Engineering adoptive T cell therapy for efficacy in ovarian cancer

Abstract

Abstract Over 20,000 women are diagnosed with ovarian cancer annually; more than half will die within 5 years, which has changed little over the last 20 years. One promising new treatment strategy employs immune T cells engineered to target proteins uniquely overexpressed in tumors, with the potential to control tumor growth without toxicity to healthy tissues. Recently, mesothelin (MSLN) has been identified as a valid antigen target in ovarian cancer; minimally expressed in healthy cells, MSLN contributes to malignant and invasive phenotypes. In preclinical studies using patient-derived cell lines or the mouse ID8 ovarian tumor model, we found that T cells engineered to express a high-affinity MSLN-specific T cell receptor (TCR) can kill ovarian tumor cells in vitro. In vivo, adoptively transferred TCR-engineered T cells preferentially accumulate within disseminated ID8 tumors, delay tumor growth and prolong mouse survival, but our data also show the tumor microenvironment (TME) can limit engineered T cell persistence and function. Other analyses show human therapy will face similar TME-mediated obstacles. The ovarian cancer TME is a nutrient- and oxygen-deprived milieu, and adaptive metabolic responses by infiltrating T cells have protean effects on T cell function. Thus, strategies that modulate T cell metabolic pathways, and thereby influence activity in the TME, might enhance T cell function and improve anti-tumor efficacy by overcoming a critical component of immune evasion by solid tumors. Ongoing studies will be discussed that are exploring strategies to overcome elements common to the human and murine TME, including direct modulation of the environment and T cell engineering to promote T cell survival and function.