Overcoming Kidney Cancer Resistance to Immune Checkpoint Inhibitors
Abstract
Objective and Rationale: Cancer remains a leading cause of mortality among Americans, with kidney cancer among the most common afflicting men and women. Survival of patients with metastatic kidney cancer is poor (~10% in 5-years). Immune checkpoint inhibitors have improved the survival of many patients with metastatic disease, but the vast majority of cases (~60%) are resistant to this treatment. Having discovered DC-HIL protein, having shown them to be responsible for suppressing immune responses that defend against cancer, and having demonstrated that suppressor cells expressing these molecules are expanded in the blood of patients with metastatic cancers, we hypothesize that they may account for the high resistance of these cases to immune checkpoint inhibitor treatment. We will: (1) evaluate the ability of blood DC-HIL levels to predict responsiveness or resistance of metastatic kidney cancer patients to checkpoint inhibitors; (2) determine whether blood DC-HIL levels associate with immune defects in tumor-environment; and (3) examine whether combined currently best checkpoint inhibitors and DC-HIL-specific inhibitor produces better outcomes for more patients. The ultimate applicability of the research: What types of patients will it help, and how will it help them? We will study patients with metastatic kidney cancer. We will identify more reliable blood markers that can sort responders (vs. non-responders) to anti-PD1 treatment. We will develop better immune checkpoint inhibitors. What are the potential clinical applications, benefits, and risks? More reliable blood markers that predict response to immunotherapy will save time, money, and morbidity of metastatic kidney cancer patients. Finally, our proposal will promote development of a potentially better immune checkpoint inhibitor that may be used as monotherapy or in combination with existing inhibitors. What is the projected time it may take to achieve a clinically relevant outcome? 3 to 4 years of research. What are the likely contributions of this study to advancing the field of kidney cancer research? Identifying reliable prognostic markers will directly benefit treatment of patients with kidney cancer. Our studies will also improve our understanding of T-cell immunity in kidney cancer biology, particularly the mechanisms involved in interactions between the PDL1/PD1 pathway and our newly discovered DC-HIL pathway. The new knowledge gained will yield insight into whether blocking both pathways yields additive, synergistic, null, or counteractive effects, and thus a basis for further studies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010906
Entities
People
- Hans Hammers
Organizations
- United States Army
- University of Texas Southwestern Medical Center