Adoptive Cell Therapy Advances Target Ovarian Cancer Solid Tumor Barriers

Key Clinical Summary

• A new study outlines why adoptive cell therapy (ACT) has shown curative potential in some cancers but remains challenging in ovarian cancer (OC) due to tumor heterogeneity, immune exclusion, and an immunosuppressive tumor microenvironment.
• The authors summarize clinical experience to date with tumor-infiltrating lymphocytes (TILs), T cell receptor–engineered (TCR-T), and chimeric antigen receptor T (CAR-T) therapies in OC, including response signals and safety considerations.
• Emerging platforms—such as BiTE-secreting T cells, dual-targeting designs, and logic-gated synthetic circuits—are highlighted as strategies to improve efficacy, persistence, and precision in OC.

Adoptive cell therapy (ACT) is being actively refined for ovarian cancer, where immune suppression and antigen heterogeneity have limited success compared with hematologic malignancies and melanoma. In this review focused on ACT in ovarian cancer (OC), the authors synthesize clinical and translational evidence across key modalities—tumor-infiltrating lymphocytes (TILs), T cell receptor–engineered (TCR-T), and chimeric antigen receptor T (CAR T) therapies—and describe newer engineering approaches intended to improve durability, reduce immune escape, and mitigate toxicity in solid tumors.

Study Findings 

The review frames OC as a high-mortality malignancy in which standard cytoreductive surgery plus platinum/taxane chemotherapy often yields initial responses, yet more than 70% of patients recur within 3 years. For relapsed disease, options remain limited, and newer agents—including bevacizumab, PARP inhibitors, and the antibody-drug conjugate mirvetuximab soravtensine for FRα-positive platinum-resistant OC—rarely produce durable remissions.

Against this backdrop, the authors summarize ACT data in OC. Early-phase TIL studies have reported objective responses in select settings. One trial using cyclophosphamide preconditioning followed by TIL infusion reported 1 complete response (CR) and 4 partial responses (PR), lasting 3–5 months. Another cohort receiving cisplatin-based chemotherapy followed by TILs reported 7 CRs and 2 PRs, with 4 CRs recurrence-free for 15 months. 

In platinum-resistant OC, a trial combining TILs with immune checkpoint blockade reported a best overall response of 1 PR and 5 stable disease (SD) cases, with SD lasting up to 12 months. The study also cites a phase 1/2 trial in which sequential TIL infusions after platinum chemotherapy produced an 86% objective response rate (ORR), while a separate study using 4-1BB/CD3-stimulated TILs plus IL-2 showed no objective responses among 16 treated patients, though 62.5% achieved at least 1 SD assessment.

For engineered products, the authors note that a phase 1/2a NY-ESO-1 TCR-T trial in HLA-A2–positive OC showed no meaningful clinical benefit and reported severe adverse events in 5 of 6 patients. CAR-T approaches targeting FRα, HER2, MUC16, and mesothelin have shown limited efficacy; an investigator-initiated mesothelin CAR T-cell therapy trial in 3 patients with OC resulted in SD in 2 and progression in 1, without high-grade toxicities. As of June 30, 2025, the review reports 16 actively enrolling CAR T-cell trials in OC.

Clinical Implications

For clinicians, the authors underscore that ACT development in ovarian cancer is shifting from “proof of concept” toward engineering strategies that directly address solid tumor barriers: limited T-cell persistence, antigen escape, and exhaustion in a suppressive microenvironment, including ascites-associated immune dysfunction. The authors describe multiple enhancement approaches—cytokine armoring (eg, IL-12, IL-15, IL-18), checkpoint modulation, metabolic reprogramming, and gene editing—to maintain functional, durable T cells.

Safety engineering is also emphasized. The study outlines risks such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and on-target/off-tumor toxicity. A cited systematic review/meta-analysis in gynecologic cancers reported grade 3/4 toxicities in 46% of ACT recipients, with CRS-related grade 3/4 dyspnea and hypotension in 14% and 16%, respectively. Logic-gated systems (“AND/OR/NOT” gating), SynNotch regulation, and suicide switches are presented as tools to improve precision and controllability—key requirements for translating more potent constructs to OC.

Finally, the authors point to scalability directions—such as allogeneic products and in vivo engineering—while noting tradeoffs including rejection risk, off-target editing, and added regulatory complexity.

Conclusion

This study maps the current ACT landscape in ovarian cancer, highlighting early clinical signals with TILs, limited efficacy to date with CAR T-cell therapy and TCR-T, and a growing pipeline of engineered strategies to improve persistence, overcome immune escape, and enhance safety. Future progress will likely depend on integrated trial correlative science and biomarker-informed patient stratification.

Reference

Santos GNDS, DeJohn C, Hess SM, Zsiros E, McGray AJR. Advancing adoptive T cell therapy in ovarian cancer: barriers, innovations, and emerging platforms. J Immunother Cancer. 2026;14:e013285. doi:10.1136/jitc-2025-013285