Multiple factors in the cancer microenvironment down-regulate tumor immunity and promote tumor progression. In melanoma, one of the dominant mechanisms is the induction of co-inhibitory receptors on tumor-specific T cells and expression of corresponding co-inhibitory ligands by tumor or other cells within tumor stroma, leading to complete or partial loss of T-cell effector functions. Amplified co-inhibitory interactions in the cancer microenvironment impede not only immune tumor surveillance, but also therapeutic immune interventions that may explain the failure of approaches aimed at stimulation of T cells, including tumor antigen-based vaccination and T cell stimulatory cytokines. A prime example of the co-inhibitory interactions is the B7-H1 (PD-L1)/PD-1 pathway. Early studies from our and other laboratories demonstrate a critical role of this pathway in the evasion of cancer immunity, and blockade of this pathway enhances ongoing immune responses against tumors. Recent phase I clinical trials conducted using a fully human antibody to PD-1 demonstrated durable objective (partial and complete) responses in 33% of pretreated metastatic melanoma patients (n=46). Collectively, these studies support B7-H1 as an important co-inhibitory molecule in the down-regulation of immune responses in the melanoma microenvironment and blockade of the B7-H1/PD-1 pathway as one of the most promising approaches for the treatment of melanoma. Project 2 will extend these laboratory and clinical findings in three directions;
The specific aims are:
Aim 1 : to assess the association between B7-H1/PD-1 expression in human melanoma microenvironment with clinical response to anti-PD-1 therapy;
Aim 2 : to study effector mechanisms of the B7-H1/PD-1 blockade in augmenting anti-melanoma immunity and in melanoma regression;
and Aim 3 : to maximize melanoma therapeutic immunity by mechanism-based combinatory approaches. Based on our finding that B7-H1 expression by melanoma is directly and extensively up-regulated by interferons, the combination of B7-H1/PD-1 blockade will be tested with IL-2 and interferon-a 2b, and with selective mutant BRAF inhibitors, which promote tumor T-cell infiltration. Our studies should have direct impact for current development of B7-H1/PD-1 blockade as a novel and promising approach for melanoma therapy.

Public Health Relevance

This proposal is based on exciting findings that the blockade of B7-H1/PD-1 interaction by an antibody can vastly augment immune responses, and produces clinical regression of advanced and metastatic melanoma in patients. The studies will identify potential predictive biomarkers for the patients who are most likely to respond to therapy, and will provide novel approaches to increase treatment efficacy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
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Special Emphasis Panel (ZCA1-RPRB-0)
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Yale University
New Haven
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