Pharmacological compoounds to reactivate mitochondrial function in exhausted T cells.
Immunotherapy is uniquely positioned to shift the paradigm of cancer treatment. Cancer cells evade immune destruction in part by generating an immunosuppressive microenvironment. One immunotherapeutic approach to cancer treatment is adoptive tumor-infiltrating lymphocyte (TIL) therapy, in which T cells isolated from tumors are expanded in vitro and then reinfused into the patient to treat other tumors and distant metastases. The most responsive T cells are activated chronically and therefore succumb to a persistent hypo-responsiveness deemed T cell ‘exhaustion.’ As the most reactive to tumor antigens, exhausted T cells are the most desirable for expansion. However, the tumor-infiltrating T cells within the tumor microenvironment that would be crucial to an effective immune response instead display crippling metabolic defects characterized by loss of mitochondrial function and proliferate less vigorously compared to non-tumor-reactive T cells. Thus, most patients derive little benefit from this approach. The metabolic exhaustion of tumor-specific T cells is a significant barrier to adoptive TIL effectiveness, but metabolic reprogramming with pharmacologic agents may represent a solution.
Technology Description
Due to chronic activation, the most tumor-reactive T cells are exhausted and fail to effectively proliferate or kill target cells. Importantly, T cells that infiltrate tumors also fail to generate new mitochondria, and display repressed expression of the transcriptional co-activator PGC1α. Restoration of PGC1α function rescues T cell function and promotes mitochondrial activity within the tumor microenvironment, allowing those cells with the highest tumor specificity to more effectively proliferate alongside their less reactive counterparts and leading to a higher representation in the final cellular product. Rosiglitazone is a PPAR gamma agonist shown to promote mitochondrial biogenesis by upregulating PCG1α expression. Alongside sirtuins and resveratrol that promote PGC1α to target genes and transcriptional activity, these pharmacological compounds may reactivate mitochondrial function to support the expansion of exhausted T cells and promote the efficacy and adoptive TIL therapy.Advantages
* No other protocols use pharmacologic intervention of metabolic pathways to promote T cell expansionApplications
* Restore metabolic function to exhausted T cells
* Enable proliferation of exhausted T cells, which are likely more tumor-reactive than their non-exhausted counterparts, for use in adoptive TIL therapy
* Improving on existing immunotherapeutic approaches to treatment of cancer
* Developing new approaches to cancer treatmentStage of Development
In vivo dataIP Status
US patent pendingInnovators
Greg Delgoffe, PhD
Assistant Professor, Department of Immunology, University of Pittsburgh School of Medicine
Member, Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center
Chair, Program in Microbiology and Immunology Admissions Committee
Dr. Delgoffe is the principal investigator at The Delgoffe Lab, which studies the metabolic ocntributions to T cell fate and function, metabolic barriers to effective cancer immunotherapy, metabolic underpinnings of T cell exhaustion, regulatory T cell metabolism, oncolytic virus immunotherapy and modalities for therapeutic enhancement, energetic contributions to T cell activation and motility, and therapeutic improvement of chimeric antigen receptor T cell function via metabolic reprogramming. His work has immediate translation potential as modalities to improve cancer immunotherapy.Education
Postdoc, St. Jude Children’s Research Hospital
PhD, Johns Hopkins University
BS, Western Michigan UniversityPublications
* Dayana B. Rivadeneira, Kristin DePeaux, Yiyang Wang, Aditi Kulkarni, Tracy Tabib, Ashley V. Menk, Padmavathi Sampath, Robert Lafyatis, Robert L. Ferris, Saumendra N. Sarkar, Stephen H. Thorne, Greg M. Delgoffe. “Oncolytic Viruses Engineered to Enforce Leptin Expression Reprogram Tumor-Infiltrating T Cell Metabolism and Promote Tumor Clearance.” Immunity. 2019 Aug 27.
* Najjar YG, Menk AV, Sander C, Rao U, Karunamurthy A, Bhatia R, Zhai S, Kirkwood JM, Delgoffe GM. “Tumor cell oxidative metabolism as a barrier to PD-1 blockade immunotherapy in melanoma.” JCI Insight. 2019 Feb 5.
* Menk AV, Scharping NE, Rivadeneira DB, Calderon MJ, Watson MJ, Dunstane D, Watkins SC, Delgoffe GM. “4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses.” Journal of Experimental Medicine. 2018 March 6.
* Menk AV*, Scharping NE*, Moreci RS, Zeng X, Guy C, Salvatore S, Bae H, Xie J, Young HA, Wendell SG, Delgoffe GM. "Early TCR Signaling Induces Rapid Aerobic Glycolysis Enabling Distinct Acute T Cell Effector Functions." Cell Reports. 2018 Feb 6.
* Scharping NE*, Menk AV*, Whetstone RD, Zeng X, and Delgoffe GM. "Efficacy of PD-1 blockade immunotherapy is potentiated by metformin-induced reduction of tumor hypoxia." Cancer Immunol Res. 2016 Dec 10.