Harnessing the Immune System to Enhance Chemotherapeutic Response of Bladder Cancer
Abstract
The current proposed research aims to address the Fiscal Year 2020 Peer Reviewed Cancer Research Program Topic Area “bladder cancer.” Bladder cancer is the second most common urologic malignancy, following prostate cancer, and it is estimated to annually cause 17,980 deaths in the United States. This is comparable to the projected 33,330 annual prostate cancer deaths in the United States. Despite these statistics, the 2017 National Cancer Institute funding allotted for bladder cancer research – approximately $23 million (M) – was significantly under-proportioned to that awarded for prostate cancer research ($233M). Therefore, this is a significantly understudied and underfunded cancer type; and thus, requires much needed research attention. Cytotoxic chemotherapy is a standard treatment for bladder cancer patients. However, it is historically thought to weaken the patients’ immune system, which is an undesirable effect. However, precisely how chemotherapy weakens bladder cancer patients’ immune system is not clarified and is the objective of the current study. Most cancer studies focus on unleashing the patients’ own immune cells, called the “killer” T cells, to blast tumor cells. This proposal is crucial to understanding how an understudied immune cell type (i.e., neutrophil) exerts “stop” signals to entrap, disable, and weaken the “killer” T cells in bladder cancer. New tumor models will be integrated with cutting edge technologies to characterize these neutrophils, and also their “stop” signals. Most importantly, at least two Food and Drug Administration (FDA)-approved drugs that are able to blast these “stop” signals away will be evaluated in an attempt to relieve the “killer” T cells and reactivate their killer status to blast bladder tumor cells. If successful, the immediate clinical impact of the current proposal is apparent. Early-phase clinical trials will be initiated at the conclusion of our study to evaluate the combination of these FDA-approved drugs with chemotherapy to reactivate the patients’ own “killer” T cells. Such therapies will directly benefit Veterans with bladder cancers, and the scientific knowledge emerging from the current study will likely extend beyond bladder cancer, to benefit Veterans suffering from other cancers. Studies from this proposal will not only identify strategies that improve chemotherapy response, but also add knowledge to another type of therapy that relies on “killer” T cell function (i.e., immune checkpoint inhibitors). Recent FDA approval of immune checkpoint inhibitors demonstrated remarkable efficacies on a subset of advanced bladder cancer patients. However, more than 70% of patients do not respond to immune checkpoint inhibitors, and ongoing clinical trials combining chemotherapy with immune checkpoint inhibitors failed miserably. Our proposal is not only crucial to explore an understudied immune cell type, but also to discover how we can manipulate them to unleash “killer” T cells. This knowledge is very valuable for other therapies (e.g. immune checkpoint inhibitors).
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110452
Entities
People
- Keith Chan
Organizations
- Cedars-Sinai Medical Center
- United States Army