2019 Mentored Investigator Grant Recipient — Alba Rodriguez-Garcia, PhD
Project Summary
Ovarian cancer ranks 5th among cancer-related deaths in women and is the most lethal of all gynecologic malignancies, with an overall 5-year survival rate of 46%. Therefore, there is a dire need for effective therapies. Chimeric antigen receptor (CAR) T cell therapy consists in engineering T cells from patients in order to express a CAR that comprises an extracellular portion based on a fragment of antibody that recognizes a tumor antigen, coupled to the intracellular signaling domains of the T cell receptor. This modification allow the T cells to specifically recognize and kill tumor cells that express the selected antigen on their surface upon reinfusion to the patient. CAR T cells targeting CD19 had shown great success in the treatment of hematologic cancers, and had been recently approved by the FDA. However, effective CAR T cell therapy for ovarian cancer has not yet been achieved. The selection of a target antigen that is overexpressed in malignant cells but not present in normal cells is crucial for the safety and efficacy of the treatment. Here we propose the Müllerian Inhibiting Substance type 2 Receptor (MISIIR) as an ideal target since it is overexpressed in the majority of ovarian cancers while has limited expression in normal tissues. Also, the natural ligand of this receptor, MIS, inhibits the growth of ovarian cancer cells, rationalizing our approach of targeting this relevant pathway with CAR T cells to kill ovarian cancer cells in an efficient manner.