Novel Breakthrough in Triple Combination Therapy with Immune Checkpoint Inhibitor, Bevacizumab, and Dose-Reduced Chemotherapy for Patients with Advanced Ovarian Cancer: A Case Series Study

Novel Breakthrough in Triple Combination Therapy with Immune Checkpoint Inhibitor, Bevacizumab, and Dose-Reduced Chemotherapy for Patients with Advanced Ovarian Cancer: A Case Series 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 Case Report Novel Breakthrough in Triple Combination Therapy with Immune Checkpoint Inhibitor, Bevacizumab, and Dose-Reduced Chemotherapy for Patients with Advanced Ovarian Cancer: A Case Series Study Yu Xiang, Wenxin Huang, Jiayi Dong, Yujia Chen, Size Chen, Lijuan Shao This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8526372/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Ovarian cancer continues to be the deadliest gynecological malignancy, with surgery and chemotherapy serving as the mainstays of treatment. However, recurrence often develops within several years after initial postoperative chemotherapy due to drug resistance, and the significant toxicity associated with long-term chemotherapy markedly impairs patients’ quality of life. Consequently, there is a pressing clinical need to develop strategies that minimize chemotherapy exposure while preserving efficacy and safety. Case Presentation This study presents three cases of stage IVB ovarian serous carcinoma treated with a triple regimen combining an immune checkpoint inhibitor (ICI), bevacizumab, and chemotherapy with a planned reduction in chemotherapy cycles. All three patients completed the regimen without experiencing treatment-related grade ≥ 3 adverse events. Patient 1 achieved a postoperative complete response, Patient 2 exhibited a partial response, and Patient 3 maintained stable disease. Conclusion Over the past two decades, immunotherapy has advanced rapidly. Although its clinical response rate in ovarian cancer remains relatively low, evidence suggests that combining ICIs with targeted therapy can significantly improve outcomes. This case series offers new insights into the application of immunotherapy in advanced ovarian cancer, highlighting a potential pathway to reduce chemotherapy burden while maintaining therapeutic benefit. Advanced ovarian cancer Combination immunotherapy Dose-Reduced Chemotherapy Bevacizumab Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Background Ovarian cancer represents the most lethal gynecologic malignancy, with the majority of patients being diagnosed at advanced stages owing to the absence of specific early symptoms and effective screening strategies. In the United States, it has been estimated that approximately 19,710 new cases will be diagnosed in 2023 [ 1 ]. The cornerstone therapeutic approaches for ovarian cancer remain surgery and chemotherapy. Nevertheless, recurrence is frequently observed, and chemotherapy resistance generally emerges within several years following initial treatment [ 2 ]. Among patients receiving first-line therapy, 60–70% of those optimally debulked (residual disease 1 cm) experience relapse, contributing to a 5-year survival rate of only 45% [ 3 – 6 ]. Over the past several years, immunotherapy with immune checkpoint inhibitors (ICIs) has transformed the management of multiple solid tumors, including gynecologic malignancies other than ovarian cancer, such as endometrial and cervical cancers [ 7 – 9 ]. The underlying reasons for the limited efficacy of immunotherapy in ovarian cancer remain incompletely understood. Ovarian cancer has been characterized as a “cold tumor”, defined by an immunosuppressive tumor microenvironment (TME) and, in some cases, a paucity of tumor-associated antigens [ 10 ]. Alterations within the immune microenvironment are thought to contribute to the suboptimal immunotherapeutic responses observed in ovarian cancer. Nevertheless, preclinical and clinical investigations have revealed that chemotherapy can upregulate tumor PD-L1 expression and facilitate infiltration of tumor-infiltrating lymphocytes and natural killer cells through the exposure of latent cancer antigens, thereby eliciting localized immune activation in ovarian cancer patients [ 11 – 17 ]. Collectively, these observations indicate that chemotherapy may augment the immunogenicity of ovarian cancer and partially reverse the immunosuppressive TME [ 18 ]. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) exert pivotal roles in attenuating anti-tumor immune responses by modifying the molecular properties of tumor endothelium, thereby establishing immunological barriers. Moreover, the VEGF–VEGFR axis not only impairs the activity of antigen-presenting cells and effector T cells but also fosters an immunosuppressive milieu by promoting the proliferation of regulatory T cells (Tregs), inducing the differentiation of CD4 + T cells into Tregs, and stimulating the function of myeloid-derived suppressor cells (MDSCs) [ 19 ]. Taken together, these findings suggest that ovarian cancer patients may derive therapeutic benefit from regimens combining ICIs with anti-angiogenic agents and chemotherapeutic drugs. In this case series, three patients with stage IVB ovarian serous carcinoma treated with triple therapy consisting of ICI, bevacizumab, and dose-reduced chemotherapy are described, highlighting the potential synergistic effects of immuno-targeted chemotherapy in advanced ovarian cancer. Case presentation Case 1 In November 2023, a 51-year-old Asian female presented with a diagnosis of stage IVB ovarian serous carcinoma and multiple distant metastases at our hospital. Physical examination findings were unremarkable upon admission. Laboratory evaluation demonstrated elevated tumor markers, with CA125 and CA15-3 measuring 786.7 U/mL and 56.9 IU/mL, respectively. D-dimer increased to 4.25 µg/mL, while alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were elevated to 53 U/L and 61 U/L, respectively. Positron emission tomography–computed tomography (PET-CT) revealed (Fig. 1) a malignant ovarian mass (11.5 cm × 12.1 cm × 12.5 cm) together with multiple metastatic lesions in the pelvic and abdominal mesentery, greater omentum, hepatic capsule, splenic capsule, retroperitoneum, posterior pancreatic body, splenic hilum, left diaphragmatic dome, and right costophrenic angle, the largest measuring approximately 2.4 cm × 2.5 cm. From November 7, 2023, to February 29, 2024, Patient 1 underwent six cycles of first-line therapy consisting of cadonilimab in combination with bevacizumab, albumin-bound paclitaxel, and carboplatin. During this period, chemotherapy doses were gradually reduced, with albumin-bound paclitaxel and carboplatin decreasing from 0.3 g every day (qd) to 0.15 g qd. Follow-up PET-CT demonstrated (Fig. 1) that after six cycles of therapy, the metabolic activity of the primary ovarian lesion was markedly suppressed, with no abnormal radiotracer uptake at metastatic sites, achieving partial response (PR) (–60.6%) according to RECIST 1.1. Given that surgical criteria were met, ovarian cancer resection was performed on March 20, 2024. Postoperatively, hyperthermic intraperitoneal chemotherapy with liposomal paclitaxel combined with cisplatin was administered. Grade III bone marrow suppression developed following hyperthermic chemotherapy and was managed with granulocyte colony-stimulating factor, resulting in leukocyte recovery. Postoperative follow-up computed tomography (CT) indicated no evidence of local recurrence at the surgical site (Fig. 2) and no apparent abdominal metastases, consistent with complete response (CR). Subsequently, between April 2024 and May 2025, the patient received 12 cycles of maintenance therapy with cadonilimab combined with bevacizumab, without additional exposure to chemotherapeutic agents. Follow-up CT scans during this period revealed neither recurrence nor metastasis (Fig. 2). From baseline to the most recent treatment cycle, tumor markers CA125 and CA15-3, as well as D-dimer, ALT, and AST, gradually returned to normal values (Fig. 3). Moreover, no severe chemotherapy- or immune-related adverse events were observed throughout the course of treatment. At the most recent follow-up, the patient remained in good clinical condition with no evidence of disease recurrence. Case 2 In May 2024, a 53-year-old Asian female presented with persistent lower abdominal distension, pain, and alternating constipation/diarrhea (symptoms lasting 3 months) and was subsequently diagnosed with stage IVB ovarian serous carcinoma with multiple distant metastases at our institution. Physical examination findings were unremarkable upon admission. Laboratory analysis demonstrated elevated tumor markers, with CA125 and CA72-4 measuring 305.8 U/mL and 60.44 U/mL, respectively. D-dimer increased to 2.79 μg/mL, and AST was elevated to 41 U/L. PET-CT imaging (Fig. 4) revealed bilateral ovarian malignant tumors (4.0 cm × 5.7 cm × 4.9 cm on the left; 4.6 cm × 4.7 cm × 5.6 cm on the right), along with multiple enlarged lymph node metastases distributed along bilateral external iliac vessels, bilateral common iliac vessels, para-aortic, and para-caval regions, the largest measuring approximately 1.1 cm × 1.0 cm. Additionally, a metastatic lesion measuring 0.8 cm × 0.6 cm was identified in liver segment S8, together with peritoneal metastases, some of which involved the adjacent intestinal and bladder walls. Between May 2024 and October 2024, Patient 2 underwent eight cycles of triple combination therapy consisting of cadonilimab, bevacizumab, and albumin-bound paclitaxel plus carboplatin, integrating immunotherapy, targeted therapy, and chemotherapy. Chemotherapy dosages were progressively reduced (albumin-bound paclitaxel decreased from 0.2 g qd to 0.1 g qd; carboplatin reduced from 0.3 g qd to 0.1 g qd and was discontinued during the seventh and eighth cycles). CT re-examination in August 2024 after the fourth cycle (Fig. 5) confirmed partial response (PR, –54.8%) according to RECIST 1.1. PET-CT reassessment in September 2024 (Fig. 4) demonstrated the absence of hypermetabolic malignant lesions in bilateral ovaries, resolution of the previously visualized hypermetabolic lymph node metastases, localized strip-like peritoneal thickening in the pelvis without abnormal radiotracer uptake, suppressed metabolic activity of peritoneal metastases, and disappearance of the mildly hypermetabolic lesion at the capsular surface of liver segment S8. From November 2024 to August 2025, the patient received 10 cycles of maintenance therapy with cadonilimab plus bevacizumab, with chemotherapy completely discontinued. Follow-up CT scans during this period showed that the volume of the primary ovarian lesion and small scattered lymph nodes remained stable compared with prior imaging. From baseline to the last treatment cycle, tumor markers CA125 and CA72-4, together with D-dimer and AST, progressively normalized (Fig. 6). Moreover, no severe chemotherapy- or immune-related adverse events were observed throughout the treatment course. The patient has remained progression-free and in good condition to date. Case 3 In August 2023, a 50-year-old Asian female diagnosed with stage IVB ovarian serous carcinoma at an external hospital was admitted for further treatment. The diagnostic and therapeutic process at the outside hospital is illustrated in Figure 7. The patient presented with persistent upper abdominal distension, while physical examination findings were unremarkable upon admission. Tumor marker CA125 was elevated to 471.5 U/mL, and D-dimer increased to 20 μg/mL. PET-CT (Fig. 8) revealed multiple peritoneal metastases following ovarian cancer surgery, with a SUVmax of 10.3 and SUVave of 7.0. Several lesions infiltrated the intestinal wall, and multiple lymph node metastases were identified in the right supraclavicular region, bilateral parasternal areas, mediastinum, pelvic mesentery, bilateral external iliac vessels, retroperitoneum, and right cardiophrenic angle, the largest measuring approximately 1.5 cm × 1.0 cm. Between September 2023 and March 2024, Patient 3 underwent eight cycles of triple combination therapy consisting of sintilimab, bevacizumab, and albumin-bound paclitaxel plus carboplatin, integrating immunotherapy, targeted therapy, and chemotherapy. Chemotherapy dosages were progressively reduced: albumin-bound paclitaxel decreased from 0.3 g qd in cycle 1 to 0.1 g qd in cycles 7–8; carboplatin was reduced from 0.2 g in cycle 1 to 0.1 g in cycles 6–7; and only albumin-bound paclitaxel was retained in cycle 8. After eight cycles, PET-CT reassessment (Fig. 8) demonstrated suppression of most peritoneal metastatic lesions (SUVmax 5.4, SUVave 3.2), disappearance of multiple lymph node metastases, and stable disease (SD) according to RECIST 1.1 criteria. From baseline to the last treatment cycle, CA125 and D-dimer progressively normalized (Fig. 9). Moreover, no severe chemotherapy-related adverse events were recorded during therapy. However, hypothyroidism occurred as an immune-related adverse event in cycles 7 and 8, graded G1 and G2, respectively (Fig. 9). The patient was lost to follow-up after the eighth cycle of treatment, and her current status is unknown. Treatment-related adverse reactions and observations (1) Hypothyroidism Hypothyroidism is the most frequent endocrine toxicity induced by ICIs, occurring in 10%–20% of treated patients and typically persisting after discontinuation of ICI therapy [20]. Thyroid dysfunction related to ICIs generally emerges approximately 6 weeks after initiation of treatment, although onset may occur at any stage during therapy. The underlying mechanism remains uncertain, but it is considered to result from autoimmune reactions secondary to blockade of physiological immune regulatory pathways [21, 22]. In this case, isolated elevation of TSH was detected in patient 3 following the seventh cycle of combination therapy (Fig. 9), consistent with grade G1 ICI-related hypothyroidism. After the eighth cycle, laboratory evaluation demonstrated elevated TSH accompanied by decreased T3 and T4 levels (Fig. 9), meeting the criteria for grade G2 ICI-related hypothyroidism and necessitating thyroid hormone replacement therapy. Following initiation of oral thyroid hormone supplementation, hypothyroid manifestations were effectively controlled. (2) Hepatic dysfunction During treatment, transient elevations of transaminases were documented in both Patient 1 and Patient 2 (Fig. 3 and Fig. 6). With progressive reduction of chemotherapy dosages and timely administration of hepatoprotective agents, transaminase levels normalized. After transition to the maintenance phase with ICIs plus bevacizumab, without further chemotherapy exposure, no recurrence of hepatic dysfunction was observed. These findings suggest that regimens incorporating ICIs and bevacizumab with reduced chemotherapy may substantially diminish chemotherapy-related toxicity and enhance the tolerability of long-term therapy. The hepatic dysfunction was attributed to chemotherapy, while immune-related hepatitis was not considered at this stage. Discussion and conclusion The clinical management of advanced ovarian cancer has long been hindered by the dual challenges of limited therapeutic efficacy and treatment-related toxicities. Most patients experience recurrence after initial surgical intervention due to chemotherapy resistance, and prolonged chemotherapy further exacerbates quality of life by inducing bone marrow suppression and liver dysfunction. Therefore, the development of new strategies capable of overcoming resistance, reducing toxicity, and optimizing efficacy is of paramount importance. This case series represents the first report demonstrating the promising outcomes of a combination therapy involving ICI, bevacizumab, and dose-reduced chemotherapy in advanced ovarian cancer, showing both good efficacy and manageable safety, thereby offering a novel approach to address the aforementioned challenges. The immunosuppressive tumor microenvironment in ovarian cancer typically manifests as insufficient T-cell infiltration and an enrichment of immunosuppressive cells, such as regulatory T cells (Tregs). Monotherapy with ICI alone is often inadequate in activating effective anti-tumor immunity. The vascular endothelial growth factor (VEGF) pathway plays a critical role in the immune suppression associated with ovarian cancer by promoting abnormal angiogenesis, restricting T-cell infiltration, inhibiting effector T-cell function, and enhancing Treg activity[ 23 ]. The addition of bevacizumab, in theory, generates a potent synergistic effect with ICIs: bevacizumab normalizes the tumor vasculature, thereby improving T-cell delivery to the tumor and creating a more favorable microenvironment for T-cell activity, while ICIs ensure the full activation of these T-cells, thereby enhancing their ability to efficiently target and kill tumor cells. This "targeting + immunotherapy" combinatorial strategy may provide a key mechanism for overcoming the immunosuppressive microenvironment of ovarian cancer. Moreover, chemotherapy in this regimen not only exerts direct cytotoxic effects but may also induce immunogenic cell death, thereby releasing tumor antigens and providing a "fuel" for ICI-driven T-cell responses. Based on previous real-world research evidence, we have summarized and applied dose-reduced chemotherapy principles for advanced cancer patients, particularly those with poor tolerance to standard doses. The core of these principles lies in implementing a "risk-adaptive dose adjustment" and a "dynamic, stepwise management" strategy, aiming to optimize the balance between efficacy and safety. Specifically, this involves: Risk-adaptive initial dosing: At the start of treatment, a pre-set dose reduction is applied. For albumin-bound paclitaxel, the starting dose (200 mg or 300 mg) is used, which is approximately 50%–80% of the standard dose. For carboplatin, the starting dose is adjusted to 50% or lower of the AUC = 5-calculated dose, primarily to avoid the risk of synergistic toxicity. Dynamic stepwise dose modulation: During the treatment course, dose reductions are implemented dynamically and stepwise based on the patient's tolerance. With the reduction of chemotherapy drugs, selective single-agent chemotherapy strategies may be employed to achieve the optimal individualized tolerable dose, ensuring both the continuity and safety of the treatment. This principle focuses on maintaining the ongoing benefit of antitumor treatment in vulnerable populations through refined dose management. Notably, by employing a "dose-reduced chemotherapy" strategy, we successfully minimized the cumulative toxicity of chemotherapy while achieving significant clinical efficacy. Patients 1 and 2 experienced only transient and reversible transaminase level elevations, which resolved with the reduction of chemotherapy drugs and the management with hepatoprotective medications, demonstrating the advantages of this approach in maintaining long-term treatment tolerability. When comparing the efficacy of this regimen with previous ICI-based therapies, the potential of this triple combination therapy becomes even more apparent. For instance, in the JAVELIN Ovarian 200 trial, avelumab (anti-PD-L1) monotherapy or its combination with chemotherapy did not significantly improve overall survival (OS) or progression-free survival (PFS) in platinum-resistant or refractory ovarian cancer[ 24 ]. Other studies investigating ICI combinations with targeted therapies, such as PARP inhibitors or VEGFR-TKIs, have shown moderate activity, with overall response rates (ORR) generally ranging from 30% to 50%[ 25 ]. In contrast, the three patients in this case series treated with the triple regimen achieved a remarkable 66.7% ORR and 100% disease control rate (DCR), with one patient achieving a postoperative complete response (CR) and maintaining long-term remission. These results are highly encouraging. Notably, the safety profile of this regimen was generally manageable, with only one patient experiencing grade 1/2 immune-related hypothyroidism, a known, manageable adverse event associated with ICIs, and no severe complications such as colitis or hypophysitis, which are commonly associated with CTLA-4 inhibition. Regarding long-term outcomes, both patient 1 and patient 2 have maintained continued remission to date, demonstrating the potential for durable disease control with this triple regimen. Patient 3, despite achieving stable disease, was lost to follow-up after cycle 8. However, this study has inherent limitations, including a small sample size, a retrospective design, and the absence of direct comparisons. Nevertheless, these preliminary findings strongly suggest that the combination of ICI, bevacizumab, and dose-reduced chemotherapy, through a multi-modal synergistic mechanism involving "immune activation + microenvironment remodeling (bevacizumab) + antigen release and toxicity reduction (dose-reduced chemotherapy)," offers a promising new therapeutic approach for advanced ovarian cancer, particularly for patients with traditionally "cold tumors." Conclusion In conclusion, our preliminary findings suggest that the triple regimen of ICI, bevacizumab, and dose-reduced chemotherapy may constitute a promising therapeutic strategy for stage IVB ovarian cancer. This approach was associated with a low incidence of adverse events and favorable tolerability, potentially offering an effective treatment option for patients with advanced disease. Incorporation of dose-reduced chemotherapy appears to reduce toxicity and mitigate the risk of drug resistance, thereby providing a therapeutic alternative that balances efficacy, tolerability, and long-term management. These preliminary findings warrant validation in large-scale clinical trials to further assess novel strategies integrating immunotherapy, targeted therapy, and chemotherapy, to improve survival outcomes in advanced ovarian cancer. Abbreviations ICI: Immune Checkpoint Inhibitor VEGF: Vascular Endothelial Growth Factor VEGFR: Vascular Endothelial Growth Factor Receptor TME: Tumor Microenvironment Tregs: Regulatory T Cells MDSCs: Myeloid-Derived Suppressor Cells CA125: Cancer Antigen 125 CA15-3: Cancer Antigen 15-3 CA72-4: Cancer Antigen 72-4 ALT: Alanine Aminotransferase AST: Aspartate Aminotransferase PET-CT: Positron emission tomography–computed tomography CT: Computed Tomography PR: Partial Response CR: Complete Response SD: Stable Disease OS: Overall Survival PFS: Progression-Free Survival ORR: Overall Response Rate DCR: Disease Control Rate AUC: Area Under the Curve G1/G2: Grade 1/Grade 2 Declarations Ethics approval and consent to participate This study was approved by the Ethics Committee of The First Affiliated Hospital of Guangdong Pharmaceutical University on September 18, 2025. The ethics committee reviewed and approved the study protocol, informed consent forms, and all related documents via expedited review. The study was conducted in accordance with the ethical standards of the institutional research committee and the principles of the Declaration of Helsinki. Written informed consent was obtained from all individual participants included in the study. This study is subject to an annual continuing review by the ethics committee. Consent for publication Written informed consent for the publication of their personal clinical details (e.g., age, laboratory indicators) and identifying medical images (e.g., PET-CT scans, CT scans) included in this manuscript was obtained from all individual participants. Availability of data and materials All data generated or analyzed during this study are included in this manuscript. Competing Interests The authors declare no competing interests. Funding This study was funded by the General Program of the Youth Fund Project of the National Natural Science Foundation of China (82203874), the National Natural Science Foundation of China (32271225), and the Special Project of the International Science and Technology Cooperation Program of the Guangdong Provincial Science and Technology Plan (20190510). We also acknowledge the support from the Innovative CAR-NK Therapy Research Team. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Authors' contributions Yu Xiang: Writing – original draft, Writing – review & editing. Wenxin Huang: Writing – review & editing. Jiayi Dong: Formal analysis. Yujia Chen: Formal analysis. Size Chen: Conceptualization, Formal analysis. Lijuan Shao: Conceptualization, Formal analysis, Writing – review & editing. All authors read and approved the final manuscript. Acknowledgements We acknowledge the support from the Innovative CAR-NK Therapy Research Team of Guangdong Pharmaceutical University. We thank the Ethics Committee of The First Affiliated Hospital of Guangdong Pharmaceutical University for their review and approval of the study protocol, and are grateful to the participants included in this study for their cooperation and contribution to the research. References Colombo I, Karakasis K, Suku S, Oza AM. Chasing immune checkpoint inhibitors in ovarian cancer: Novel combinations and biomarker discovery. Cancers. 2023;15(12):3220. DOI: 10.3390/cancers15123220 Kaur P, Singh SK, Mishra MK, Singh S, Singh R. Nanotechnology for boosting ovarian cancer immunotherapy. Journal of Ovarian Research. 2024;17(1):202. Foley OW, Rauh-Hain JA, Del Carmen MG. Recurrent epithelial ovarian cancer: an update on treatment. Oncology. 2013;27(4):288. Cortez AJ, Tudrej P, Kujawa KA, Lisowska KM. Advances in ovarian cancer therapy. Cancer chemotherapy and pharmacology. 2018;81(1):17-38. Baldwin LA, Huang B, Miller RW, Tucker T, Goodrich ST, Podzielinski I, et al. Ten-year relative survival for epithelial ovarian cancer. Obstetrics & Gynecology. 2012;120(3):612-8. Gogineni V, Morand S, Staats H, Royfman R, Devanaboyina M, Einloth K, et al. Current ovarian cancer maintenance strategies and promising new developments. Journal of Cancer. 2021;12(1):38. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359(6382):1350-5. Makker V, Colombo N, Casado Herráez A, Santin AD, Colomba E, Miller DS, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. New England Journal of Medicine. 2022;386(5):437-48. Colombo N, Dubot C, Lorusso D, Caceres MV, Hasegawa K, Shapira-Frommer R, et al. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. New England Journal of Medicine. 2021;385(20):1856-67. Galon J, Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nature reviews Drug discovery. 2019;18(3):197-218. Lo CS, Sanii S, Kroeger DR, Milne K, Talhouk A, Chiu DS, et al. Neoadjuvant chemotherapy of ovarian cancer results in three patterns of tumor-infiltrating lymphocyte response with distinct implications for immunotherapy. Clinical Cancer Research. 2017;23(4):925-34. Böhm S, Montfort A, Pearce OM, Topping J, Chakravarty P, Everitt GL, et al. Neoadjuvant chemotherapy modulates the immune microenvironment in metastases of tubo-ovarian high-grade serous carcinoma. Clinical Cancer Research. 2016;22(12):3025-36. Mesnage S, Auguste A, Genestie C, Dunant A, Pain E, Drusch F, et al. Neoadjuvant chemotherapy (NACT) increases immune infiltration and programmed death-ligand 1 (PD-L1) expression in epithelial ovarian cancer (EOC). Annals of oncology. 2017;28(3):651-7. Kim H-S, Kim J-Y, Lee YJ, Kim SH, Lee J-Y, Nam EJ, et al. Expression of programmed cell death ligand 1 and immune checkpoint markers in residual tumors after neoadjuvant chemotherapy for advanced high-grade serous ovarian cancer. Gynecologic Oncology. 2018;151(3):414-21. Jiménez-Sánchez A, Cybulska P, Mager KL, Koplev S, Cast O, Couturier D-L, et al. Unraveling tumor–immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy. Nature Genetics. 2020;52(6):582-93. Peng J, Hamanishi J, Matsumura N, Abiko K, Murat K, Baba T, et al. Chemotherapy induces programmed cell death-ligand 1 overexpression via the nuclear factor-κB to foster an immunosuppressive tumor microenvironment in ovarian cancer. Cancer research. 2015;75(23):5034-45. Ghaffari A, Peterson N, Khalaj K, Vitkin N, Robinson A, Francis J-A, et al. STING agonist therapy in combination with PD-1 immune checkpoint blockade enhances response to carboplatin chemotherapy in high-grade serous ovarian cancer. British journal of cancer. 2018;119(4):440-9. Liu M, Tayob N, Penter L, Sellars M, Tarren A, Chea V, et al. Improved T-cell immunity following neoadjuvant chemotherapy in ovarian cancer. Clinical Cancer Research. 2022;28(15):3356-66. Rahma OE, Hodi FS. The intersection between tumor angiogenesis and immune suppression. Clinical Cancer Research. 2019;25(18):5449-57. Wright JJ, Powers AC, Johnson DB. Endocrine toxicities of immune checkpoint inhibitors. Nature Reviews Endocrinology. 2021;17(7):389-99. Tan MH, Iyengar R, Mizokami-Stout K, Yentz S, MacEachern MP, Shen LY, et al. Spectrum of immune checkpoint inhibitors-induced endocrinopathies in cancer patients: a scoping review of case reports. Clinical diabetes and endocrinology. 2019;5(1):1. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. New England Journal of Medicine. 2018;378(2):158-68. Ghisoni E, Morotti M, Sarivalasis A, Grimm AJ, Kandalaft L, Laniti DD, et al. Immunotherapy for ovarian cancer: towards a tailored immunophenotype-based approach. Nature Reviews Clinical Oncology. 2024;21(11):801-17. Pujade-Lauraine E, Fujiwara K, Ledermann JA, Oza AM, Kristeleit R, Ray-Coquard I-L, et al. Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): an open-label, three-arm, randomised, phase 3 study. 2021;22(7):1034-46. Lee J-M, Cimino-Mathews A, Peer CJ, Zimmer A, Lipkowitz S, Annunziata CM, et al. Safety and clinical activity of the programmed death-ligand 1 inhibitor durvalumab in combination with poly (ADP-ribose) polymerase inhibitor olaparib or vascular endothelial growth factor receptor 1-3 inhibitor cediranib in women's cancers: a dose-escalation, phase I study. 2017;35(19):2193-202. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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-8526372","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":578281013,"identity":"0b7c87b0-2062-4d25-97fd-5ee29652c42a","order_by":0,"name":"Yu Xiang","email":"","orcid":"","institution":"The First Affiliated Hospital of Guangdong Pharmaceutical University","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Xiang","suffix":""},{"id":578281014,"identity":"3933ab45-b954-4fdd-96f1-c9a2ae7981bd","order_by":1,"name":"Wenxin Huang","email":"","orcid":"","institution":"The First Affiliated Hospital of Guangdong Pharmaceutical University","correspondingAuthor":false,"prefix":"","firstName":"Wenxin","middleName":"","lastName":"Huang","suffix":""},{"id":578281015,"identity":"66e38c65-13ae-4b7f-af8d-c53b1cbf2f33","order_by":2,"name":"Jiayi Dong","email":"","orcid":"","institution":"The First Affiliated Hospital of Guangdong Pharmaceutical University","correspondingAuthor":false,"prefix":"","firstName":"Jiayi","middleName":"","lastName":"Dong","suffix":""},{"id":578281016,"identity":"0dc78876-af52-4f6f-9ac2-3b2b45d0f124","order_by":3,"name":"Yujia Chen","email":"","orcid":"","institution":"The First Affiliated Hospital of Guangdong Pharmaceutical University","correspondingAuthor":false,"prefix":"","firstName":"Yujia","middleName":"","lastName":"Chen","suffix":""},{"id":578281017,"identity":"04de781c-6ddf-49cf-b5f5-a2419b7bff36","order_by":4,"name":"Size Chen","email":"","orcid":"","institution":"The First Affiliated Hospital of Guangdong Pharmaceutical University","correspondingAuthor":false,"prefix":"","firstName":"Size","middleName":"","lastName":"Chen","suffix":""},{"id":578281018,"identity":"e4e84116-a487-462f-a082-cf3694c6ddc7","order_by":5,"name":"Lijuan Shao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8ElEQVRIiWNgGAWjYDACCSB+YMAGJJkPMPCAhRKI0JIA1sKWQIoWMIvHgDgt8rObHz5IKOBL7J/d8/nF2x2HGfjZcwwYfu7ArcXgzjFjA6DDEmfcObvNcu6ZwwySPW8MGHvP4NEikWAmAdLScCN3mzFv22EGgxs5BsyMbXgcNiP9G1jL/Bs5z8Ba7AlpYbiRA7Flw40c5sdgWyQIaAE6oxjkF+ONN9LMGOeeSeeROPOs4GAvfodtfPDhzzHZeTeSH394u8Najr89eeODn/gcBgHHQASbBGMDJGoOENTAwFADIpg/ALWMglEwCkbBKMAAAHe/VXQhVqqLAAAAAElFTkSuQmCC","orcid":"","institution":"The First Affiliated Hospital of Guangdong Pharmaceutical University","correspondingAuthor":true,"prefix":"","firstName":"Lijuan","middleName":"","lastName":"Shao","suffix":""}],"badges":[],"createdAt":"2026-01-06 04:08:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8526372/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8526372/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":100952270,"identity":"9a268a06-daa2-4bb5-a145-790e55be64e8","added_by":"auto","created_at":"2026-01-23 07:12:24","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2883393,"visible":true,"origin":"","legend":"","description":"","filename":"CaseSeries.docx","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/5f307cefb3377677df202852.docx"},{"id":100930006,"identity":"627cd57e-44c3-4014-a76a-9dd9fc3bf2f1","added_by":"auto","created_at":"2026-01-23 00:39:25","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":7373,"visible":true,"origin":"","legend":"","description":"","filename":"acd6dc2ffbd14d5690c1cf6b0e2ada3d.json","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/85535a0faff9742c10713f39.json"},{"id":100929993,"identity":"0825d463-14c3-41a8-aae6-02277f496acd","added_by":"auto","created_at":"2026-01-23 00:39:24","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":82914,"visible":true,"origin":"","legend":"","description":"","filename":"acd6dc2ffbd14d5690c1cf6b0e2ada3d1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/000deee106b677c130635ce3.xml"},{"id":100929983,"identity":"ba9d24cf-81fe-49d6-95d9-1cffa8936aa7","added_by":"auto","created_at":"2026-01-23 00:39:22","extension":"png","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":608543,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/97549bbab94acc42ff479d6d.png"},{"id":100929982,"identity":"a8c76d51-aec0-4e75-addc-cf8190bc4ce8","added_by":"auto","created_at":"2026-01-23 00:39:22","extension":"png","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":167312,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/38fe93bef700a23b1bedfdb1.png"},{"id":100929999,"identity":"2f6ec8d9-e3f9-4e4a-94f0-317d24ac07e7","added_by":"auto","created_at":"2026-01-23 00:39:25","extension":"png","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":183812,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/dede123b1f135f21e071c0df.png"},{"id":100950999,"identity":"edd30b6d-5d03-4d00-b4da-e837e8f0bcbf","added_by":"auto","created_at":"2026-01-23 07:09:48","extension":"png","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":682738,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/b304116422f34c61c07e2041.png"},{"id":100952249,"identity":"e5e7d73f-da35-485b-b870-c136824ac5fb","added_by":"auto","created_at":"2026-01-23 07:12:21","extension":"png","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":180061,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/474197245811c9b8f1f5001a.png"},{"id":100930064,"identity":"da3f9b3a-8ff0-45dd-91ec-217e5a3d4283","added_by":"auto","created_at":"2026-01-23 00:39:27","extension":"png","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":143962,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/602002e9af8e895bafa782eb.png"},{"id":100929987,"identity":"edd09599-c6d6-4bc5-b383-2ba83f51493a","added_by":"auto","created_at":"2026-01-23 00:39:23","extension":"png","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":131717,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/be8ae5a3034afe9e97678017.png"},{"id":100929991,"identity":"07de0045-b3d1-4fa7-899f-becbd0769987","added_by":"auto","created_at":"2026-01-23 00:39:23","extension":"png","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":571954,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage8.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/94d1c6a17bd98b89ccd6402b.png"},{"id":100930035,"identity":"09f6a414-1d1c-4c58-ba9f-d6051b4a08cb","added_by":"auto","created_at":"2026-01-23 00:39:26","extension":"jpeg","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":242238,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage9.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/9389bdb5b187a90ea625cd87.jpeg"},{"id":100930087,"identity":"c7e6c9b5-e60a-40f5-b911-faf1a0bfe09e","added_by":"auto","created_at":"2026-01-23 00:39:29","extension":"png","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":78940,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/6407930c3815458f3709cfca.png"},{"id":100929995,"identity":"9c326580-1e85-47cc-88a9-a8155cda76cf","added_by":"auto","created_at":"2026-01-23 00:39:24","extension":"png","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":33576,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/47e0a55221d5441b87bb1ecb.png"},{"id":100930013,"identity":"01f3e433-f944-4509-bb90-24efeaa0b8a5","added_by":"auto","created_at":"2026-01-23 00:39:26","extension":"png","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":37852,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/debf996eff7f50dc23e780a8.png"},{"id":100930065,"identity":"6fc3c03f-6229-486a-9216-cf402a2310e3","added_by":"auto","created_at":"2026-01-23 00:39:27","extension":"png","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":94636,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/2a041e1db270bc7e5206828e.png"},{"id":100930055,"identity":"ce63799a-a953-4adf-b916-4db80b167d7a","added_by":"auto","created_at":"2026-01-23 00:39:27","extension":"png","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":38465,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/adef304c6f124845f0743e74.png"},{"id":100930005,"identity":"a52a08e3-c6b3-45fe-91d4-2db73d6bb750","added_by":"auto","created_at":"2026-01-23 00:39:25","extension":"png","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":28478,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/9433578d9a70c0f7ff900551.png"},{"id":100929988,"identity":"7aea4e1d-53cb-46bc-8d05-6417f1597f0e","added_by":"auto","created_at":"2026-01-23 00:39:23","extension":"png","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":45582,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/e8386932961f0fe92887dcb0.png"},{"id":100930011,"identity":"69393cc3-3fff-4d83-a7c8-e05ab4e9f11b","added_by":"auto","created_at":"2026-01-23 00:39:25","extension":"png","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":74823,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage8.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/125b02ba6c0c120608927efa.png"},{"id":100930045,"identity":"bf4074c8-e4f8-48ab-b956-23eaeee703e8","added_by":"auto","created_at":"2026-01-23 00:39:27","extension":"png","order_by":20,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":62929,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage9.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/16ed425eaec1e2e8151d8d9c.png"},{"id":100929972,"identity":"eec2a18f-6901-4e70-851e-23898b31ba50","added_by":"auto","created_at":"2026-01-23 00:39:21","extension":"xml","order_by":21,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":81643,"visible":true,"origin":"","legend":"","description":"","filename":"acd6dc2ffbd14d5690c1cf6b0e2ada3d1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/3d62497edc7955e6caffebcd.xml"},{"id":100929975,"identity":"deb0e1f2-a47e-4c29-9c90-c8283a57e8e6","added_by":"auto","created_at":"2026-01-23 00:39:22","extension":"html","order_by":22,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":91164,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/07ebb0d87c61f8f02d0ec413.html"},{"id":100929980,"identity":"4e2146cd-d404-4331-b248-19bac82880b1","added_by":"auto","created_at":"2026-01-23 00:39:22","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":613812,"visible":true,"origin":"","legend":"\u003cp\u003eFluorodeoxyglucose positron emission tomography–computed tomography (FDG-PET/CT) images of patient 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A)\u003c/strong\u003e Pre-treatment scan (November 2023) shows a large irregular cystic-solid pelvic mass and extensive metastatic deposits throughout the peritoneum and abdominal cavity.\u003cbr\u003e\n \u003cstrong\u003e(B)\u003c/strong\u003e Scan after six cycles of therapy (February 2024) demonstrates a marked reduction in the size and metabolic activity of the primary mass and metastatic lesions.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/0500d47e5e32d35de8d6aac7.png"},{"id":100930074,"identity":"ac0bb048-f5a6-463e-b0e1-ec517fb9a6ed","added_by":"auto","created_at":"2026-01-23 00:39:28","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":168897,"visible":true,"origin":"","legend":"\u003cp\u003eCT scans of patient 1 demonstrated the complete disappearance of the primary ovarian carcinoma lesion postoperatively. Serial postoperative CT examinations revealed no radiological evidence of local recurrence or distant metastasis.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/ba2dfe74c2f5214941bfeec5.png"},{"id":100930085,"identity":"10272a45-0fe4-45c6-97ed-6dd23c38ee22","added_by":"auto","created_at":"2026-01-23 00:39:29","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":183812,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in indicators of patient 1. (A) Changes in tumor marker CA125. (B) Changes in tumor marker CA15-3. (C) Changes in D-dimer. (D) Changes in ALT and AST.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/a8575d77a5422f1cdc831c14.png"},{"id":100929985,"identity":"43503c0a-b92c-46c8-af6b-7582d421a80f","added_by":"auto","created_at":"2026-01-23 00:39:22","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":687313,"visible":true,"origin":"","legend":"\u003cp\u003eFDG-PET/CT images of patient 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A)\u003c/strong\u003e Pre-treatment scan (May 2024) reveals irregular, abnormal cystic-solid mass shadows are visible in the bilateral adnexal regions within the pelvic cavity, with multiple metastatic lesions in the para-aortic lymph nodes, and some metastatic lesions involving the intestinal wall.\u003cbr\u003e\n \u003cstrong\u003e(B)\u003c/strong\u003e Scan prior to the seventh treatment cycle (September 2024) showed normalization of bilateral ovarian morphology, with no hypermetabolic lymph node lesions and intestinal wall metastases detected.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/8e1a5892d87b271f85d8c8ea.png"},{"id":100930012,"identity":"914cecda-f5e8-4039-9acc-b89708eedb22","added_by":"auto","created_at":"2026-01-23 00:39:25","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":190145,"visible":true,"origin":"","legend":"\u003cp\u003eCT images of patient 2 after four cycles: ovarian carcinoma lesions were markedly reduced compared with baseline (–54.8%).\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/212c4ba9ecb592810845c99d.png"},{"id":100929967,"identity":"eb27a5f7-4754-4088-a44a-440a775ea6a1","added_by":"auto","created_at":"2026-01-23 00:39:19","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":143962,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in the indicators of patient 2. (A) Changes in tumor marker CA125. (B) Changes in tumor marker CA72-4. (C) Changes in D-dimer. (D) Changes in AST.\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/c05265a3f270d3450a10afb6.png"},{"id":100929981,"identity":"6c43ed42-bbe0-4a45-8344-a49dfa69584c","added_by":"auto","created_at":"2026-01-23 00:39:22","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":131717,"visible":true,"origin":"","legend":"\u003cp\u003eTreatment course of patient 3 at the external hospital.\u003c/p\u003e","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/1e6f8a03c1a33358e3356b21.png"},{"id":100930003,"identity":"589e463f-cf21-4cb5-8668-058681274618","added_by":"auto","created_at":"2026-01-23 00:39:25","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":576382,"visible":true,"origin":"","legend":"\u003cp\u003eFDG-PET/CT images of patient 3.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e（A）\u003c/strong\u003ePre-treatment scan (August 2023) shows that after ovarian cancer surgery and prior to subsequent treatment, multiple metastatic lesions are present in the hepatic capsule and mesentery, as well as multiple lymph node metastatic lesions in the sternum regions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e（B）\u003c/strong\u003eScan at the 8th treatment cycle (March 2024) shows that most of the metastatic lesions in the hepatic capsule and mesentery are significantly suppressed after treatment, with reduced scope and decreased metabolism compared with the previous scan; The previously noted lymph node metastatic lesions have basically disappeared from imaging.\u003c/p\u003e","description":"","filename":"floatimage8.png","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/4bc5dc4e97ced298cbb902a9.png"},{"id":100930093,"identity":"e2f72373-84c5-463a-9565-ce0961347047","added_by":"auto","created_at":"2026-01-23 00:39:30","extension":"jpeg","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":242238,"visible":true,"origin":"","legend":"\u003cp\u003eDynamic changes in tumor, coagulation, and thyroid parameters of patient 3. (A) CA125. (B) D-dimer. (C) Serum levels of free triiodothyronine (FT3, blue) and free thyroxine (FT4, orange). (D) Serum levels of triiodothyronine (T3, blue) and thyroxine (T4, orange). (E) Serum thyroid-stimulating hormone (TSH, blue).\u003c/p\u003e","description":"","filename":"floatimage9.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/0abe9ed6637826406cb6b929.jpeg"},{"id":105455162,"identity":"efb73484-f928-43f4-8ad8-74f071afc74e","added_by":"auto","created_at":"2026-03-26 08:58:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3621385,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8526372/v1/87063f0a-07b3-406d-936f-dd096e46a09c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Novel Breakthrough in Triple Combination Therapy with Immune Checkpoint Inhibitor, Bevacizumab, and Dose-Reduced Chemotherapy for Patients with Advanced Ovarian Cancer: A Case Series Study","fulltext":[{"header":"Background","content":"\u003cp\u003eOvarian cancer represents the most lethal gynecologic malignancy, with the majority of patients being diagnosed at advanced stages owing to the absence of specific early symptoms and effective screening strategies. In the United States, it has been estimated that approximately 19,710 new cases will be diagnosed in 2023 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The cornerstone therapeutic approaches for ovarian cancer remain surgery and chemotherapy. Nevertheless, recurrence is frequently observed, and chemotherapy resistance generally emerges within several years following initial treatment [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Among patients receiving first-line therapy, 60\u0026ndash;70% of those optimally debulked (residual disease\u0026thinsp;\u0026lt;\u0026thinsp;1 cm) and 80\u0026ndash;85% of those suboptimally debulked (residual disease\u0026thinsp;\u0026gt;\u0026thinsp;1 cm) experience relapse, contributing to a 5-year survival rate of only 45% [\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOver the past several years, immunotherapy with immune checkpoint inhibitors (ICIs) has transformed the management of multiple solid tumors, including gynecologic malignancies other than ovarian cancer, such as endometrial and cervical cancers [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The underlying reasons for the limited efficacy of immunotherapy in ovarian cancer remain incompletely understood. Ovarian cancer has been characterized as a \u0026ldquo;cold tumor\u0026rdquo;, defined by an immunosuppressive tumor microenvironment (TME) and, in some cases, a paucity of tumor-associated antigens [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Alterations within the immune microenvironment are thought to contribute to the suboptimal immunotherapeutic responses observed in ovarian cancer. Nevertheless, preclinical and clinical investigations have revealed that chemotherapy can upregulate tumor PD-L1 expression and facilitate infiltration of tumor-infiltrating lymphocytes and natural killer cells through the exposure of latent cancer antigens, thereby eliciting localized immune activation in ovarian cancer patients [\u003cspan additionalcitationids=\"CR12 CR13 CR14 CR15 CR16\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Collectively, these observations indicate that chemotherapy may augment the immunogenicity of ovarian cancer and partially reverse the immunosuppressive TME [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) exert pivotal roles in attenuating anti-tumor immune responses by modifying the molecular properties of tumor endothelium, thereby establishing immunological barriers. Moreover, the VEGF\u0026ndash;VEGFR axis not only impairs the activity of antigen-presenting cells and effector T cells but also fosters an immunosuppressive milieu by promoting the proliferation of regulatory T cells (Tregs), inducing the differentiation of CD4\u0026thinsp;+\u0026thinsp;T cells into Tregs, and stimulating the function of myeloid-derived suppressor cells (MDSCs) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Taken together, these findings suggest that ovarian cancer patients may derive therapeutic benefit from regimens combining ICIs with anti-angiogenic agents and chemotherapeutic drugs. In this case series, three patients with stage IVB ovarian serous carcinoma treated with triple therapy consisting of ICI, bevacizumab, and dose-reduced chemotherapy are described, highlighting the potential synergistic effects of immuno-targeted chemotherapy in advanced ovarian cancer.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003e\u003cstrong\u003eCase 1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn November 2023, a 51-year-old Asian female presented with a diagnosis of stage IVB ovarian serous carcinoma and multiple distant metastases\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eat our hospital. Physical examination findings were unremarkable upon admission. Laboratory evaluation demonstrated elevated tumor markers, with CA125 and CA15-3 measuring 786.7 U/mL and 56.9 IU/mL, respectively. D-dimer increased to 4.25 \u0026micro;g/mL, while alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were elevated to 53 U/L and 61 U/L, respectively. Positron emission tomography\u0026ndash;computed tomography (PET-CT) revealed (Fig. 1) a malignant ovarian mass (11.5 cm \u0026times; 12.1 cm \u0026times; 12.5 cm) together with multiple metastatic lesions in the pelvic and abdominal mesentery, greater omentum, hepatic capsule, splenic capsule, retroperitoneum, posterior pancreatic body, splenic hilum, left diaphragmatic dome, and right costophrenic angle, the largest measuring approximately 2.4 cm \u0026times; 2.5 cm.\u003c/p\u003e\n\u003cp\u003eFrom November 7, 2023, to February 29, 2024, Patient 1 underwent six cycles of first-line therapy consisting of cadonilimab in combination with bevacizumab, albumin-bound paclitaxel, and carboplatin. During this period, chemotherapy doses were gradually reduced, with albumin-bound paclitaxel and carboplatin decreasing from 0.3 g every day (qd) to 0.15 g qd. Follow-up PET-CT demonstrated (Fig. 1) that after six cycles of therapy, the metabolic activity of the primary ovarian lesion was markedly suppressed, with no abnormal radiotracer uptake at metastatic sites, achieving partial response (PR) (\u0026ndash;60.6%) according to RECIST 1.1. Given that surgical criteria were met, ovarian cancer resection was performed on March 20, 2024. Postoperatively, hyperthermic intraperitoneal chemotherapy with liposomal paclitaxel combined with cisplatin was administered. Grade III bone marrow suppression developed following hyperthermic chemotherapy and was managed with granulocyte colony-stimulating factor, resulting in leukocyte recovery. Postoperative follow-up computed tomography (CT) indicated no evidence of local recurrence at the surgical site (Fig. 2) and no apparent abdominal metastases, consistent with complete response (CR). Subsequently, between April 2024 and May 2025, the patient received 12 cycles of maintenance therapy with cadonilimab combined with bevacizumab, without additional exposure to chemotherapeutic agents. Follow-up CT scans during this period revealed neither recurrence nor metastasis (Fig. 2). From baseline to the most recent treatment cycle, tumor markers CA125 and CA15-3, as well as D-dimer, ALT, and AST, gradually returned to normal values (Fig. 3). Moreover, no severe chemotherapy- or immune-related adverse events were observed throughout the course of treatment.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eAt the most recent follow-up, the patient remained in good clinical condition with no evidence of disease recurrence.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn May 2024, a 53-year-old Asian female presented with persistent lower abdominal distension, pain, and alternating constipation/diarrhea (symptoms lasting 3 months) and was subsequently diagnosed with stage IVB ovarian serous carcinoma with multiple distant metastases\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eat our institution. Physical examination findings were unremarkable upon admission. Laboratory analysis demonstrated elevated tumor markers, with CA125 and CA72-4 measuring 305.8 U/mL and 60.44 U/mL, respectively. D-dimer increased to 2.79 \u0026mu;g/mL, and AST was elevated to 41 U/L. PET-CT imaging (Fig. 4) revealed bilateral ovarian malignant tumors (4.0 cm \u0026times; 5.7 cm \u0026times; 4.9 cm on the left; 4.6 cm \u0026times; 4.7 cm \u0026times; 5.6 cm on the right), along with multiple enlarged lymph node metastases distributed along bilateral external iliac vessels, bilateral common iliac vessels, para-aortic, and para-caval regions, the largest measuring approximately 1.1 cm \u0026times; 1.0 cm. Additionally, a metastatic lesion measuring 0.8 cm \u0026times; 0.6 cm was identified in liver segment S8, together with peritoneal metastases, some of which involved the adjacent intestinal and bladder walls.\u003c/p\u003e\n\u003cp\u003eBetween May 2024 and October 2024, Patient 2 underwent eight cycles of triple combination therapy consisting of cadonilimab, bevacizumab, and albumin-bound paclitaxel plus carboplatin, integrating immunotherapy, targeted therapy, and chemotherapy. Chemotherapy dosages were progressively reduced (albumin-bound paclitaxel decreased from 0.2 g qd to 0.1 g qd; carboplatin reduced from 0.3 g qd to 0.1 g qd and was discontinued during the seventh and eighth cycles). CT re-examination in August 2024 after the fourth cycle (Fig. 5) confirmed partial response (PR, \u0026ndash;54.8%) according to RECIST 1.1. PET-CT reassessment in September 2024 (Fig. 4) demonstrated the absence of hypermetabolic malignant lesions in bilateral ovaries, resolution of the previously visualized hypermetabolic lymph node metastases, localized strip-like peritoneal thickening in the pelvis without abnormal radiotracer uptake, suppressed metabolic activity of peritoneal metastases, and disappearance of the mildly hypermetabolic lesion at the capsular surface of liver segment S8. From November 2024 to August 2025, the patient received 10 cycles of maintenance therapy with cadonilimab plus bevacizumab, with chemotherapy completely discontinued. Follow-up CT scans during this period showed that the volume of the primary ovarian lesion and small scattered lymph nodes remained stable compared with prior imaging. From baseline to the last treatment cycle, tumor markers CA125 and CA72-4, together with D-dimer and AST, progressively normalized (Fig. 6). Moreover, no severe chemotherapy- or immune-related adverse events were observed throughout the treatment course.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThe patient has remained progression-free and in good condition to date.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 3\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn August 2023, a 50-year-old Asian female diagnosed with stage IVB ovarian serous carcinoma at an external hospital was admitted for further treatment. The diagnostic and therapeutic process at the outside hospital is illustrated in Figure 7. The patient presented with persistent upper abdominal distension, while physical examination findings were unremarkable upon admission. Tumor marker CA125 was elevated to 471.5 U/mL, and D-dimer increased to 20 \u0026mu;g/mL. PET-CT (Fig. 8) revealed multiple peritoneal metastases following ovarian cancer surgery, with a SUVmax of 10.3 and SUVave of 7.0. Several lesions infiltrated the intestinal wall, and multiple lymph node metastases were identified in the right supraclavicular region, bilateral parasternal areas, mediastinum, pelvic mesentery, bilateral external iliac vessels, retroperitoneum, and right cardiophrenic angle, the largest measuring approximately 1.5 cm \u0026times; 1.0 cm.\u003c/p\u003e\n\u003cp\u003eBetween September 2023 and March 2024, Patient 3 underwent eight cycles of triple combination therapy consisting of sintilimab, bevacizumab, and albumin-bound paclitaxel plus carboplatin, integrating immunotherapy, targeted therapy, and chemotherapy. Chemotherapy dosages were progressively reduced: albumin-bound paclitaxel decreased from 0.3 g qd in cycle 1 to 0.1 g qd in cycles 7\u0026ndash;8; carboplatin was reduced from 0.2 g in cycle 1 to 0.1 g in cycles 6\u0026ndash;7; and only albumin-bound paclitaxel was retained in cycle 8. After eight cycles, PET-CT reassessment (Fig. 8) demonstrated suppression of most peritoneal metastatic lesions (SUVmax 5.4, SUVave 3.2), disappearance of multiple lymph node metastases, and stable disease (SD) according to RECIST 1.1 criteria. From baseline to the last treatment cycle, CA125 and D-dimer progressively normalized (Fig. 9). Moreover, no severe chemotherapy-related adverse events were recorded during therapy. However, hypothyroidism occurred as an immune-related adverse event in cycles 7 and 8, graded G1 and G2, respectively (Fig. 9). The patient was lost to follow-up after the eighth cycle of treatment, and her current status is unknown.\u003c/p\u003e\n\u003cp\u003eTreatment-related adverse reactions and observations\u003c/p\u003e\n\u003cp\u003e(1) Hypothyroidism\u003c/p\u003e\n\u003cp\u003eHypothyroidism is the most frequent endocrine toxicity induced by ICIs, occurring in 10%\u0026ndash;20% of treated patients and typically persisting after discontinuation of ICI therapy [20]. Thyroid dysfunction related to ICIs generally emerges approximately 6 weeks after initiation of treatment, although onset may occur at any stage during therapy. The underlying mechanism remains uncertain, but it is considered to result from autoimmune reactions secondary to blockade of physiological immune regulatory pathways [21, 22].\u003c/p\u003e\n\u003cp\u003eIn this case, isolated elevation of TSH was detected in patient 3 following the seventh cycle of combination therapy (Fig. 9), consistent with grade G1 ICI-related hypothyroidism. After the eighth cycle, laboratory evaluation demonstrated elevated TSH accompanied by decreased T3 and T4 levels (Fig. 9), meeting the criteria for grade G2 ICI-related hypothyroidism and necessitating thyroid hormone replacement therapy. Following initiation of oral thyroid hormone supplementation, hypothyroid manifestations were effectively controlled.\u003c/p\u003e\n\u003cp\u003e(2) Hepatic dysfunction\u003c/p\u003e\n\u003cp\u003eDuring treatment, transient elevations of transaminases were documented in both Patient 1 and Patient 2 (Fig. 3 and Fig. 6). With progressive reduction of chemotherapy dosages and timely administration of hepatoprotective agents, transaminase levels normalized. After transition to the maintenance phase with ICIs plus bevacizumab, without further chemotherapy exposure, no recurrence of hepatic dysfunction was observed. These findings suggest that regimens incorporating ICIs and bevacizumab with reduced chemotherapy may substantially diminish chemotherapy-related toxicity and enhance the tolerability of long-term therapy. The hepatic dysfunction was attributed to chemotherapy, while immune-related hepatitis was not considered at this stage.\u003c/p\u003e"},{"header":"Discussion and conclusion","content":"\u003cp\u003eThe clinical management of advanced ovarian cancer has long been hindered by the dual challenges of limited therapeutic efficacy and treatment-related toxicities. Most patients experience recurrence after initial surgical intervention due to chemotherapy resistance, and prolonged chemotherapy further exacerbates quality of life by inducing bone marrow suppression and liver dysfunction. Therefore, the development of new strategies capable of overcoming resistance, reducing toxicity, and optimizing efficacy is of paramount importance. This case series represents the first report demonstrating the promising outcomes of a combination therapy involving ICI, bevacizumab, and dose-reduced chemotherapy in advanced ovarian cancer, showing both good efficacy and manageable safety, thereby offering a novel approach to address the aforementioned challenges.\u003c/p\u003e \u003cp\u003eThe immunosuppressive tumor microenvironment in ovarian cancer typically manifests as insufficient T-cell infiltration and an enrichment of immunosuppressive cells, such as regulatory T cells (Tregs). Monotherapy with ICI alone is often inadequate in activating effective anti-tumor immunity. The vascular endothelial growth factor (VEGF) pathway plays a critical role in the immune suppression associated with ovarian cancer by promoting abnormal angiogenesis, restricting T-cell infiltration, inhibiting effector T-cell function, and enhancing Treg activity[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The addition of bevacizumab, in theory, generates a potent synergistic effect with ICIs: bevacizumab normalizes the tumor vasculature, thereby improving T-cell delivery to the tumor and creating a more favorable microenvironment for T-cell activity, while ICIs ensure the full activation of these T-cells, thereby enhancing their ability to efficiently target and kill tumor cells. This \"targeting\u0026thinsp;+\u0026thinsp;immunotherapy\" combinatorial strategy may provide a key mechanism for overcoming the immunosuppressive microenvironment of ovarian cancer.\u003c/p\u003e \u003cp\u003eMoreover, chemotherapy in this regimen not only exerts direct cytotoxic effects but may also induce immunogenic cell death, thereby releasing tumor antigens and providing a \"fuel\" for ICI-driven T-cell responses. Based on previous real-world research evidence, we have summarized and applied dose-reduced chemotherapy principles for advanced cancer patients, particularly those with poor tolerance to standard doses. The core of these principles lies in implementing a \"risk-adaptive dose adjustment\" and a \"dynamic, stepwise management\" strategy, aiming to optimize the balance between efficacy and safety. Specifically, this involves: Risk-adaptive initial dosing: At the start of treatment, a pre-set dose reduction is applied. For albumin-bound paclitaxel, the starting dose (200 mg or 300 mg) is used, which is approximately 50%\u0026ndash;80% of the standard dose. For carboplatin, the starting dose is adjusted to 50% or lower of the AUC\u0026thinsp;=\u0026thinsp;5-calculated dose, primarily to avoid the risk of synergistic toxicity. Dynamic stepwise dose modulation: During the treatment course, dose reductions are implemented dynamically and stepwise based on the patient's tolerance. With the reduction of chemotherapy drugs, selective single-agent chemotherapy strategies may be employed to achieve the optimal individualized tolerable dose, ensuring both the continuity and safety of the treatment. This principle focuses on maintaining the ongoing benefit of antitumor treatment in vulnerable populations through refined dose management. Notably, by employing a \"dose-reduced chemotherapy\" strategy, we successfully minimized the cumulative toxicity of chemotherapy while achieving significant clinical efficacy. Patients 1 and 2 experienced only transient and reversible transaminase level elevations, which resolved with the reduction of chemotherapy drugs and the management with hepatoprotective medications, demonstrating the advantages of this approach in maintaining long-term treatment tolerability.\u003c/p\u003e \u003cp\u003eWhen comparing the efficacy of this regimen with previous ICI-based therapies, the potential of this triple combination therapy becomes even more apparent. For instance, in the JAVELIN Ovarian 200 trial, avelumab (anti-PD-L1) monotherapy or its combination with chemotherapy did not significantly improve overall survival (OS) or progression-free survival (PFS) in platinum-resistant or refractory ovarian cancer[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Other studies investigating ICI combinations with targeted therapies, such as PARP inhibitors or VEGFR-TKIs, have shown moderate activity, with overall response rates (ORR) generally ranging from 30% to 50%[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In contrast, the three patients in this case series treated with the triple regimen achieved a remarkable 66.7% ORR and 100% disease control rate (DCR), with one patient achieving a postoperative complete response (CR) and maintaining long-term remission. These results are highly encouraging. Notably, the safety profile of this regimen was generally manageable, with only one patient experiencing grade 1/2 immune-related hypothyroidism, a known, manageable adverse event associated with ICIs, and no severe complications such as colitis or hypophysitis, which are commonly associated with CTLA-4 inhibition. Regarding long-term outcomes, both patient 1 and patient 2 have maintained continued remission to date, demonstrating the potential for durable disease control with this triple regimen. Patient 3, despite achieving stable disease, was lost to follow-up after cycle 8.\u003c/p\u003e \u003cp\u003eHowever, this study has inherent limitations, including a small sample size, a retrospective design, and the absence of direct comparisons. Nevertheless, these preliminary findings strongly suggest that the combination of ICI, bevacizumab, and dose-reduced chemotherapy, through a multi-modal synergistic mechanism involving \"immune activation\u0026thinsp;+\u0026thinsp;microenvironment remodeling (bevacizumab)\u0026thinsp;+\u0026thinsp;antigen release and toxicity reduction (dose-reduced chemotherapy),\" offers a promising new therapeutic approach for advanced ovarian cancer, particularly for patients with traditionally \"cold tumors.\"\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, our preliminary findings suggest that the triple regimen of ICI, bevacizumab, and dose-reduced chemotherapy may constitute a promising therapeutic strategy for stage IVB ovarian cancer. This approach was associated with a low incidence of adverse events and favorable tolerability, potentially offering an effective treatment option for patients with advanced disease. Incorporation of dose-reduced chemotherapy appears to reduce toxicity and mitigate the risk of drug resistance, thereby providing a therapeutic alternative that balances efficacy, tolerability, and long-term management. These preliminary findings warrant validation in large-scale clinical trials to further assess novel strategies integrating immunotherapy, targeted therapy, and chemotherapy, to improve survival outcomes in advanced ovarian cancer.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eICI: Immune Checkpoint Inhibitor\u003c/p\u003e\n\u003cp\u003eVEGF: Vascular Endothelial Growth Factor\u003c/p\u003e\n\u003cp\u003eVEGFR: Vascular Endothelial Growth Factor Receptor\u003c/p\u003e\n\u003cp\u003eTME: Tumor Microenvironment\u003c/p\u003e\n\u003cp\u003eTregs: Regulatory T Cells\u003c/p\u003e\n\u003cp\u003eMDSCs: Myeloid-Derived Suppressor Cells\u003c/p\u003e\n\u003cp\u003eCA125: Cancer Antigen 125\u003c/p\u003e\n\u003cp\u003eCA15-3: Cancer Antigen 15-3\u003c/p\u003e\n\u003cp\u003eCA72-4: Cancer Antigen 72-4\u003c/p\u003e\n\u003cp\u003eALT: Alanine Aminotransferase\u003c/p\u003e\n\u003cp\u003eAST: Aspartate Aminotransferase\u003c/p\u003e\n\u003cp\u003ePET-CT: Positron emission tomography\u0026ndash;computed tomography\u003c/p\u003e\n\u003cp\u003eCT: Computed Tomography\u003c/p\u003e\n\u003cp\u003ePR: Partial Response\u003c/p\u003e\n\u003cp\u003eCR: Complete Response\u003c/p\u003e\n\u003cp\u003eSD: Stable Disease\u003c/p\u003e\n\u003cp\u003eOS: Overall Survival\u003c/p\u003e\n\u003cp\u003ePFS: Progression-Free Survival\u003c/p\u003e\n\u003cp\u003eORR: Overall Response Rate\u003c/p\u003e\n\u003cp\u003eDCR: Disease Control Rate\u003c/p\u003e\n\u003cp\u003eAUC: Area Under the Curve\u003c/p\u003e\n\u003cp\u003eG1/G2: Grade 1/Grade 2\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of The First Affiliated Hospital of Guangdong Pharmaceutical University on September 18, 2025. The ethics committee reviewed and approved the study protocol, informed consent forms, and all related documents via expedited review. The study was conducted in accordance with the ethical standards of the institutional research committee and the principles of the Declaration of Helsinki. Written informed consent was obtained from all individual participants included in the study. This study is subject to an annual continuing review by the ethics committee.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eWritten informed consent for the publication of their personal clinical details (e.g., age, laboratory indicators) and identifying medical images (e.g., PET-CT scans, CT scans) included in this manuscript was obtained from all individual participants.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this manuscript.\u003c/p\u003e\n\u003cp\u003eCompeting Interests\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis study was funded by the General Program of the Youth Fund Project of the National Natural Science Foundation of China (82203874), the National Natural Science Foundation of China (32271225), and the Special Project of the International Science and Technology Cooperation Program of the Guangdong Provincial Science and Technology Plan (20190510). We also acknowledge the support from the Innovative CAR-NK Therapy Research Team. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions\u003c/p\u003e\n\u003cp\u003eYu Xiang:\u0026nbsp;Writing \u0026ndash; original draft, Writing \u0026ndash; review \u0026amp; editing.\u0026nbsp;Wenxin Huang:\u0026nbsp;Writing \u0026ndash; review \u0026amp; editing.\u0026nbsp;Jiayi Dong:\u0026nbsp;Formal analysis.\u0026nbsp;Yujia Chen:\u0026nbsp;Formal analysis.\u0026nbsp;Size Chen:\u0026nbsp;Conceptualization, Formal analysis.\u0026nbsp;Lijuan Shao:\u0026nbsp;Conceptualization, Formal analysis, Writing \u0026ndash; review \u0026amp; editing.\u0026nbsp;All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eWe acknowledge the support from the Innovative CAR-NK Therapy Research Team of Guangdong Pharmaceutical University. We thank the Ethics Committee of The First Affiliated Hospital of Guangdong Pharmaceutical University for their review and approval of the study protocol, and are grateful to the participants included in this study for their cooperation and contribution to the research.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eColombo I, Karakasis K, Suku S, Oza AM. Chasing immune checkpoint inhibitors in ovarian cancer: Novel combinations and biomarker discovery. Cancers. 2023;15(12):3220. DOI: 10.3390/cancers15123220 \u003c/li\u003e\n\u003cli\u003eKaur P, Singh SK, Mishra MK, Singh S, Singh R. Nanotechnology for boosting ovarian cancer immunotherapy. Journal of Ovarian Research. 2024;17(1):202. \u003c/li\u003e\n\u003cli\u003eFoley OW, Rauh-Hain JA, Del Carmen MG. Recurrent epithelial ovarian cancer: an update on treatment. Oncology. 2013;27(4):288. \u003c/li\u003e\n\u003cli\u003eCortez AJ, Tudrej P, Kujawa KA, Lisowska KM. Advances in ovarian cancer therapy. Cancer chemotherapy and pharmacology. 2018;81(1):17-38. \u003c/li\u003e\n\u003cli\u003eBaldwin LA, Huang B, Miller RW, Tucker T, Goodrich ST, Podzielinski I, et al. Ten-year relative survival for epithelial ovarian cancer. Obstetrics \u0026amp; Gynecology. 2012;120(3):612-8. \u003c/li\u003e\n\u003cli\u003eGogineni V, Morand S, Staats H, Royfman R, Devanaboyina M, Einloth K, et al. Current ovarian cancer maintenance strategies and promising new developments. Journal of Cancer. 2021;12(1):38. \u003c/li\u003e\n\u003cli\u003eRibas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359(6382):1350-5. \u003c/li\u003e\n\u003cli\u003eMakker V, Colombo N, Casado Herr\u0026aacute;ez A, Santin AD, Colomba E, Miller DS, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. New England Journal of Medicine. 2022;386(5):437-48. \u003c/li\u003e\n\u003cli\u003eColombo N, Dubot C, Lorusso D, Caceres MV, Hasegawa K, Shapira-Frommer R, et al. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. New England Journal of Medicine. 2021;385(20):1856-67. \u003c/li\u003e\n\u003cli\u003eGalon J, Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nature reviews Drug discovery. 2019;18(3):197-218. \u003c/li\u003e\n\u003cli\u003eLo CS, Sanii S, Kroeger DR, Milne K, Talhouk A, Chiu DS, et al. Neoadjuvant chemotherapy of ovarian cancer results in three patterns of tumor-infiltrating lymphocyte response with distinct implications for immunotherapy. Clinical Cancer Research. 2017;23(4):925-34. \u003c/li\u003e\n\u003cli\u003eB\u0026ouml;hm S, Montfort A, Pearce OM, Topping J, Chakravarty P, Everitt GL, et al. Neoadjuvant chemotherapy modulates the immune microenvironment in metastases of tubo-ovarian high-grade serous carcinoma. Clinical Cancer Research. 2016;22(12):3025-36. \u003c/li\u003e\n\u003cli\u003eMesnage S, Auguste A, Genestie C, Dunant A, Pain E, Drusch F, et al. Neoadjuvant chemotherapy (NACT) increases immune infiltration and programmed death-ligand 1 (PD-L1) expression in epithelial ovarian cancer (EOC). Annals of oncology. 2017;28(3):651-7. \u003c/li\u003e\n\u003cli\u003eKim H-S, Kim J-Y, Lee YJ, Kim SH, Lee J-Y, Nam EJ, et al. Expression of programmed cell death ligand 1 and immune checkpoint markers in residual tumors after neoadjuvant chemotherapy for advanced high-grade serous ovarian cancer. Gynecologic Oncology. 2018;151(3):414-21. \u003c/li\u003e\n\u003cli\u003eJim\u0026eacute;nez-S\u0026aacute;nchez A, Cybulska P, Mager KL, Koplev S, Cast O, Couturier D-L, et al. Unraveling tumor\u0026ndash;immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy. Nature Genetics. 2020;52(6):582-93. \u003c/li\u003e\n\u003cli\u003ePeng J, Hamanishi J, Matsumura N, Abiko K, Murat K, Baba T, et al. Chemotherapy induces programmed cell death-ligand 1 overexpression via the nuclear factor-\u0026kappa;B to foster an immunosuppressive tumor microenvironment in ovarian cancer. Cancer research. 2015;75(23):5034-45. \u003c/li\u003e\n\u003cli\u003eGhaffari A, Peterson N, Khalaj K, Vitkin N, Robinson A, Francis J-A, et al. STING agonist therapy in combination with PD-1 immune checkpoint blockade enhances response to carboplatin chemotherapy in high-grade serous ovarian cancer. British journal of cancer. 2018;119(4):440-9. \u003c/li\u003e\n\u003cli\u003eLiu M, Tayob N, Penter L, Sellars M, Tarren A, Chea V, et al. Improved T-cell immunity following neoadjuvant chemotherapy in ovarian cancer. Clinical Cancer Research. 2022;28(15):3356-66. \u003c/li\u003e\n\u003cli\u003eRahma OE, Hodi FS. The intersection between tumor angiogenesis and immune suppression. Clinical Cancer Research. 2019;25(18):5449-57. \u003c/li\u003e\n\u003cli\u003eWright JJ, Powers AC, Johnson DB. Endocrine toxicities of immune checkpoint inhibitors. Nature Reviews Endocrinology. 2021;17(7):389-99. \u003c/li\u003e\n\u003cli\u003eTan MH, Iyengar R, Mizokami-Stout K, Yentz S, MacEachern MP, Shen LY, et al. Spectrum of immune checkpoint inhibitors-induced endocrinopathies in cancer patients: a scoping review of case reports. Clinical diabetes and endocrinology. 2019;5(1):1. \u003c/li\u003e\n\u003cli\u003ePostow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. New England Journal of Medicine. 2018;378(2):158-68. \u003c/li\u003e\n\u003cli\u003eGhisoni E, Morotti M, Sarivalasis A, Grimm AJ, Kandalaft L, Laniti DD, et al. Immunotherapy for ovarian cancer: towards a tailored immunophenotype-based approach. Nature Reviews Clinical Oncology. 2024;21(11):801-17. \u003c/li\u003e\n\u003cli\u003ePujade-Lauraine E, Fujiwara K, Ledermann JA, Oza AM, Kristeleit R, Ray-Coquard I-L, et al. Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): an open-label, three-arm, randomised, phase 3 study. 2021;22(7):1034-46. \u003c/li\u003e\n\u003cli\u003eLee J-M, Cimino-Mathews A, Peer CJ, Zimmer A, Lipkowitz S, Annunziata CM, et al. Safety and clinical activity of the programmed death-ligand 1 inhibitor durvalumab in combination with poly (ADP-ribose) polymerase inhibitor olaparib or vascular endothelial growth factor receptor 1-3 inhibitor cediranib in women\u0026apos;s cancers: a dose-escalation, phase I study. 2017;35(19):2193-202. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Advanced ovarian cancer, Combination immunotherapy, Dose-Reduced Chemotherapy, Bevacizumab","lastPublishedDoi":"10.21203/rs.3.rs-8526372/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8526372/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eOvarian cancer continues to be the deadliest gynecological malignancy, with surgery and chemotherapy serving as the mainstays of treatment. However, recurrence often develops within several years after initial postoperative chemotherapy due to drug resistance, and the significant toxicity associated with long-term chemotherapy markedly impairs patients\u0026rsquo; quality of life. Consequently, there is a pressing clinical need to develop strategies that minimize chemotherapy exposure while preserving efficacy and safety.\u003c/p\u003e\u003ch2\u003eCase Presentation\u003c/h2\u003e \u003cp\u003eThis study presents three cases of stage IVB ovarian serous carcinoma treated with a triple regimen combining an immune checkpoint inhibitor (ICI), bevacizumab, and chemotherapy with a planned reduction in chemotherapy cycles. All three patients completed the regimen without experiencing treatment-related grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events. Patient 1 achieved a postoperative complete response, Patient 2 exhibited a partial response, and Patient 3 maintained stable disease.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eOver the past two decades, immunotherapy has advanced rapidly. Although its clinical response rate in ovarian cancer remains relatively low, evidence suggests that combining ICIs with targeted therapy can significantly improve outcomes. This case series offers new insights into the application of immunotherapy in advanced ovarian cancer, highlighting a potential pathway to reduce chemotherapy burden while maintaining therapeutic benefit.\u003c/p\u003e","manuscriptTitle":"Novel Breakthrough in Triple Combination Therapy with Immune Checkpoint Inhibitor, Bevacizumab, and Dose-Reduced Chemotherapy for Patients with Advanced Ovarian Cancer: A Case Series Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-23 00:39:01","doi":"10.21203/rs.3.rs-8526372/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"81418756-e3c6-4ae5-8784-2f7c43395fd6","owner":[],"postedDate":"January 23rd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-26T08:56:35+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-23 00:39:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8526372","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8526372","identity":"rs-8526372","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}