My laboratory has a long-standing interest in delineating how metabolism impacts T cell immune responses. We employ a top-down approach whereby we study primary human biospecimens and further understand direct mechanisms of action using cell line and murine models. Our primary goal is to translate our findings into interventions that can be applied in the context of cancer immunotherapies, with a focus on ovarian and prostate cancer.
Project 1: The Metabolic Ecosystem of Cancer and T Cells
Cancer cells and lymphocytes co-exist and interact in a dynamic environment. One outcome of this ecological interaction is exploitative competition for resources or interference competition involving direct secretion of immune suppressive metabolites by cancer cells. Our laboratory is interrogating metabolite profiles of human ovarian cancers (e.g. tumors, T cells, serum, interstitial fluids) using mass-spectrometry-based approaches to gain a better understanding of how the metabolism of different cellular compartments in the tumor microenvironment regulate antitumor responses.
Project 2: Engineering Designer CAR-T Cells
CAR-T cells have revolutionized how we approach treating cancers. However, they only work in a small number of patients. The environment created by the tumor presents a significant metabolic barrier for CAR-T cells to penetrate, survive, and function. Our research uses CRISPR-Cas9-based genome-editing technology to enhance the antitumor properties of CAR-T cells. A number of candidate metabolic genes are currently being tested using both gain- and loss-of-function approaches, and we expect to uncover further pathways that promote CAR-T cell efficacy in our metabolite profiling studies. This engineering approach will create designer CAR-T cells for testing in human clinical trials.
Project 3: Autophagy Regulation of T Cell Metabolism
Autophagy is a 'self-eating' program that cells can use to supply resources during periods of starvation and/or nutrient deprivation. Both cancer cells and T cells are able to activate autophagy, yet the outcomes and effects of autophagy are context dependent. We recently uncovered a surprising result that loss of autophagy function in T cells enhances tumor rejection. Our current research centers around understanding how autophagy can switch T effector cells into a more highly functional antitumor state. We are combining epigenetic and metabolomic studies to study this problem in the context of vaccinations in humans.
Project 4: Improving Metabolic Fidelity during CAR-T Cell Manufacturing
The process of manufacturing 'clinic ready' T cells for treating patients is highly complex. Further, the are no established methods that include metabolism in the criteria for evaluating predicted efficacy of CAR-T cells. Indeed, this manufacturing process is performed in an artificial system whereby CAR-T cells are grown in a non-physiological medium. We hypothesize that CAR-T cells become 'addicted' to these culture conditions and lose their metabolic fidelity after being infused into patients. We are using stable isotope labeling coupled with mass-spectrometry to establish the metabolic behavior of CAR-T cells throughout the manufacturing process. This information will then be used to tailor the processing steps such that the release mproduct is primed for high efficacy upon reaching the tumor microenvironment.
Project 5: Radiation and Immunotherapy
Radiation therapy is the most common type of treatment for cancer. In most jurisdictions, greater than 50% of all patients receive some form of radiation during the course of their care. There is unequivocal evidence that radiation has immune stimulating properties and this can be harnessed by combining radiation with immunotherapy. However, it is unclear which type of radiation is most appropriate, at what time it should be delivered, and which immunotherapy drug it should be delivered in combination with.
Our work focuses on external beam radiation and radionuclide therapy. Radionuclide therapy involves the use of different particles of radiation that are conjugated to targeting molecules (e.g. peptides, antibodies) that bind to cancer cells. In this way, a 'radiation payload' is given to the tumor that will subsequently prime the immune system through a process called immunogenic cell death. Currently, we are studying the combination of 177Lu-PSMA617 plus checkpoint inhibition therapy in treating hormone refractory metastatic prostate cancer.