Enhancement of Anti-Melanoma Tumor Targeting Utilizing CARs and TILS – PI: James Cripps

Treatments for solid cancers mainly rely on traditional non-specific targeted therapies. In the past several decades the ability of harnessing and engineering of our own immune system to better combat cancer has went from a dream to a reality. This field termed immunotherapy is focused on enhancement of our own immune system in the battle against cancer. Specifically, the area of cellular immunotherapy utilizes cells from the patient’s body which are removed, enhanced, and re-introduced via a process known as adoptive cell therapy (ACT). The two most successful forms of ACT are the use of tumor infiltrating lymphocytes (TILs) and chimeric antigen receptor T cells (CAR-T cells). TILs are successfully utilized to treat multiple cancers including Melanoma. CAR-T cells are widely used successfully in the treatment of blood cancers such as acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). However, approximately half of melanoma patients don’t respond to TIL therapy and CAR-T cells have yet to be effective in treating solid tumors. This study will determine if we can enhance existing Melanoma therapies by combining TILs and CAR-T cells. We have developed a novel CAR construct that recognizes MUC-18, an antigen expressed on Melanoma cells but not regular melanocytes or skin cells. The construct also produces a PD-1 antibody, which can counter the immune systems down regulation of T cells. Based on this we propose the following aims.

Aim 1: Can the MUC-18 and anti-PD-1 containing construct be successfully expressed in T cells from peripheral blood mononuclear cells from healthy donors? Aim 2: Can the MUC-18 and anti-PD-1 containing construct be successfully expressed in TILs and sentinel lymph node T cells isolated from melanoma patients? If any of these aims prove successful or demonstrate superior efficacy to current treatment paradigms, we would have a substantial step forward in utilizing Immunotherapy to treat Melanoma and other solid malignancies.