Epigenetic Effectors of Tumor Response to Immune Checkpoint Inhibitors
Abstract
Melanoma is a major world health problem with an incidence rate that is rising rapidly. Though early-stage disease may be cured with surgery, late-stage disease is often fatal. Within the past several years, there has been tremendous progress in novel melanoma therapies, particularly with regard to immunotherapy highlighted by the Food and Drug Administration (FDA) approval of ipilimumab (anti-CTLA4 antibody) in 2011 and pembrolizumab and nivolumab (anti-PD1 antibodies) for melanoma in 2014 and 2015. Though response rates for monotherapy with these agents are modest (~15% for anti-CTLA4 and ~34% for anti-PD1), such responses are often durable with 2-year survival rates for up to 43% in patients treated with anti-PD-1 monotherapy and a 10-year survival rate of 20% for those treated with anti-CTLA4. When CTLA-4 and PD-1 blockade are combined, response rates and durability of responses are significantly higher, leading to the FDA approval of this regimen (ipilimumab + nivolumab) in 2015; however, associated toxicity with this regimen is admittedly high. Importantly, even with these advances, a significant proportion of patients still do not achieve clinical response to these agents. Therefore, there is tremendous need to identify actionable strategies that will enhance the effectiveness of these potent therapies in patients most likely to benefit. Some recent studies have provided evidence that inhibition of epigenetic enzymes, DNA methyltransferases and histone deacetylases, along with anti-PD1 may improve response rates in animal models. However, these studies provide isolated examples that are not based on unbiased systematic analysis of molecular changes during response to immune-checkpoint blockade. Whether specific patterns of alterations in chromatin modifications (or ?states?) may be associated with response to immune checkpoint inhibitors and could be used to design biomarkers has not been systematically tested. Our preliminary studies to systematically characterize epigenome in a small number of patient samples have shown that specific chromatin modification states may associate with response to anti-PD1 antibodies. Therefore, the goals of this proposal are to (1) systematically identify epigenetic alterations associated with response, (2) design rationale combinations of epigenetic inhibitors with anti-PD1 and anti-CTLA4 therapy, and (3) perform unbiased screens to identify epigenetic factors that potentiate cytotoxic T cells for tumor infiltration and enhanced response with anti-PD1/anti-CTLA4 therapy. Our approach will consist of utilizing cutting-edge high-throughput epigenomic methods, state-of-the-art computational analysis methodologies in patient samples, and genetically engineered mouse models to address these goals. This project is timely, as we have already collected longitudinal samples for epigenome analysis and the methods are in place to assay the epigenome directly from tumor samples. To achieve the goals of this project, we have gathered excellent support from world-renowned scientist Dr. Jennifer Wargo who is an expert in immune checkpoint blockade therapy in melanoma. My designated mentor will be Dr. Andrew Futreal, a pioneer in cancer genomics who discovered BRAF mutations in melanoma and was part of many other seminal discoveries. His current focus is on utilization of cancer genomics data for translation purposes, which fits perfectly with the goals of this Career Development Award. With him being the chair of my department and proximity to my lab, I believe he would serve as a perfect mentor for my proposal and my career development. If successful, the proposed studies will not only enhance our knowledge on role of epigenome in resistance to immune-checkpoint blockade, but also provide solid foundation to future clinical trials for epigenomic prognostic assays and combination therapy strategies in melanoma as well as other kinds of cancers such as lung cancer. In summary, our st
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710269
Entities
People
- Kunal Rai
Organizations
- United States Army
- University of Texas at Austin