T cell therapy targeting oncogenic antigens in ovarian cancer

Abstract

Abstract Over 20,000 women are diagnosed with ovarian cancer annually, and more than half will die within 5 years. This rate has changed very little in the last 20 years, highlighting the need for innovative therapies. Reprogramming immune system cells to target and kill ovarian cancer cells represents a potentially promising new treatment strategy. Immune T cells have the potential to control tumor growth without toxicity to healthy tissues if engineered to target proteins uniquely overexpressed in tumors. Recent technological advances have helped identify and validate Wilms’ Tumor Antigen 1 (WT1) and mesothelin (MSLN) as promising ovarian cancer antigen targets; these proteins contribute to malignant and invasive phenotypes and have limited expression in healthy cells. Using patient-derived cell lines and the murine ID8 tumor, we show that T cells engineered to express a high-affinity T cell receptor (TCR) targeting either WT1 or MSLN can kill human and murine ovarian tumor cells in vitro. Moreover, in an in vivo model of established disease with disseminated ID8 tumor, adoptively transferred TCR-engineered T cells infiltrated and preferentially accumulated within ovarian tumors, delayed tumor growth and prolonged survival. However, our data revealed that the tumor microenvironment (TME) limits the survival and killing capacity of these engineered T cells. Cellular and molecular analyses of human tumor specimens have revealed human therapy will face similar obstacles. Therefore, ongoing studies will be discussed that are further exploring strategies to overcome these common elements of the immunosuppressive TME, including direct modulation of the environment and T cell engineering to promote T cell survival and function.