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Principal Investigator: Kayvan R Keshari
Organization: SLOAN-KETTERING INST CAN RESEARCH
Fiscal Year: 2024
Award: $668,212
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
While checkpoint inhibitors and chimeric antigen receptor (CAR) T cells undergo widespread investigation as
approaches to unleash the immune system’s tumor-targeting abilities, the mechanisms by which these therapies
fail is the subject of great debate. In the setting of solid tumors, it is believed that the microenvironment is hostile,
excluding T cells and/or inhibiting their ability to proliferate or be activated. A dearth of metabolic precursors,
most notably glucose, has been implicated as inhibiting T-cell function. There remains an unmet need for
approaches to better understand T-cell metabolism and its impact on tumors in vivo, as well as a method to modulate
this metabolic limitation to overcome T-cell exhaustion.
Given extensive preliminary data, we have developed a model system to explore T-cell exhaustion using primary T
cells stimulated in vitro. We have also identified a metabolic mechanism that can overcome limited glycolytic flux by
utilizing another biologically available substrate: fructose. Moreover, we have optimized methods to trace
metabolism in vitro and in vivo using hyperpolarized magnetic resonance (HP MR), which can detect changes in
metabolism in real time. Taken together, these approaches provide a platform for studying immunometabolism both
in vitro and in vivo in a syngeneic model of melanoma, which has great potential for future immunotherapeutics.
The objective of this innovative proposal is to utilize our in vitro and in vivo models to interrogate the metabolism of
T cells. In Aim 1, we will explore T-cell metabolism in vivo in order to reverse the reduced glycolytic flux in exhausted
T cells. In Aim 2, taking advantage of our newly developed HP fructose, we will metabolically image fructose
metabolism in T cells using our newly developed HP microNMR and in vivo with HP magnetic resonance
spectroscopic imaging (MRSI). We will then translate this approach to tumor-bearing mice in Aim 3, where we
combine T-cell therapy and HP MRI to treat a syngeneic model of melanoma.
It is the overarching goal of this proposal to use these novel approaches in metabolism and metabolic imaging to
further our understanding of immunometabolism and lay the foundation for future immunotherapy strategies in
patients.
Terms: <1H- Nuclear Magnetic Resonance Spectroscopic Imaging><Address><Animal Model><Animal Models and Related Studies><Bioavailability><Biochemistry><Biologic Models><Biological Availability><Biological Chemistry><Biological Models><Body Tissues><CAR T cells><CAR modified T cells><CAR-T><CAR-Ts><Cancer Biology><Cancers><Carbon><Cell Function><Cell Physiology><Cell Process><Cellular Function><Cellular Metabolic Process><Cellular Physiology><Cellular Process><Charge><Checkpoint inhibitor><Clinic><D-Glucose><Data><Dextrose><Diet><Dietary Component><Effectiveness><Energy Expenditure><Energy Metabolism><Engineering><Enzyme Gene><Enzymes><Exclusion><Exhibits><Foundations><Fructose><Future><GLUT-2 protein><GLUT2><GLUT2 gene><GLUT2 protein><Gluconeogenesis><Glucose><Glucose Binding Protein><Glucose Transport Protein><Glucose Transporter><Glucose transporter type 2 protein><Glycolysis><Goals><Humulin R><Image><Immune checkpoint inhibitor><Immune mediated therapy><Immune system><Immunologically Directed Therapy><Immunotherapeutic agent><Immunotherapy><In Vitro><Insulin><Intermediary Metabolism><Investigation><Isotopes><Ketohexokinase><Kidney><Kidney Urinary System><L-Serine><LC/MS><Levulose><Liver><MR Imaging><MR Tomography><MRI><MRIs><MRSI><Magnetic Resonance><Magnetic Resonance Imaging><Malignant Cell><Malignant Melanoma><Malignant Neoplasms><Malignant Tumor><Measures><Mediating><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Melanoma><Metabolic><Metabolic Processes><Metabolism><Methods><Mice><Mice Mammals><Model System><Modeling><Monosaccharides><Motivation><Murine><Mus><NMR Imaging><NMR Tomography><Novolin R><Nuclear Magnetic Resonance Imaging><Nutrient><O element><O2 element><Oxygen><Pathway interactions><Patients><Physiologic Availability><Production><Proliferating><Proton Magnetic Resonance Spectroscopic Imaging><Regular Insulin><Research><Serine><Small Intestines><Solid Neoplasm><Solid Tumor><Subcellular Process><System><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell targeted therapeutics><T cell therapy><T cells for CAR><T-Cell Activation><T-Cells><T-Lymphocyte><T-cell therapeutics><T-cell transfer therapy><Technology><Teff cell><Time><Tissues><Titrations><Translating><Translations><Tumor Cell><Warburg Effect><Work><Zeugmatography><activate T cells><adoptive T cell transfer><adoptive T-cell therapy><anti-cancer immunotherapy><anticancer immunotherapy><beta-D-fructopyranose 1-phosphate><cancer biomarkers><cancer cell><cancer immunotherapy><cancer markers><cancer microenvironment><cell metabolism><cellular metabaolism><check point blockade><check point inhibition><checkpoint blockade><checkpoint inhibition><chimeric antigen T cell receptor><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cells><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><diets><effector T cell><engineered T cells><exhaust><exhaustion><extracellular><fructose-1-phosphate><genetically engineered T-cells><glucose biosynthesis><hepatic body system><hepatic organ system><imaging><imaging approach><imaging based approach><immune check point blockade><immune check point inhibition><immune check point inhibitor><immune checkpoint blockade><immune checkpoint inhibition><immune drugs><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapeutics><immune-based therapies><immune-based treatments><immuno therapy><immunologic therapeutics><immunotherapeutics><immunotherapy agent><immunotherapy for cancer><immunotherapy of cancer><in vivo><in vivo Model><innovate><innovation><innovative><liquid chromatography mass spectrometry><magnetic resonance spectroscopic imaging><malignancy><metabolic imaging><metabolism measurement><metabolomics><metabonomics><model of animal><neoplasm/cancer><neoplastic cell><new approaches><new technology><non-invasive imaging><noninvasive imaging><novel><novel approaches><novel strategies><novel strategy><novel technologies><overexpress><overexpression><pathway><renal><response><small bowel><solute carrier family 2, facilitated glucose transporter, member 2 protein><sugar><therapeutic T-cell platform><thymus derived lymphocyte><tool><trafficking><transgenic T- cells><translation><tumor><tumor microenvironment>