Defining mechanisms of immunotherapy resistance and targeting TIGIT in hepatobiliary cancers - Project Summary/Abstract Advanced stage hepatobiliary cancers, including hepatocellular carcinoma (HCC) and biliary tract cancers (BTC), are often rapidly fatal diseases due to a lack of effective systemic treatments for most patients. While anti-PD-1/L1 therapies have emerged as frontline treatments for hepatobiliary cancers, they only induce responses in a minority of patients. Identifying and thwarting resistance mechanisms to anti-PD-1/L1 therapies in hepatobiliary cancers is critical to expanding the effectiveness of immunotherapies in these diseases. T cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed on lymphocytes and NK cells, and is a candidate compensatory immune checkpoint which may mediate anti-PD-1/L1 treatment resistance in hepatobiliary cancers. This proposal presents a five-year research career development program encompassing the study of an anti-TIGIT antibody as a novel treatment in refractory hepatobiliary cancers and training objectives that will enable the applicant to independently lead clinical trial investigations, learn new technologies and computational methods using spatial and single-cell data, and gain an expertise in tumor immunology. The central hypothesis is that concomitant blockade of TIGIT and PD-1 will induce robust anti-tumor immunity against HCCs and BTCs. This hypothesis will be tested in the following aims: Aim 1) Conduct a phase 2 trial of an anti- TIGIT plus anti-PD-1 antibody regimen in hepatobiliary cancers refractory to PD-1 blockade. Aim 2) Characterize immune and molecular features of anti-PD-1/L1 therapy refractory tumors and identify markers of resistance or response to TIGIT blockade. Aim 3) Assess dynamics in circulating tumor DNA (ctDNA) to define genetic markers of anti-PD-1 and/or anti-TIGIT therapy resistance and evaluate its use as a non-invasive pharmacodynamic marker. These studies have the potential to expand the treatment armamentarium against hepatobiliary cancers, and uncover mechanisms of anti-PD-1/L1 or anti-TIGIT therapy resistance through systematic investigations of longitudinally collected tissue and blood specimens. The long-term goal of the applicant is to become a leader in clinical investigations of novel immunotherapies in hepatobiliary cancers integrated with in-depth and systematic studies to elucidate mechanisms of response and resistance. The proposed study will be conducted under the mentorship of Dr. David Gerber, a clinical trialist and translational investigator, Dr. Tao Wang, a cancer immunologist and computational scientist, and Dr. Hao Zhu, a translational scientist in the fields of liver regeneration and tumorigenesis. In addition to the candidate’s passion for science, the enthusiastic support of his experienced mentors, and the breadth of resources and expertise at UT Southwestern, this award will enable the applicant to transition into an independent investigator and generate new hypotheses or treatment approaches to improve the lives of patients with hepatobiliary cancers.
