Overcoming immunological tolerance to melanoma: Targeting CTLA-4.
Abstract 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.
Hodi
F Stephen
FS
Dana-Farber Cancer Institute, Boston, Massachusetts, USA. stephen_hodi@dfci.harvard.edu
D000818:Animals; D019138:Antibodies, Blocking / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology*; D060908:CTLA-4 Antigen; D002986:Clinical Trials as Topic; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D007167:Immunotherapy / Q000379:methods; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology*
D019138:Antibodies, Blocking; D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human