James P. Allison 
University of California, Berkeley, CA

Removing The Brakes: Antibody Blockade of Inhibitory T-Cell Costimulation in Tumor Immunotherapy

Activation of naïve T cells is a complex and dynamic process involving not only recognition by the T-cell antigen receptor (TCR) but also additional costimulatory signals. Particularly crucial are the costimulatory signals mediated by the interaction of CD28 on the T cell with members of the B7 family of the antigen-presenting cell, and inhibitory signals mediated by interaction between CTLA-4 on the T cell with B7 on the APC. The dynamic integration of the TCR, CD28 and CTLA-4 signals determines the outcome of T-cell activation.

Over the past several years, we have demonstrated that blockade of the inhibitory CTLA-4 signals by administration of anti-CTLA-4 antibodies can greatly enhance T-cell responses in vivo. We have applied CTLA-4 blockade to a number of experimental tumor systems in mice. Administration of anti-CTLA-4 by itself is sufficient to induce rejection of many highly immunogenic tumors, including well-established tumors. Rejection is accompanied by long-lived immunity to tumor rechallenge. Tumors considered to be non-immunogenic, including the B16 melanoma and the SM1 mammary carcinoma, are resistant to treatment with anti-CTLA-4 alone. However, we have shown that administration of anti-CTLA-4 along with irradiated GM-CSF producing tumor cell vaccines results in prophylactic immunity and can lead to rejection of established tumors. In the case of B16 melanoma, rejection is accompanied by a progressive autoimmune depigmentation. The effect of anti-CTLA-4 in combination with the tumor cell vaccine in this setting is the induction of a potent CD8+ T-cell response directed against a melanocyte differentiation antigen TRP-2. Studies of the mechanism of the combination therapy have led to two very interesting observations. The first is that tumor rejection obtained by the combination therapy does not require the presence of CD4+ T cells, suggesting that blockade of CTLA-4 allows the protection of CD8+ T cells in a T helper cell independent manner. The second observation is that the antitumor response elicited by the combination CTLA-4 treatment is more potent in the absence of CD4+, and in particular CD25+CD4+ Treg cells. This suggests that CTLA-4 and CD25+ Treg cells are independently regulating the antitumor response

We have also applied the CTLA-4 blockade approach to a transgenic model of prostate cancer (TRAMP, Norm Greenberg, Baylor). We have found that CTLA-4 blockade can delay and reduce the severity of primary tumors, can induce rejection of early established transplantable tumors, and can reduce the incidence of metastases that occur upon surgical removal of established tumors. Finally, we have used the potentiating effect of CTLA-4 blockade to obtain TRAMP-specific T-cell lines, and used these to obtain cDNAs encoding T-cell defined prostate tumor epitopes.

Antibodies to human CTLA-4 have been produced (Genpharm, Inc.) and Phase I clinical trials in both prostate cancer and melanoma are underway (Medarex). Preliminary results of these trials will be discussed.