Human cancers are caused by the accumulation of mutations in specific genes. During the previous funding periods, our group was the first to determine the sequence of protein coding genes in human cancer and extended this approach to many tumor types. Through this work, we were able to identify candidate genes which had not been previously linked to tumorigenesis, define the basic genomic and neoantigen landscape of common human cancers, and point to pathways that underlie the complex genetic alterations in individual tumor types. More recently, we have identified genomic alterations that are important in the sensitivity and resistance of common targeted therapies as well as immunotherapy. We have pioneered the development of non-invasive circulating tumor DNA approaches to detect and monitor tumors, and have shown that these may be broadly applicable to many cancer patients. These analyses provided new insights into the mechanisms underlying tumorigenesis and have delineated novel avenues for clinical intervention. The recent intersection of cancer genomics with novel immunologic approaches is promising to revolutionize cancer therapeutics. Immune checkpoint inhibitors have demonstrated notable clinical benefit in a variety of tumor types and it is thought that these therapies exert their effects in large part through the immune recognition of mutation associated neoantigens encoded in the genomes of cancer cells. Unfortunately, despite initial successes, a large fraction of patients do not benefit from these treatments or develop resistance after an initial response. Our preliminary data suggest that clinical outcome to immune checkpoint blockade may be determined by the evolving genomic and neoantigen landscape in cancer and that dynamics of the T cell receptor repertoire may be a useful measure of therapeutic outcome. The purpose of this competitive renewal application is to extend our large-scale sequencing efforts to focus on understanding how the evolving genomic and immune landscapes regulate response and resistance to immune checkpoint blockade. First, we propose genome-wide analyses of tumors to examine cancer genome changes under the selective pressure of these therapies. We will develop and utilize computational approaches to predict mutation-associated neoantigens and functionally validate these through novel approaches in patient-specific T cell cultures. Finally, we will develop non-invasive approaches involving circulating tumor DNA and the T cell receptor repertoire to dynamically measure response and resistance to immune checkpoint blockade. The knowledge gained from the studies described in this application will help to broaden our understanding of the underlying mechanisms of response and resistance to immunotherapy. We envision that these analyses will be rapidly translated into the clinical setting, providing new approaches for predicting patient response to current immune-targeted therapies and for development of new treatment strategies.

Public Health Relevance

The research project in this application is focused on using genome-wide analyses to provide insights into mechanisms of response and resistance to immune targeted therapies, including immune checkpoint blockade. The proposed studies are likely to lead to a greater understanding of tumor evolution and evasion during these therapies, improved approaches for patient selection and tumor monitoring, and new avenues for diagnostic and therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA121113-11
Application #
9448461
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Ossandon, Miguel
Project Start
2006-05-01
Project End
2023-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
11
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Cottrell, T R; Thompson, E D; Forde, P M et al. (2018) Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC). Ann Oncol 29:1853-1860
Boudadi, Karim; Suzman, Daniel L; Anagnostou, Valsamo et al. (2018) Ipilimumab plus nivolumab and DNA-repair defects in AR-V7-expressing metastatic prostate cancer. Oncotarget 9:28561-28571
Forde, Patrick M; Chaft, Jamie E; Smith, Kellie N et al. (2018) Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med 378:1976-1986
Danilova, Ludmila; Anagnostou, Valsamo; Caushi, Justina X et al. (2018) The Mutation-Associated Neoantigen Functional Expansion of Specific T Cells (MANAFEST) Assay: A Sensitive Platform for Monitoring Antitumor Immunity. Cancer Immunol Res 6:888-899
Vaz, Michelle; Hwang, Stephen Y; Kagiampakis, Ioannis et al. (2017) Chronic Cigarette Smoke-Induced Epigenomic Changes Precede Sensitization of Bronchial Epithelial Cells to Single-Step Transformation by KRAS Mutations. Cancer Cell 32:360-376.e6
Spira, Avrum; Yurgelun, Matthew B; Alexandrov, Ludmil et al. (2017) Precancer Atlas to Drive Precision Prevention Trials. Cancer Res 77:1510-1541
Liu, Joyce F; Palakurthi, Sangeetha; Zeng, Qing et al. (2017) Establishment of Patient-Derived Tumor Xenograft Models of Epithelial Ovarian Cancer for Preclinical Evaluation of Novel Therapeutics. Clin Cancer Res 23:1263-1273
Husain, Hatim; Velculescu, Victor E (2017) Cancer DNA in the Circulation: The Liquid Biopsy. JAMA 318:1272-1274
Anagnostou, Valsamo; Smith, Kellie N; Forde, Patrick M et al. (2017) Evolution of Neoantigen Landscape during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer. Cancer Discov 7:264-276
AACR Project GENIE Consortium (2017) AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov 7:818-831

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