Advances in tumor immunology have led to a better understanding of the immunoinhibitory mechanisms (e.g. inhibitory ligands/receptors and regulatory T cells) that create a major barrier to effective anti-tumor immunity. One of the most critical pathways responsible for mediating tumor-induced immune suppression is the programmed death-1 (PD-1) pathway. While the early results seen with PD-1 pathway blocking antibodies (Abs) in cancer have been encouraging, further study is required to optimize their use in RCC patients. Preliminary correlative studies suggest that while tumor PD-L1 expression may increase the likelihood of benefit with anti-PD-1, it fails to identify all responders. Predictive biomarker development and validation will help to guide this approach to the proper patients (Aims 1 and 2). The application of PD-1 blockade in the treatment nave setting may yield even better results and obviate the need for subsequent lines of therapy (Aim 2). Using a multi-faceted approach, this project will provide a better understanding of the mechanisms of action and resistance to PD-1 pathway blockade, thereby facilitating the development of effective combination regimens (Aims 2 and 3). We will study the impact of intra-tumoral heterogeneity on biomarker development through our unique collection of matched primary tumor and metastasis specimens in our SPORE Tissue Bank and samples obtained from two prospective clinical trials of patients receiving anti-PD-1 antibodies. Laboratory experiments will integrate novel Abs, engineered proteins and genetic tools including: 1) anti-PD-1, PD-L1, and PD-L2 monoclonal Abs for IHC of human tissues and long term treatment of mice; 2) whole-exome and transcriptome sequencing of both tumor and infiltrating T cells (TILs), which can be used to explore mechanisms of innate resistance, and 3) innovative murine models such as mice that conditionally lack PD-1 on specific cell types and reporter mice that enable FoxP3 visualization. This highly collaborative team of basic and clinical scientists brings together an exceptional collective expertise in RCC immunotherapy trials, the PD-1 pathway and tumor immunoregulation, which should facilitate the generation of clinically meaningful results.

Public Health Relevance

The proposed studies will determine the utility of various predictive biomarkers and the activity of anti-PD-1 therapy in treatment nave patients with RCC. Further, they will provide a better understanding of the mechanisms of action and resistance to PD-1 pathway blockade, which will facilitate the development of combination regimens. The results of these studies are not limited to simply improving the treatment of patients with clear cell (cc) and non-ccRCC, but could also inform the development of immunotherapy strategies for patients with other tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA101942-14
Application #
9554207
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Kuzmin, Igor A
Project Start
Project End
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
14
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
Scelo, Ghislaine; Muller, David C; Riboli, Elio et al. (2018) KIM-1 as a Blood-Based Marker for Early Detection of Kidney Cancer: A Prospective Nested Case-Control Study. Clin Cancer Res 24:5594-5601
Zhang, Jinfang; Bu, Xia; Wang, Haizhen et al. (2018) Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature 553:91-95
Gao, Xin; Jegede, Opeyemi; Gray, Connor et al. (2018) Comprehensive Genomic Profiling of Metastatic Tumors in a Phase 2 Biomarker Study of Everolimus in Advanced Renal Cell Carcinoma. Clin Genitourin Cancer 16:341-348
Liu, Wenjing; Chen, Binbin; Wang, Yang et al. (2018) RGMb protects against acute kidney injury by inhibiting tubular cell necroptosis via an MLKL-dependent mechanism. Proc Natl Acad Sci U S A 115:E1475-E1484
Iorgulescu, J Bryan; Braun, David; Oliveira, Giacomo et al. (2018) Acquired mechanisms of immune escape in cancer following immunotherapy. Genome Med 10:87
Gopal, Raj K; Kübler, Kirsten; Calvo, Sarah E et al. (2018) Widespread Chromosomal Losses and Mitochondrial DNA Alterations as Genetic Drivers in Hürthle Cell Carcinoma. Cancer Cell 34:242-255.e5
Nakashima, Hiroshi; Alayo, Quazim A; Penaloza-MacMaster, Pablo et al. (2018) Modeling tumor immunity of mouse glioblastoma by exhausted CD8+ T cells. Sci Rep 8:208
Signoretti, Sabina; Flaifel, Abdallah; Chen, Ying-Bei et al. (2018) Renal Cell Carcinoma in the Era of Precision Medicine: From Molecular Pathology to Tissue-Based Biomarkers. J Clin Oncol :JCO2018792259
Hamieh, Lana; Choueiri, Toni K; Ogórek, Barbara et al. (2018) Mechanisms of acquired resistance to rapalogs in metastatic renal cell carcinoma. PLoS Genet 14:e1007679
Gao, Xin; McDermott, David F (2018) Ipilimumab in combination with nivolumab for the treatment of renal cell carcinoma. Expert Opin Biol Ther 18:947-957

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