Preclinical development of CM-CX1 for the treatment of ovarian clear cell and renal cell carcinomas

PROJECT SUMMARY Cancer is one of the leading causes of death worldwide. Over the years, a number of conventional cytotoxic approaches for neoplastic diseases has been developed. However, due to their limited effectiveness in accordance with the heterogeneity of cancer cells, there is a constant search for therapeutic approaches with improved outcome, such as immunotherapy that utilizes and enhances the normal capacity of the patientandapos;s immune system. Of note, renal cell carcinoma and ovarian cancer are considered immunogenic, or “hot” cancers, in that tumors are infiltrated with T cells. This provides optimism that the immune system can be harnessed to be a potent and durable weapon against these cancers. Chimeric antigen receptor (CAR) T-cell therapy represents a major advancement in personalized cancer treatment. In this strategy, a patientandapos;s own T cells are genetically engineered to express a synthetic receptor that binds a tumor antigen. We have developed a CAR T cell therapy, CM-CX1, designed to target a very specific marker (TIM-1) in renal and ovarian cancers. Expression of TIM-1 in healthy tissues is limited to absent. The goal of this Fast Track proposal is to finalize the preclinical work required for CM-CX1 filing of an IND for first-in-human evaluation.NARRATIVE Much progress has been made in the dosing and scheduling optimization of conventional chemotherapy to maximize their effectiveness. Despite this, many solid tumors including ovarian and renal cell carcinomas, especially those diagnosed at advanced stages, progress and become refractory to treatment. Ovarian cancer and renal cell carcinomas are especially difficult cancers to treat in advanced stages as evidenced by a combined annual mortality of ~30,000 patients in the United States each year. We have developed and characterized a chimeric antigen receptor (CAR) T cell therapy that specifically targets tumor cells that express a novel target with high prevalence in clear cell carcinomas of the ovary and kidney but minimal/no expression in normal tissues.