Defining Impact of HDAC Inhibitors on Tumor Immunogenicity, T-Cell Functionality, and PD-1 Blockade Response in NSCLC Patients
Abstract
Scientific Objective and Rationale: In one of the most significant breakthroughs in cancer treatment, recent studies have demonstrated the ability of immunotherapy to induce deep and durable anti-tumor responses. The most promising approaches, with activity across multiple cancer types, target immune system cells called T cells by increasing their activity against tumors (e.g., the PD-1 blockade approach). However, the actual response rates are relatively low (e.g., ~20% in unselected lung cancer patients using PD-1 blockade). Consequently, there is an urgent need to develop new combinatory approaches to enhance and sustain benefit from PD-1 blockade. In our recently published work, we found that strategies that increase the expression of genes that enhance T cell presence in tumors greatly augment the response to PD-1 blockade. Specifically, we found that epigenetic agents in the form of histone deacetylase inhibitors (HDACi) possess the ability to enhance T cell presence in tumors. These findings have led to a Merck-supported Phase I/II clinical trial that is currently accruing patients to test the combination of HDACi and PD-1 blockade (ClinicalTrials.gov; Identifier: NCT02638090). This novel clinical trial will determine whether concurrent administration of HDACi vorinostat and the PD-1 blockade agent pembrolizumab will result in a higher response rate and progression-free survival than pembrolizumab alone. The studies proposed in this application will specifically help define tumor characteristics associated with response to PD-1 blockade and the impact of HDACi on tumor immunogenicity and response. These important correlative studies can provide a framework to assess how PD-1 blockade and HDACi modulate the tumor microenvironment, characterize the potential utility of gene expression biomarkers in response to treatment, and identify resistance mechanisms. The preclinical studies will investigate novel ways of boosting T cell levels and immunotherapy response through a new combination of epigenetic agents. Overall, these studies could have a significant impact on the area of immunotherapy by helping understand the impact of PD-1 blockade and epigenetic agents on the tumor environment and linking these changes to patient response. These studies directly address the following three Lung Cancer Research Program Areas of Emphasis: 1. Identify innovative strategies for prevention and treatment of early and/or localized lung cancer. 2. Understand predictive and prognostic markers to identify responders and non-responders. 3. Understand susceptibility or resistance to treatment. Applicability of the Research: Key points related to the applicability of this research are summarized below. 1. Types of Patients: The studies proposed here can provide substantial benefit to lung cancer patients. Moreover, since the underlying mechanisms we are studying may also exist in other cancer types, the applicability of this research can be much broader. 2. Clinical Applications: These studies will determine whether a combination of PD-1 blockade and HDACi is an efficacious strategy for lung cancer patients and investigate the underlying mechanisms of action of this combined treatment. 3. Clinical Timeframe: We believe that we can achieve a clinically useful outcome upon completion of this 3-year proposal. Impact on Lung Cancer Research: The studies proposed here will investigate the potential mechanisms of action of a new combination therapy that could have a significant impact on treatment strategies for lung cancer patients. Project Relevance: Lung cancer is the leading cause of cancer deaths worldwide. Despite some therapeutic advances over the last several decades, the overall 5-year survival remains low. If successful, the studies proposed here could have a significant impact on reducing lung cancer mortality in military Service members, as well as in the general population.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810409
Entities
People
- Amer Beg
Organizations
- H. Lee Moffitt Cancer Center & Research Institute
- United States Army