Diacylglycerol Activation of T-Cell Receptor Signaling for Cancer Immunotherapy
Abstract
Project Objective and Rationale: Harnessing one?s immune system to destroy tumor cells (i.e., immunotherapy) shows great promise for treatment of a wide range of cancers. The recent success of immunotherapies (e.g., Yervoy?, Opdivo?, and Keytruda?) have clearly illustrated the benefits of this treatment strategy for producing durable responses in patients suffering from melanoma, non-small cell lung cancer, renal cell carcinoma, classical Hodgkin?s lymphoma, and head and neck squamous cell cancer. Current immunotherapies produce clinical responses by blocking inhibitory receptors found on the surface of immune cells involved in recognition and elimination of tumor cells (i.e., T cells). Thus, patients receiving these treatments have a lowered activation threshold for developing an effective immune response against cancer. Despite remarkable success in the clinic, only 25%-30% of patients respond to current immunotherapies. These clinical results highlight the need to identify new molecular targets to overcome additional inhibitory mechanisms present in tumors that limit the full efficacy of immunotherapies. The goal of the proposed research is to disrupt ?fat? (i.e., lipid) signaling in T cells to boost the immune response against cancer. The Principal Investigator (PI) has identified a small molecule inhibitor that inactivates an enzyme, which limits T cell activity by controlling the metabolism of lipid signals in these immune cells. Dysfunctional T cells isolated from patient tumors contain high levels of this metabolic enzyme, suggesting that blockade of this inhibitory lipid pathway could serve as a new therapeutic strategy for restoring T cell function in tumors. The PI will apply innovative chemical biology and mass spectrometry technologies to elucidate mechanism of action of the lead compound and test its therapeutic efficacy in preclinical melanoma models. The overall goal is to advance this compound as a clinical drug candidate to expand treatment options available to U.S. military beneficiaries suffering from melanoma. Career Goals: The PI?s career goal is to become a leader in the cancer immunotherapy field by building an internationally recognized, translational research program that combines chemistry and mass spectrometry to understand and manipulate lipid metabolism to enhance the immune system?s ability to fight cancer. The Career Development Award will enable the PI to work closely with the designated mentor, Prof. Don Hunt (Professor of Chemistry, University of Virginia [UVa]), to learn the state of the art in mass spectrometry and cancer immunotherapy. The PI and Prof. Hunt have worked together to develop a career plan that will cultivate the PI?s career, management, grant writing, and leadership skills through seminars, training workshops, and international meetings. The PI will also have the opportunity to collaborate with the Human Immune Therapy Center (HITC) at UVa to integrate with the local clinical and cancer patient community. Benefits to Cancer Patients and Anticipated Timeline for Clinical Outcome: First, we aim to understand how the compound blocks protein activity in T cells to enable future drug development. Next, we will test the therapeutic efficacy of our lead compound in mouse models of melanoma. If successful, we will leverage the clinical trial infrastructure of the HITC to initiate Phase 1 clinical trials for melanoma patients whose primary tumors were surgically removed or have metastatic disease. We anticipate these studies can be accomplished in 3 years. Importantly, the lead compound has already been tested in humans for other diseases and found to be safe, which will greatly reduce the time frame and costs required to develop a drug candidate for clinical testing. Impact on Cancer Research and Patient Care: The proposed studies will deepen our fundamental understanding of lipid signaling involved in suppressing the immune response against cancer. A
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710487
Entities
People
- Ku-lung Hsu
Organizations
- United States Army
- University of Virginia