Tumor-Specific T-Cell Receptor–Redirected T Cells for Epithelial Ovarian Cancer

By: Julia Cipriano, MS
Posted: Wednesday, August 20, 2025

Knockout of the inhibitory receptor TIM3 appears to enhance the antitumor efficacy of T cells engineered with T-cell receptors specific for the tumor-associated antigen WT1 in epithelial ovarian cancer, according to Chiara Bonini, MD, of Universita Vita-Salute San Raffaele, Milan, Italy, and colleagues. Their findings were presented in poster format during the American Association for Cancer Research (AACR) Annual Meeting 2025 (Abstract LB027) and simultaneously published in the journal Cancer Research.  

“T cells engineered with WT1-, MSLN-, and NY-ESO-1–specific T-cell receptors exhibited potent and specific elimination of target cells, with WT1–T-cell receptors [WT1-TCR] emerging as the most promising candidate for further development,” the investigators commented. “We hypothesized that disrupting inhibitory receptor pathways could shield engineered T cells from immunosuppression within the tumor microenvironment, thereby enhancing their therapeutic efficacy.” 

The investigators thus engineered T-cell products to express WT1-TCR and incorporate gene disruptions of specific inhibitory receptors (ie, TIM3, LAG3). WT1-TCR T cells with and without inhibitory receptor knockout were tested against WT1-positive, HLA-A02:01–positive primary cultures and tumor organoids for antitumor efficacy.  

The WT1-TCR T cells with vs without inhibitory receptor knockout were found to demonstrate superior cytotoxicity; those with knockout of TIM3 showed heightened effectiveness against tumor cells expressing TIM3 ligands. According to the investigators, in patient-derived organoids, co-culture experiments further confirmed the increased induction of apoptosis mediated by TIM3- and LAG3-knockout WT1-TCR T cells vs their inhibitory receptor–competent counterparts. In vivo, both TIM3-knockout and inhibitory receptor–competent WT1-TCR T cells seemed to significantly inhibit tumor growth compared with T-cell therapy–unexposed control groups. Ultrasound imaging showed a reduction in the size of abdominal masses, with treatment with TIM3-knockout WT1-TCR T cells achieving the greatest decrease in mass diameter, particularly in the intermediate size range (4–8 mm).   

Disclosure: No information regarding conflicts of interest was provided.

AACR Annual Meeting 2025

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