years, every 2 months for 3 years, and every 6 months thereafter. Another primary endpoint was investigator-assessed safety. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT was used at the baseline and the best effect to detect residual tumor activity. The evaluation of complete metabolic response (CMR) was based on the Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) 1.0 [13].\u003c/p\u003e\n\u003cp\u003eThe secondary endpoints were DOR, PFS, OS. PFS was the time from the initial treatment until the date of disease progression or the date of death from any cause, whichever occurred first; and OS was the time from the initial treatment until the date of death from any cause. Survival was assessed every 2 months after the discontinuation of therapy. DCR was the proportion of patients with a best overall response of CR, PR, and stable disease (SD).\u003c/p\u003e\n\u003cp\u003eTumor biopsy samples were obtained from 31 patients and pleural fluid sediment samples were obtained from another 2 patients before treatment initiation. We did not detect the PD-L1 expression, CD8\u003csup\u003e+\u0026nbsp;\u003c/sup\u003etumor infiltrating lymphocyte (TIL), and other tumor biomarkers in pleural fluid sediment specimens. PD-L1 expression was assessed by means of the PD-L1 immunohistochemistry (IHC) 22C3 pharmDx assay (Agilent) in formalin-fixed tumor samples obtained before the treatment. Expression was categorized according to the tumor proportion score (TPS) (i.e., the percentage of tumor cells with membranous PD-L1 staining).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEfficacy and safety analyses included patients who received one or more treatment. We estimated ORR and its 95% CI using the binomial exact method. We estimated PFS, OS and DOR using the Kaplan-Meier method. Median follow-up was calculated as the time from first treatment to data cutoff for all patients. Patients without a progression event were censored at the date of the last non-PD assessment. DOR was based on investigator assessment. Analyses were performed using a data cut-off date of October 31, 2023.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatients and Treatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 33 patients (19 squamous patients and 14 non-squamous patients) were enrolled between May 17, 2019, and January 15, 2021. Baseline demographic and clinical characteristics are listed in Table 1. As of the data cutoff-October 31, 2023 median follow-up was 40.5 months (range, 38.0 to 43.0 months). Median treatment duration was 9.4 months (range, 0.8 to 39.0 months). 1 patient was still receiving treatment, 1 patient lost, and 15 patients were still alive at the time of analysis. Seven patients [2 (10.5%) of 19 squamous patients and 5 (35.7%) of 14 non-squamous patients] received 2 or more years of treatment with Sintilimab (Figure S1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEfficacy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt data cut-off, nine patients continue response to the treatment.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eTwenty - three patients [15 (78.9%) of 19 squamous patients, 8 (57.1%) of 14 non-squamous patients] experienced PD or died, and 1 patient lost. Median PFS was 18.1 months (95% CI, 10.1 to 24.0 months) for all patients (Figs 1A). The Kaplan-Meier estimate of PFS at 3 years was 33.8% among all patients. And seventeen patients [12 (63.2%) of 19 squamous patients and 5 (35.7%) of 14 non-squamous patients] had dead. Median OS was 37.4 months (95% CI, 26.6 to 37.4 months) for all patients (Figs 1B). The Kaplan-Meier estimate of OS at 3 years was 54.5% among all patients.\u003c/p\u003e\n\u003cp\u003eAmong all 33 treated patients, 7 (21.2%) achieved CR/CMR, 20 (60.6%) achieved PR, and 6 (18.2%) achieved SD, for the DCR of 100% (Table 2; Fig 1C). In total, 15 (45.5%) patients experienced a DCR of PD. Median time to response was 1.5 months (95% CI, range:0.7 to 6.5 months), and median duration of response was 19.9 months (95% CI, range, 10.5 to 26.2 months). Of those who achieved CR/CMR, median time to response was 1.5 months (95% CI, range, 1.4 to 2.8 months), and median duration of response was NR (95% CI, range: range: NR to NR months). Response was ongoing in 71.4% (n = 5) of patients who achieved CR/CMR (n = 7).\u003c/p\u003e\n\u003cp\u003eIn subgroup analysis, a trend for improvement in PFS and OS was observed for non-squamous patients versus squamous patients, this was not statistically significant (HR, 0.53; 95% CI, 0.22 to 1.27; \u003cem\u003eP\u003c/em\u003e= 0.165; Fig 2A). The median PFS was 23.5 months (95% CI, 10.1 to 23.5) versus 17 (95% CI, 4.9 to 24) with non-squamous patients versus squamous patients, respectively. The median OS was NR (95% CI, NR to NR) versus 27.6 (95% CI, 13.4 to 36.5) months with non-squamous patients versus squamous patients, respectively (Fig 2B).\u003c/p\u003e\n\u003cp\u003ePD-L1 expression level has exhibited a positive correlation with tumor response in previous studies of ICIs monotherapies [14, 15]. Fifteen PD-L1 positive samples (48.4%) and sixteen PD-L1 negative samples (51.6%) were identified in the study. Among patients with PD-L1 TPS of 1% or greater (PD-L1-positive patients), median PFS and median OS were NR and NR (95% CI, NR to NR months; 95% CI, NR to NR months) and the 3-year PFS rate and OS rare were 60.0% and 73.3%, respectively. Among the patients with PD-L1 TPS of less than 1% (PD-L1-negative patients), median PFS was 10.1 months (95% CI, 4.9 to 19.2 months) (Fig 3A); median OS was 26.6 months (95% CI, 15.6 to 37.4 months) and the 3year OS rate was 37.5%. PD-L1-positive patients had a statistically significant PFS [HR, 0.25; 95% CI, 0.10 to 0.61; \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.001] and OS [HR, 0.36; 95% CI, 0.13 to 0.95; \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.044] advantage compared with PD-L1-negative patients (Fig 3B).\u003c/p\u003e\n\u003cp\u003eAdditional clinical characters analyzed for correlation with clinical efficacy included age, sex, smoking, ECOG PS and tumor metastatic stage. Among the subgroups, patients with ECOG PS \u0026lt; 1 had\u0026nbsp;a longer PFS, and a longer OS than the rest of the patients (P = 0.005, P = 0.033, respectively) (Fig 3C; Fig 3D).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe treatment-related adverse events (TRAEs) were reported in 32 (93.0%) patients (Table 3). Grade 3 or greater TRAEs occurred in 22 (66.7%) patients. Grade 3 or greater TRAEs of more than 5% included neutropenia (60.6%), fatigue (51.5%), nausea (63.6%), leukopenia (69.7%), thrombocytopenia (30.3%), hypothyroidism (33.3%), and pneumonia (15.2%). Immune-related adverse events (irAEs) occurred in 15 (45.5%) patients (Table 3). Grade 3 or greater irAEs occurred in 4 (12.1%) patients. Grade 3 or greater irAEs included pneumonia (5.9%), cardiomyopathy (2.9%), dysphagia (2.9%), rash (2.9%), and cough (2.9%). The only grade 5 immune mediated AEs to occur in 1 patient was pneumonitis (2.9%) after 2 cycles of treatment (Table 3).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn a review of the literature, we found that, to date, this trial has been the first study of CIK cells immunotherapy combination with PD-1 inhibitor plus chemotherapy in lung cancer. Three-year outcomes from our study represent the longest follow-up of patients with advanced/metastatic NSCLC who received CIK cells immunotherapy combination with PD-1 inhibitor plus chemotherapy. Overall, it is clear that these outcomes represent a clinically meaningful improvement over the 3-year OS rate and PFS rate with immunotherapies for the treatment of advanced/metastatic NSCLC. Together with the results from ORIENT-11 [16] and ORIENT-12 [9], the data from CCICC-002 suggests that introducing CIK as a first-line therapy may have a favorable long-term effect on outcomes.\u003c/p\u003e \u003cp\u003eFor squamous NSCLC, the median PFS was 17.0 month and the median OS was 27.6 month. Whereas, in keynote189 China study [17, 18], the median PFS was 8.3 month and the median OS was 29.9 months, respectively. However, among the 13 advanced squamous cell carcinoma patients who experienced disease progression, 4 refused to accept second-line or supportive treatment in which all patients died within 3 months after progression. The median OS was 7.1 months in the 4 patients. This may be the reason for the prolonged PFS (17.0 months), but PFS is not converted into OS in squamous patients. Meanwhile in the 14 non-squamous patients, 7 patients developed into disease progression who all received second line treatment, and 3 are all alive. The median OS and the median PFS were NR. And OS are consistent with PFS.\u003c/p\u003e \u003cp\u003eTo our knowledge, the survival benefit associated with the anti-PD-1 combination therapy was related to PD-L1 expression. In this study, higher PD-L1 expression was associated with longer OS and PFS. patients with PD-L1 TPS of 1% or greater, median PFS and median OS were NR.\u003c/p\u003e \u003cp\u003eAmong the seven patients achieved CR/CMR, one developed into disease progression. Among the three patients with brain metastasis at baseline, one achieved CR, one achieved CMR and one achieved PR. The observed intracranial and systemic responses were comparable, indicating that the regimen had synergistic effects in the brain. This finding was consistent with the Phase 1b Study of Sintilimab Plus Anlotinib [19] and the KEYNOTE-189 posthoc analysis.\u003c/p\u003e \u003cp\u003eThe TRAEs were 93.0%, grade 3 or greater TRAEs were 66.7%, and one patient (2.9%) died from grade 5 immune-related pneumonia. The ORR was 81.8%, DCR was 100.0%, median DOR was 19.9 months, median PFS was 18.1 months, and median OS was 37.4 months. These results showed that CIK cells combined with PD-1 inhibitor and chemotherapy had good tolerance and encouraging efficacy in advanced NSCLC. In conclusion, autologous CIK cells immunotherapy in combination with Sintilimab plus chemotherapy continued to demonstrate prolonged survival and durable antitumor activity after 3 years of follow-up, with manageable toxicity, in patients with previously untreated advanced/metastatic NSCLC without EGFR/ALK alterations. These results continue to support the combination of first line autologous CIK cells immunotherapy in combination with Sintilimab plus chemotherapy as an important care for these patients.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCIK: Cytokine-induced killer; CR: complete response; CMR: complete metabolic response; ECOG: Eastern Cooperative Oncology Group; irAEs: Immune-related adverse events; IHC: immunohistochemistry; MHC: major histocompatibility complex; NSCLC: non\u0026ndash;small-cell lung cancer; ORR: objective response rate; PD-1: programmed cell death-1; PR: partial response; RECIST: Response Evaluation Criteria in Solid Tumors; SD: stable disease; TRAEs: Treatment-related AEs; TPS: tumor proportion score; TIL: tumor infiltrating lymphocyte\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWeihong Zhang, Yanping Chen, Li Zhou: Conceptualization, Investigation, Formal analysis, Data curation, Writing \u0026ndash; original draft; Yanjuan Xiong, Fan Yang, Meng Shen, Shuzhan Li, Jiali Zhang, Weijiao Du, Zhenzhen Hui, Xiao Tian, Ying Han, Yang Wang, Shunju Pang, Baozhu Ren, Xinwei Zhang, Shui Cao: Validation, Investigation, Data curation, Writing \u0026ndash; original draft; Runmei Li: Validation, Investigation, Data curation, Writing \u0026ndash; review \u0026amp; editing, Supervision, Project administration. Liang Liu, Xiubao Ren: Conceptualization, Methodology, Writing \u0026ndash; review \u0026amp; editing, Supervision, Project administration. \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors reported no potential conflicts of interest.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData are available on reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the State Food and Drug Administration of China (2006L01023), the National Key Technologies R\u0026amp;D Program of China (2018YFC1313400) and the Ethical Committee of Cancer Hospital of Tianjin Medical University (no. Ey2022004), according to the guidelines of the Declaration of Helsinki. Informed consent was obtained from all subjects.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is funded by National Natural Science Foundation of China (U20A20375, 82372779, 82303196, 82373279, 82373283, 82103001), Tianjin Science and Technology Commission project (No. 21JCQNJC01430) and Tianjin Key Medical Discipline (Specialty) Construction Project (No. TJYXZDXK-009A).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the patients who participated in this study and their families, thank the Suzhou Xinda biopharmaceutical Co., LTD for assistance with statistical analysis.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSocinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med. 378 (2018) 2288-301. https://doi.org/10.1056/NEJMoa1716948.\u003c/li\u003e\n\u003cli\u003ePaz-Ares L, Luft A, Vicente D, Tafreshi A, Gumus M, Mazieres J, et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med. 379 (2018) 2040-51. https://doi.org/10.1056/NEJMoa1810865.\u003c/li\u003e\n\u003cli\u003eGandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 378 (2018) 2078-92. https://doi.org/10.1056/NEJMoa1801005.\u003c/li\u003e\n\u003cli\u003eWest H, McCleod M, Hussein M, Morabito A, Rittmeyer A, Conter HJ, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 20 (2019) 924-37. https://doi.org/10.1016/S1470-2045(19)30167-6.\u003c/li\u003e\n\u003cli\u003eSharma P, Allison JP. The future of immune checkpoint therapy. Science. 348 (2015) 56-61. https://doi.org/10.1126/science.aaa8172.\u003c/li\u003e\n\u003cli\u003eRami-Porta R, Bolejack V, Giroux DJ, Chansky K, Crowley J, Asamura H, et al. The IASLC lung cancer staging project: the new database to inform the eighth edition of the TNM classification of lung cancer. J Thorac Oncol. 9 (2014) 1618-24. https://doi.org/10.1097/JTO.0000000000000334.\u003c/li\u003e\n\u003cli\u003eOken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 5 (1982) 649-55. \u003c/li\u003e\n\u003cli\u003eEisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 45 (2009) 228-47. https://doi.org/10.1016/j.ejca.2008.10.026.\u003c/li\u003e\n\u003cli\u003eZhou L, Xiong Y, Wang Y, Meng Y, Zhang W, Shen M, et al. A Phase IB Trial of Autologous Cytokine-Induced Killer Cells in Combination with Sintilimab, Monoclonal Antibody Against Programmed Cell Death-1, plus Chemotherapy in Patients with Advanced Non-Small-Cell Lung Cancer. Clin Lung Cancer. 23 (2022) 709-19. https://doi.org/10.1016/j.cllc.2022.07.009.\u003c/li\u003e\n\u003cli\u003eLiu L, Zhang W, Qi X, Li H, Yu J, Wei S, et al. Randomized study of autologous cytokine-induced killer cell immunotherapy in metastatic renal carcinoma. Clin Cancer Res. 18 (2012) 1751-9. https://doi.org/10.1158/1078-0432.CCR-11-2442.\u003c/li\u003e\n\u003cli\u003eLi R, Wang C, Liu L, Du C, Cao S, Yu J, et al. Autologous cytokine-induced killer cell immunotherapy in lung cancer: a phase II clinical study. Cancer Immunol Immunother. 61 (2012) 2125-33. https://doi.org/10.1007/s00262-012-1260-2.\u003c/li\u003e\n\u003cli\u003eLiu L, Gao Q, Jiang J, Zhang J, Song X, Cui J, et al. Randomized, multicenter, open-label trial of autologous cytokine-induced killer cell immunotherapy plus chemotherapy for squamous non-small-cell lung cancer: NCT01631357. Signal Transduct Target Ther. 5 (2020) 244. https://doi.org/10.1038/s41392-020-00337-x.\u003c/li\u003e\n\u003cli\u003eWahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: Evolving Considerations for PET response criteria in solid tumors. J Nucl Med. 50 Suppl 1 (2009) 122S-50S. https://doi.org/10.2967/jnumed.108.057307.\u003c/li\u003e\n\u003cli\u003eMok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 393 (2019) 1819-30. https://doi.org/10.1016/S0140-6736(18)32409-7.\u003c/li\u003e\n\u003cli\u003eReck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 375 (2016) 1823-33. https://doi.org/10.1056/NEJMoa1606774.\u003c/li\u003e\n\u003cli\u003eYang Y, Sun J, Wang Z, Fang J, Yu Q, Han B, et al. Updated Overall Survival Data and Predictive Biomarkers of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC in the Phase 3 ORIENT-11 Study. J Thorac Oncol. 16 (2021) 2109-20. https://doi.org/10.1016/j.jtho.2021.07.015.\u003c/li\u003e\n\u003cli\u003eCheng Y, Zhang L, Hu J, Wang D, Hu C, Zhou J, et al. Pembrolizumab Plus Chemotherapy for Chinese Patients With Metastatic Squamous NSCLC in KEYNOTE-407. JTO Clin Res Rep. 2 (2021) 100225. https://doi.org/10.1016/j.jtocrr.2021.100225.\u003c/li\u003e\n\u003cli\u003eGarassino MC, Gadgeel S, Speranza G, Felip E, Esteban E, Domine M, et al. Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. J Clin Oncol. 41 (2023) 1992-8. https://doi.org/10.1200/JCO.22.01989.\u003c/li\u003e\n\u003cli\u003eChu T, Zhong R, Zhong H, Zhang B, Zhang W, Shi C, et al. Phase 1b Study of Sintilimab Plus Anlotinib as First-line Therapy in Patients With Advanced NSCLC. J Thorac Oncol. 16 (2021) 643-52. https://doi.org/10.1016/j.jtho.2020.11.026.\u003cbr\u003e \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eDemographic and Disease Characteristics of Patients at Baseline.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN = 33\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e62.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eRange\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e40-73\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eGender, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e29 (87.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e4 (12.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eECOG PS, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e13 (39.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e19 (57.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eSmoking history, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eCurrent/former\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e28 (84.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eNever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e5 (15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eHistology, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eSquamous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e19 (57.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eNon-squamous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e14 (42.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eStage at diagnosis, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eIIIB/IIIC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e6 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e27 (81.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eSites of metastasis, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eLiver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e6 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eBrain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e3 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eBone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e3 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eOther\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e21 (63.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003ePD-L1 subgroups, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eTPS \u0026ge; 1%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e15 (45.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eTPS＜1%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e16 (48.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e2 (6.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: ECOG, Eastern Cooperative Oncology Group; PS, performance status score; PD-L1, programmed death ligand-1; TPS, tumor proportion score, the percentage of tumor cells with membranous programmed cell death protein ligand-1 staining.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u0026nbsp;\u003c/strong\u003eSummary of Response in The Phase IB Study.\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eITT (N=33)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSQ (N=19)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNSQ (N=14)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003eORR, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e27 (81.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e14 (73.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e13 (92.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e64.5-93.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e48.8-90.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e66.1-99.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003eDCR, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e33 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e19 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e14 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e89.4-100.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e82.4-100.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e76.8-100.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003eCR, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e2 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e2 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003eCMR, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e5 (15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e3 (15.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e2 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003ePR, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e20 (60.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e11 (57.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e9 (64.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003eSD, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e6 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e5 (26.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e1 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003eMedian time to response, months (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e1.5\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(0.7-6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e1.5\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(0.7-6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e1.7\u003c/p\u003e\n \u003cp\u003e(1.4-3.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003eMedian DOR, months\u003c/p\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e19.9\u003c/p\u003e\n \u003cp\u003e(10.5-26.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e17.9\u003c/p\u003e\n \u003cp\u003e(6.6-26.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22px;\"\u003e\n \u003cp\u003e19.9\u003c/p\u003e\n \u003cp\u003e(2.8-22.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eAbbreviations: ITT, intention to treat analysis; SQ, squamous; NSQ, non-squamous; ORR, objective response rate; CI, confidence interval; DCR, disease control rate; CR, complete response; CMR, complete metabolic response; PR, partial response; SD, stable disease; DOR, duration of response; NR, not reached; NA, not available.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e Adverse Events in The Phase IB Study.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment-Related Adverse Events\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAny Grade\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 3, 4, or 5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u003cstrong\u003enumber of patients (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eAny event\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e31 (93.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e22 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eEvent leading to discontinuation of\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 20px;\"\u003e\n \u003cp\u003e2 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 28px;\"\u003e\n \u003cp\u003e2 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eall treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eDiscontinuation of Sintilimab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e4 (12.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e4 (12.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eDiscontinuation of CIK cells\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e2 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e2 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eDiscontinuation of Chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e3 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e3 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eEvent leading to death\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eAnemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e23 (69.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eNeutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e20 (60.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e8 (24.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eLeukopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e23 (69.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e3 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eThrombocytopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e10 (30.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e2 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e21 (63.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e3 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eAlanine aminotransferase increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e7 (21.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eAspartate aminotransferase increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e4 (12.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eHypoalbuminemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e13 (39.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e17 (51.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e7 (21.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eRash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e4 (12.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eCough\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e10 (30.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003ePneumonia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e5 (15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e2 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eHypothyroidism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e11 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eAdrenal insufficiency\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e3 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eCardiomyopathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eMucostitis oral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eDysphagia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003ehyperparathyroidism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eImmune-Related Adverse Event\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAny Grade\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 3, 4, or 5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u003cstrong\u003enumber of patients (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eAny event\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e15 (45.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e4 (12.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eEvent leading to death\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eHypothyroidism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e11 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003ePneumonia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e5 (14.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e2 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eRash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e4 (11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eAdrenal insufficiency\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e3 (8.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eCough\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e2 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eCardiomyopathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003eDysphagia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 51px;\"\u003e\n \u003cp\u003ehyperparathyroidism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e1 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: CIK, cytokine-induced killer.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"NSCLC, Cytokine-Induced Killer Cell, Sintilimab, Chemotherapy, Safety, Efficacy","lastPublishedDoi":"10.21203/rs.3.rs-6139702/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6139702/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWe present 3-year results from the CCICC-002a study (ClinicalTrials.gov number: NCT03987867). Autologous CIK cells immunotherapy plus Sintilimab and chemotherapy demonstrated favorable tolerability and encouraging efficacy in previously untreated, advanced NSCLC patients. The CCICC-002a study enrolled 33 patients (34 patients were enrolled at the first analysis, 1 patient was excluded by EGFR mutation in the secondary biopsy). The media follow-up was 40.5 months (range, 38.0 to 43.0 months). By the cut-off date of October 31, 2023, 17 patients had died. Estimated 3-year OS rates was 54.4%; median OS was 37.4 months (95% CI, 27.6\u0026ndash;37.4 months). In subgroups, median OS was 27.6 months (95% CI, 13.4\u0026ndash;36.5 months) in squamous NSCLC and not reached (95% CI, 29.9 months -not reached) in non-squamous NSCLC, respectively. Estimated 3-year PFS rates were 33.8% and median PFS was 18.1 months (95% CI, 10.1\u0026ndash;24.0 months) in all patients; median PFS was 17.0 months (95% CI, 5.0\u0026ndash;24.0 months) in squamous NSCLC and 23.5 months (95% CI, 5.7 months -not reached) in non-squamous NSCLC. Median response duration was 19.9 months (95% CI, 10.5\u0026ndash;26.2); 24.2% of patients were ongoing at data cut-off; the longest response was ongoing at 51.7 months. Treatment-related AEs (TRAEs) occurred in 97% of patients and resulted in study discontinuation in 6.1%; 66.7% experienced grade 3/4 TRAE. This long-term analysis of CCICC-002a represents the longest follow-up for CIK to date and confirms the durable antitumor activity and tolerability of CIK cells therapy in combination with Sintilimab plus chemotherapy in advanced NSCLC.\u003c/p\u003e","manuscriptTitle":"Autologous Cytokine-Induced Killer (CIK) Cell Immunotherapy plus Sintilimab and Chemotherapy in Advanced Non‒Small-Cell Lung Cancer: 3-Year Outcomes From the Phase Ib CCICC-002a Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-11 08:47:19","doi":"10.21203/rs.3.rs-6139702/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-03-06T12:33:51+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-04T09:29:22+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-04T09:28:14+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2025-03-02T13:36:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"65e69ab9-6820-4942-92be-8c55275cd1f1","owner":[],"postedDate":"March 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-04-10T20:38:10+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-11 08:47:19","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6139702","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6139702","identity":"rs-6139702","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}