Overcoming immunological tolerance to melanoma: Targeting CTLA‐4

The use of immunotherapeutics in melanoma has received much attention, and recent advances to further characterize the regulatory components of the immune system and the importance of co‐stimulatory molecules have opened a new area for clinical investigation. Cytotoxic T lymphocyte‐associated antigen 4 (CTLA‐4) serves as a negative regulator of immunity. Recent trials administering fully human anti‐CTLA‐4 monoclonal antibodies to melanoma patients have demonstrated clinically meaningful responses. Treatment with CTLA‐4 blocking antibodies, however, is not without potential toxicities. Autoimmune side‐effects, the most common being colitis‐associated diarrhea, are frequently associated with clinical responses. In efforts to build upon prior vaccination efforts as well as attempt to offer patients clinically meaningful immune responses with a CTLA‐4 blockade but without significant toxicities, we conducted a clinical trial in patients who previously received autologous tumor cells engineered to secrete granulocyte‐macrophage colony stimulating factor (GVAX; Cell Genesys, South San Francisco, CA, USA) with periodic infusions of CTLA‐4 blocking antibodies. This sequential treatment resulted in clinically significant anti‐tumor immunity without grade 3 or 4 toxicity in most patients. Pathological analyses following treatment of pre‐existing tumors revealed a linear correlation between tumor necrosis and the ratio of intra‐tumoral CD8+ effector cells to FoxP3+ regulatory cells (T regs ). Effective anti‐tumor immunity and serious autoimmunity can be disassociated. Further targeting of anti‐tumor T regs in combinatorial therapy approaches may be a rich avenue of future investigation.