Tipping the DAMP/iDAMP Balance: Converting Immune Checkpoint Nonresponders into Responders
Abstract
The current proposed research aims to address the Fiscal Year 2018 Peer Reviewed Cancer Research Program Topic Area of immunotherapy, using bladder, pancreatic, and colon cancers as study models to demonstrate proof of concept. Immune checkpoint inhibitors are emerging as a promising treatment option for advanced cancer patients (e.g., Veterans), with remarkably durable response in certain patients. However, >70% of patients are non-responders, with undetermined causes. The objective is straightforward, to identify Food and Drug Administration (FDA)-approved drugs that can convert immune-checkpoint non-responders into responders. Rationale: Immune checkpoint inhibitors works by harnessing patients own immune cells (particularly T killer cells) to kill cancer cells. Analogous to car engineering, immune checkpoint inhibitors operate by removing the brakes on T killer cells, under the presumption that the ignition of T killer cells have been initiated to turn them on properly. We hypothesize that in immune checkpoint non-responders, the ignition of T killer cells are not properly sparked by another type of immune cell, i.e., dendritic cells. Therefore, simply removing brakes from unignited T cells will not work. In this proposal, we will propose a paradigm shifting concept to spark T cells properly to induce specific killing of cancer cells. By properly sparking T cells and concurrently removing the brakes by immune checkpoint inhibitors, we have realistic expectation to repurpose FDA-approved drugs that can spark T cells into clinical applications. The immediate clinical impact will be the subsequent initiation of clinical trials that can benefit Veterans with bladder, pancreatic or colon cancers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910775
Entities
People
- Keith Chan
Organizations
- Cedars-Sinai Medical Center
- United States Army