The promise of cancer immunotherapy is based upon the exquisite specificity of the immune system, through which a potent machinery can eliminate targeted cells. However, despite some notable examples of success, progress in developing this form of cancer therapy has fallen short of expectations. Major insights explaining the limitations of T cell-based cancer immunotherapies have come from the discovery of inhibitory co-receptors or pathways termed immune checkpoints, which restrain T cell functions in normal physiologic settings as well as in the context of neoplastic disease. Recent evidence suggests that tumors may "usurp" immunological checkpoint mechanisms to create a barrier against antitumor immune responses - including endogenous responses and those induced by immunotherapies such as cancer vaccines. Animal cancer models demonstrate that blocking the interaction of inhibitory molecules on tumor cells with their co-receptors on tumor-specific T cells can "release the brakes" on antitumor immunity and cause tumor regression. Thus, checkpoint inhibition, applied alone or in combination with vaccines, represents an important new therapeutic approach for enhancing antitumor immunity. One of the most interesting inhibitory co-receptors is PD-1, that is induced on activated T cells and down-modulates critical functions in both CD4+ ("helper") and CD8+ ("killer") subsets. The major ligand for PD-1 is B7-H1 (PDL1), a B7 family member normally expressed by several leukocyte subsets upon activation, and aberrantly expressed in many human cancers. These findings, highlighting multiple mechanisms by which PD-1/B7-H1 interactions may inhibit antitumor immunity, have provided a rationale for clinical trials in cancer patients using fully human antibodies blocking PD-1 or B7-H1. Notably, objective tumor regressions were observed in the first phase I trial of PD-1 blockade in patients with advanced treatment-refractory metastatic solid tumors. It is now critically important to better understand the regulation and function of PD-1 and B7-H1, and to discern the effects of PD-1/B7-H1 blockade on antitumor immunity. In current proposal, we will test hypothesis that modulation of B7-H1/PD-1 inhibitory pathway could vastly enhance efficacy of cancer immunotherapy by improving tumor microenvironment and protecting ongoing T cell activity. The current proposal integrates basic and clinical science, and will use animal models and human in vitro systems to achieve the following aims: 1) To define mechanisms regulating B7-H1 expression by tumor cells and other cell types in the tumor microenvironment;2) To characterize factors influencing PD-1 expression by T cells, particularly in the context of vaccine-induced stimulation;and 3) To characterize immunological mechanisms underlying the clinical effects of B7-H1/PD-1 blockade in cancer therapy. Taken together, results from these studies will enable the rational clinical development of PD-1/B7-H1 blockade, alone or in combinatorial regimens, in cancer therapy.

Public Health Relevance

Although remarkable progress has been made on a scientific level in understanding regulatory processes governing the activity of the immune system against cancer, the clinical application of these findings to develop effective cancer therapies will require a more detailed knowledge of the molecules and pathways involved. Our objectives are 1) to elucidate how interactions of the immune regulatory molecules B7-H1, expressed by cancer cells, and PD-1, expressed by activated antitumor T lymphocytes, support cancer progression;and 2) to use this knowledge to develop effective cancer immunotherapies based on blockade of B7-H1/PD-1 ligation.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA142779-05
Application #
8676698
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Song, Min-Kyung H
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Nghiem, Paul T; Bhatia, Shailender; Lipson, Evan J et al. (2016) PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. N Engl J Med 374:2542-52
Danilova, Ludmila; Wang, Hao; Sunshine, Joel et al. (2016) Association of PD-1/PD-L axis expression with cytolytic activity, mutational load, and prognosis in melanoma and other solid tumors. Proc Natl Acad Sci U S A 113:E7769-E7777
Lipson, Evan J; Bagnasco, Serena M; Moore Jr, Jack et al. (2016) Tumor Regression and Allograft Rejection after Administration of Anti-PD-1. N Engl J Med 374:896-8
Rodić, Nemanja; Anders, Robert A; Eshleman, James R et al. (2015) PD-L1 expression in melanocytic lesions does not correlate with the BRAF V600E mutation. Cancer Immunol Res 3:110-5
Taube, Janis M; Young, Geoffrey D; McMiller, Tracee L et al. (2015) Differential Expression of Immune-Regulatory Genes Associated with PD-L1 Display in Melanoma: Implications for PD-1 Pathway Blockade. Clin Cancer Res 21:3969-76
Lipson, Evan J; Forde, Patrick M; Hammers, Hans-Joerg et al. (2015) Antagonists of PD-1 and PD-L1 in Cancer Treatment. Semin Oncol 42:587-600
Topalian, Suzanne L; Drake, Charles G; Pardoll, Drew M (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27:450-61
Chen, Lieping; Han, Xue (2015) Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J Clin Invest 125:3384-91
Sunshine, Joel; Taube, Janis M (2015) PD-1/PD-L1 inhibitors. Curr Opin Pharmacol 23:32-8
Flies, Dallas B; Higuchi, Tomoe; Chen, Lieping (2015) Mechanistic Assessment of PD-1H Coinhibitory Receptor-Induced T Cell Tolerance to Allogeneic Antigens. J Immunol 194:5294-304

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