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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA121974-07
Application #
8557715
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
7
Fiscal Year
2013
Total Cost
$145,475
Indirect Cost
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Brash, Douglas E (2015) UV signature mutations. Photochem Photobiol 91:15-26
Jilaveanu, Lucia B; Parisi, Fabio; Barr, Meaghan L et al. (2015) PLEKHA5 as a Biomarker and Potential Mediator of Melanoma Brain Metastasis. Clin Cancer Res 21:2138-47
Kong, Yong; Krauthammer, Michael; Halaban, Ruth (2014) Rare SF3B1 R625 mutations in cutaneous melanoma. Melanoma Res 24:332-4
Taube, Janis M; Klein, Alison; Brahmer, Julie R et al. (2014) Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 20:5064-74
Zito, Giovanni; Saotome, Ichiko; Liu, Zongzhi et al. (2014) Spontaneous tumour regression in keratoacanthomas is driven by Wnt/retinoic acid signalling cross-talk. Nat Commun 5:3543
Leonhardt, Ralf M; Abrahimi, Parwiz; Mitchell, Susan M et al. (2014) Three tapasin docking sites in TAP cooperate to facilitate transporter stabilization and heterodimerization. J Immunol 192:2480-94
Sanmamed, Miguel F; Chen, Lieping (2014) Inducible expression of B7-H1 (PD-L1) and its selective role in tumor site immune modulation. Cancer J 20:256-61
Ho, Ping-Chih; Meeth, Katrina M; Tsui, Yao-Chen et al. (2014) Immune-based antitumor effects of BRAF inhibitors rely on signaling by CD40L and IFN?. Cancer Res 74:3205-17
Paglino, Justin C; Andres, Wells; van den Pol, Anthony N (2014) Autonomous parvoviruses neither stimulate nor are inhibited by the type I interferon response in human normal or cancer cells. J Virol 88:4932-42
Troche, Jose Ramon; Ferrucci, Leah M; Cartmel, Brenda et al. (2014) Systemic glucocorticoid use and early-onset basal cell carcinoma. Ann Epidemiol 24:625-7

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