Balancing T-Cell Function and Metabolism for Immunotherapy
Abstract
Significance and Impact: Immunotherapy has revolutionized the treatment of cancers. Two major advances in immunotherapy have been the discovery of antibodies (proteins) that can re-invigorate immune cells, classified as checkpoint blockade, and the evolution of cell-based drugs, called adoptive cell therapy. While antibody-based checkpoint blockade immunotherapy has the potential to offer responses in patients with tumors that have immune cell infiltrates, adoptive cell therapy utilizes expanded, and optionally modified, cells as drugs. The clinical translation of cells as drugs in turn enables new challenges for biomanufacturing and in determining the efficacy of these drugs prior to infusion. Solid tumors like melanoma demonstrate abnormal features including the irregular growth of blood vessels. This non-uniform pattern of blood vessels in turn impacts the delivery of oxygen and nutrients to the different parts of the tumor. Thus, tumors harbor regions where there is an extreme competition for the available scarce nutrients and oxygen, and the tumor cells have evolved mechanisms to be able to effectively outcompete other types of cells including immune cells, for these nutrients. When translating cells as drugs, one of the major obstacles to effective treatment is that the infused cells must be able to compete effectively with the tumor cells for these nutrients within the tumor microenvironment. Despite this, however, within immune cell populations, the link between metabolism, the ability to utilize nutrients, and function, the ability to kill tumor cells is not very well-documented. The objective of this proposal is to develop a single-cell based methodology for directly mapping the dynamic metabolic profile of immune cells and their ability to kill tumor cells in high-throughput. The hypothesis underlying this proposal is that understanding mechanisms that allow immune cells to balance metabolism and function will enable the engineering of cells that have the ability to survive and function within the harsh tumor microenvironment, and this in turn will lead to superior anti-tumor efficacy, and ultimately better patient outcomes. Although we have chosen melanoma as the tumor to study, advances in studying immune cell metabolism is likely to have broad applicability across diverse solid tumors since nutrient competition is a conserved featured of solid tumors. We anticipate that the advances stemming from this 3-year proposal can be translated into the clinic, and our collaborators at MD Anderson Cancer Center have already initiated clinical trials infusing cells as drugs. Career Objectives: This research is very well aligned with the Principal Investigator’s career objectives of using engineering approaches to solve clinical problems. Towards this objective, he has already established a multidisciplinary research group and has pioneered the development of translational single cell methods to determine the potency of a variety of adoptive cell therapies. His mentor on this grant, Dr. Hwu, is a renowned clinical oncologist who has made seminal contributions to immunotherapy and has worked extensively on cells as drugs. In order to broaden his training, one of the major goals of the mentored phase of the grant is to experience the clinical care of patients undergoing treatment with immunotherapies to enhance his understanding of the current clinical questions in this field and, in the long term, to inform him regarding emerging opportunities to ultimately translate his work to the clinic. Military Relevance: The U.S. military and general populations may have differences either in the exposure to sunlight or to other underlying risk factors associated with melanoma. The most recent and comprehensive study comparing the military versus the National Cancer Institute Surveillance, Epidemiology, and End Results Program (SEER) demonstrated that the overall melanoma incidence rate in active duty milita
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710370
Entities
People
- Navin Varadarajan
Organizations
- United States Army
- University of Houston