Immunotherapy with PD-1 or PD-L1 blockade is changing the landscape of cancer therapy. Nowhere is this more evident than in melanoma, where PD-1/L1 blockade induces sustained tumor responses in a significant number of patients leading to the first approval of the anti-PD-1 antibody pembrolizumab by the FDA. We have been studying response and resistance to this therapy and we are now in the position to propose mechanistic studies aimed at providing a molecular understanding of response, innate and acquired resistance to PD-1 blockade.
In Aim 1 we propose to characterize the T cell responses unleashed by blocking PD-1 in patient-derived samples. This will include phenotypic and functional studies in tumor infiltrating lymphocytes (TIL), as well as analyses of the fine antigen specificity of the therapeutic T cells. With the long term follow up of the initial cohortsof patients treated with the PD-1 blocking antibody pembrolizumab we are now seeing cases of delayed tumor progression after a long period of objective tumor response.
In Aim 2 we will study the potential mechanisms of these acquired resistance cases by analyzing changes in T cell function, antigen processing machinery and neoepitope mutational changes. We want to better understand response and resistance to PD-1/L1 blockade in an animal model. Therefore, in Aim 3 we propose generating a panel of BRAF-driven murine melanomas through carcinogenic exposure and characterize their response and resistance to anti-PD-1 therapy. These models will also be used to test combinatorial approaches to improve on the antitumor activity of PD-1/L1 blocking therapy. In conclusion, our proposal is based on hypothesis-driven bench-to-bedside-and-back mechanistic studies with the goal of patient-centric advances in cancer immunotherapy.

Public Health Relevance

Studies of the mechanisms of response and resistance to anti-PD-1 and anti-PD-L1 therapies in biopsies of patients with advanced melanoma and in melanoma murine models will provide useful information to design new combinatorial therapies for this cancer. In addition, we envision that this information will be useful to expand the use of anti-PD-1/L1 therapies to other cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA199205-01
Application #
8962676
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Mccarthy, Susan A
Project Start
2015-07-01
Project End
2016-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Shin, Daniel Sanghoon; Zaretsky, Jesse M; Escuin-Ordinas, Helena et al. (2017) Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations. Cancer Discov 7:188-201
Robert, Lidia; Ribas, Antoni; Hu-Lieskovan, Siwen (2016) Combining targeted therapy with immunotherapy. Can 1+1 equal more than 2? Semin Immunol 28:73-80
Homet Moreno, B; Ribas, A (2015) Anti-programmed cell death protein-1/ligand-1 therapy in different cancers. Br J Cancer 112:1421-7
Hu-Lieskovan, Siwen; Homet Moreno, Blanca; Ribas, Antoni (2015) Excluding T Cells: Is ?-Catenin the Full Story? Cancer Cell 27:749-50
Teng, Michele W L; Ngiow, Shin Foong; Ribas, Antoni et al. (2015) Classifying Cancers Based on T-cell Infiltration and PD-L1. Cancer Res 75:2139-45