Overcoming immunological tolerance to melanoma: Targeting CTLA-4
Article first published online: 1 MAR 2010
© 2010 The Author. Journal Compilation © Blackwell Publishing Asia Pty Ltd
Asia-Pacific Journal of Clinical Oncology
Special Issue: Gaining Momentum in Immunotherapy: Where Are We Now?
Volume 6, Issue Supplement s1, pages S16–S23, March 2010
How to Cite
HODI, F. S. (2010), Overcoming immunological tolerance to melanoma: Targeting CTLA-4. Asia-Pacific Journal of Clinical Oncology, 6: S16–S23. doi: 10.1111/j.1743-7563.2010.01271.x
- Issue published online: 1 MAR 2010
- Article first published online: 1 MAR 2010
- Accepted for publication 18 December 2009.
- combination therapy;
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 (Tregs). Effective anti-tumor immunity and serious autoimmunity can be disassociated. Further targeting of anti-tumor Tregsin combinatorial therapy approaches may be a rich avenue of future investigation.