Full T-cell activation requires recognition of antigen by the T-cell receptor and provision of a costimulatory signal. In particular, B7 on antigen-presenting cells binds to CD28 on the T cell, thereby delivering an important positive costimulatory signal.1,2
Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) is a critical negative regulatory element for T-cell expansion and activation that serves as a natural braking mechanism to return T cells to homeostasis following an immune response. Following T-cell activation, T cells up-regulate CTLA4, which binds to B7 receptors on antigen-presenting cells and sends an inhibitory signal that down-regulates T-cell proliferation, interleukin-2 expression, and T-cell-receptor signaling.3
Anti-CTLA4 monoclonal antibodies can block the interaction of B7 with CTLA4, thus blocking the negative signaling from CTLA4 and allowing B7 to bind to CD28. This prolongs and enhances T-cell activation and proliferation (ie, releasing a brake for T-cell activation).2 It is hypothesized that anti-CTLA4 blocking antibodies can increase the mobilization and proliferation of tumor antigen-specific cytotoxic T lymphocytes.
Tremelimumab is a fully human anti-CTLA4 monoclonal antibody that blocks the binding of CTLA4 and is believed to prevent an inhibitory signal that down-regulates T-cell activation.
Tumor types being studied
- Advanced metastatic melanoma in combination with PF-3512676 (TLR9 agonist)
- Advanced non-small cell lung cancer as single agent
- Advanced renal cell cancer in combination with sunitinib malate
A Phase II, single-agent refractory study in patients with metastatic melanoma has completed enrollment.
Tremelimumab and PF-3512676 are investigational compounds.
Information in the Oncology Investigational Pipeline relates to therapies currently being researched.
References: 1. Inman BA, Frigola X, Dong H, Kwon ED. Costimulation, coinhibition and cancer. Curr Cancer Drug Targets. 2007;7:15-30. 2. Ribas A, Camacho LH, Lopez-Berestein G, et al. Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol. 2005;23:8968-8977. 3. Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A. 2003;100:8372-8377.