Chimeric antigen receptor T-cell (CAR-T) represents a breakthrough technology in oncology that provides antigen-specific MHC-independent tumor recognition with prolonged T-cell immune response exceeding the effectiveness of existing cancer treatment options, including chemotherapy, radiotherapy as well as targeted therapy. By expressing synthetic antigen receptors able to redirect cytotoxicity towards tumor associated antigene (TAA), CAR-T therapy enables precision and persistence as well as a possibility of long-lived immunosurveillance. Subsequent generations of CARs demonstrate increasingly refined therapeutic potential: second- and third-generation constructs possessing CD28 or 4-1BB costimulatory domains enhance expansion and persistence, but fourth- and fifth-generation ”armored” CAR-T effectors either secrete cytokines or carry cytokine receptor signaling motifs to counter exhaustion and reshape the suppressive tumor microenvironment (TME).

While CAR-T therapy has been highly successful in hematologic malignancies, transitioning this treatment to solid tumors, such as ovarian cancer, has been more challenging. Initial clinical and preclinical studies directed against folate receptor-α (FRα), mesothelin, MUC16 (CA125), HER2, or EGFR have shown an acceptable safety profile and evidence of antitumor activity, but durable clinical response rates are low. Key hurdles include extensive antigen diversity, an immune-evasive TME abundant in TGF-β, IL-10, regulatory T (Treg) cells, and myeloid-derived suppressor cell populations, and suboptimal migration/infiltration of intravenously infused CARs at peritoneal tumor sites. To address these challenges many strategies have arisen, such as intraperitoneal CAR-T delivery for local concentration, chemokine receptor modification to enhance homing, platforms of multi-antigen CARs to decrease immune escape and armored CAR-T capable of cytokine secretion or checkpoint-resistant signaling. Together, these developments underscore the potential of CAR-T for ovarian cancer while emphasizing the importance of further engineering and combinatory strategies to achieve a meaningful and durable therapeutic benefit.

Keywords: CAR-T, Tumor microenvironment, Armored CARs, Multi-antigen targeting Immunotherapy, Next-generation CAR constructs