Overcoming immunological tolerance to melanoma: Targeting CTLA-4

Asia Pac J Clin Oncol. 2010 Mar;6 Suppl 1:S16-23. doi: 10.1111/j.1743-7563.2010.01271.x.

Abstract

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.

Publication types

  • Review

MeSH terms

  • Animals
  • Antibodies, Blocking / therapeutic use
  • Antigens, CD / immunology*
  • CTLA-4 Antigen
  • Clinical Trials as Topic
  • Humans
  • Immune Tolerance / drug effects
  • Immune Tolerance / immunology*
  • Immunotherapy / methods
  • Melanoma / drug therapy
  • Melanoma / immunology*

Substances

  • Antibodies, Blocking
  • Antigens, CD
  • CTLA-4 Antigen
  • CTLA4 protein, human