Optimizing PD-1 Immunotherapy Through Increased T Cell Regeneration and Reduced Antigen Load
Abstract
The fiscal year 2022 (FY22) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas to be studied are: (1) Metastatic Cancers and (2) Stomach Cancer. The proposal addresses the FY22 PRCRP Overarching Challenge to advance immunotherapy across the different PRCRP Topic Areas. Stomach cancer is a devastating disease. There are approximately 1 million new gastric cancer cases and 700,000 gastric cancer deaths worldwide per year, accounting for almost 10% of all cancer deaths. The majority of gastric cancer patients present with locally advanced or metastatic disease. Chemotherapy is the standard first line treatment resulting in a median survival of only 10-12 months. The addition of immunotherapy to chemotherapy has modestly increased this survival. Immunotherapies seek to activate the patient’s immune system to fight cancer. One type of immunotherapy, immune checkpoint blockade, takes the brakes off the immune system and has the potential to revolutionize cancer care. However, immune checkpoint blockade using anti-PD-1 antibodies is limited by substantial resistance, with many if not most patients not achieving durable anti-tumor responses. There is limited mechanistic understanding of resistance to anti-PD-1. It was originally thought that anti-PD-1 restores potency to anti-tumor T cells, which express the highest levels of PD-1. Recent breakthroughs demonstrate that anti-PD-1 instead, induces proliferation and differentiation of precursors to anti-tumor T cells that that express intermediate or low levels of PD-1. These precursor T cells express a protein called PI3K-delta. This proposal tests the primary hypothesis that anti-PD-1 immunotherapy for gastric adenocarcinoma will be most effective when BOTH (1) the availability of precursor T cells is optimized by inhibition of PI3K-delta and (2) tumor antigen load is reduced by targeted anti-tumor therapy. Current biomarkers cannot adequately predict patients sensitivity and resistance to immunotherapy owing to incomplete understanding of how anti-PD-1 impacts T cell biology. In our mouse studies, anti-PD1 and PI3K-delta inhibition was associated with a higher ratio of TCF1+ to TCF- T cells (T cell regenerative index) in tumor and blood compared to anti-PD-1 alone. The secondary hypothesis is that the T cell regenerative index and tumor burden in patients with advanced gastric cancer can predict responsiveness to anti-PD-1 therapy and chemotherapy. This proposal has two Specific Aims. Aim 1: Determine whether PI3K-delta inhibition and tumor burden reduction improve anti-PD-1 immunotherapy in mouse models of gastric cancer. Aim 2: Assess quantitation of T cell regenerative capacity and tumor burden as predictive biomarkers of patient response to anti-PD-1 immunotherapy and chemotherapy for advanced gastric cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310635
Entities
People
- Sam Yoon
Organizations
- Columbia University
- United States Army