Virally-mediated genetic reprogramming of CAR T cells to boost metabolic function for use in solid tumor immunotherapy.
Immunotherapy is a paradigm-shifting treatment for advanced cancers. One type of immunotherapy at the forefront of the field is the use of chimeric antigen receptor (CAR) T cells to genetically redirect T cells to tumor targets. CAR T cell therapy has been remarkably effective in blood cancers, but has yet to yield positive results in solid tumors due to the immunosuppressive microenvironment within the tumor, which represses T cell activity via chronic activation and metabolic destruction in a process deemed T cell ‘exhaustion’. In order to reap the benefits that this treatment has yielded for hematologic malignancies, CAR T cells will need to be more metabolically durable in order to perform in the microenvironment of solid tumors.
Technology Description
Using virally-mediated genetic reprogramming may be key to creating metabolically robust CAR T cells for use in solid tumor immunotherapy. Several target genes including Ppargc1a, Tfam, Nrf2, and ERRalpha, have been identified as overexpressing in T cells and promoting mitochondrial biogenesis, a crucial component of cellular metabolic fitness. During the process of CAR T cell generation, the metabolism of the target cell can also be modified by expressing factors involved in mitochondrial biogenesis. Further, these factors have been re-engineered to have higher transcriptional activity and resist negative regulation. Increased mitochondrial activity leads to increased metabolic fitness, promoting CAR T cell effectiveness even in currently-resistant solid tumors.Advantages
* Promotes overall health of the T cell
* Higher transcriptional activity compared to non-engineered genes
* Resistant to negative regulationApplications
* Promote metabolic function in and fitness in CAR T cells
* CAR T cell therapy for solid tumorsStage 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.