Targeting Ovarian Cancer Using Double CAR T cells

Epithelial ovarian cancer (EOC) is the fourth most common cause of cancer-related death in women in the developed world and the leading cause of death from gynecological malignancies. EOC is often diagnosed at advanced-stage disease with an overall 5-year survival rate of <40%. While significant progress in surgical and chemotherapeutic treatments for EOC, the survival rates for this disease have only modestly improved.

Chimeric antigen receptor (CAR) T cells therapy, pioneered in our lab, is a powerful tool for cancer treatment. CARs enable T cells to directly bind tumor-associated antigens in an MHC-independent manner inducing tumor rejection. While CAR-T cell therapy shows great promise in hematological malignancies, its implication for solid tumors is far more difficult. A major barrier is the lack of true tumor-specific antigens followed by risk of “on-target off-tumor” toxicity. Innovative approaches are therefore needed to increase the specificity of CAR modified T cells exclusively against tumors.

The aim of this study is generating redirected T cells with dual specificity, expressing two complementary CARs (Double CARs) for specific and effective treatment of ovarian cancer. The complementary chimeric receptors transmit full T cell activation signal only upon dual engagement with tumor-associated antigens. Our working hypothesis is that double CAR-T cells will demonstrate higher cytotoxic activity towards a tumor tissue while sparing non-tumor tissues. We have constructed several double-CARs co-targeting dual combination of overexpressed known markers of ovarian cancer. Double-CARs were expressed in human lymphocytes and their functionality toward human ovarian cancer cell lines was evaluated in-vitro. Our results show that the modified T cell showed specific response against double-antigen presenting target cells. We next plan to evaluate the therapeutic potential of the double CARs in-vivo using animal models. We expect our study to offer powerful and safe strategy with clinical potential for the treatment of ovarian cancer.