Improving the efficacy of T-cell therapy and related treatments.
Cancers of the blood account for an estimated 8% of all cancers in adults, with 5-year survival projections as low as 47%. Treatment costs can surpass $800,000 in acute cases, with an average of $200,000 spent during the first two years of treatment. As the population ages, doctors anticipate a rise in the number of hematological malignancies and an increased demand for safe, effective means of treating these difficult-to-treat cancers. Chimeric antigen receptor (CAR) T cells are an emerging technology that have revolutionized cancer treatment, but an estimated 50% of patients do not respond to CAR T cell therapy. In nearly half of these cases failure is due to decreased persistence of the re-infused cells.
Technology Description
Cultured T cells capable of performing oxidative metabolism are more fit for the metabolic conditions they will encounter in vivo, such that promoting oxidative metabolism will increase their in vivo persistence. Oxidative metabolism also inversely correlates with how differentiated a cell becomes, which further impacts their survival. Thus, a major goal of cellular therapies has been to make effector cells both less differentiated and more oxidative before transfer into recipients. Increasing signaling through the cellular energy sensor AMP-activated protein kinase (AMPK) upregulates oxidative metabolism in human T cells while keeping them less differentiated. These changes are expected to increase both the durability and function of cellular therapies by promoting T cell longevity. By overexpressing the regulatory component of the AMPK heterotrimeric complex via lentiviral transduction, Pitt researchers propose to modulate AMPK activity and thereby improve the efficacy of multiple therapeutic interventions dependent upon T cells.Advantages
Improved in vivo persistence of ex vivo and in vitro manipulated effector T cells
Increased in vitro expansion of T cells during the culture period
Increased stability and suppressive functionality of regulatory T cells
May make adoptive cellular therapies effective for an estimated 20% of unresponsive patientsApplications
Increasing the efficacy of T cell therapy for treating cancer
Preventing or treating autoimmune diseases
Treating graft-versus-host disease
Preventing rejection following solid organ transplantationStage of Development
In vitro dataIP Status
Provisional patent application filed
Innovators
Craig A. Byersdorfer, MD, PhD
Associate Professor of Pediatrics, University of Pittsburgh School of Medicine
Associate Professor of Immunology, University of Pittsburgh School of Medicine
Assistant Medical Director, Hematopoietic Stem Cell Laboratory, UPMC Children’s Hospital of Pittsburgh
Dr. Byersdorfer Is a board-certified pediatric hematologist and oncologist with interests in blood and marrow transplantation and cellular therapies for the treatment of cancer. His research focuses on graft-versus-host disease and developing methods to improve the persistence of leukemia-targeting cellular therapies. His research accomplishments and mentorship have been awarded the Amy Strelzer-Manasevit Award from the American Society of Blood and Marrow Transplantation, the UPMC Hillman Cancer Center Junior Scholar Award in Basic Science, an Allen Humphrey Excellence in Mentoring Award, and the Medical Student Research Mentoring Merit award from the University of Pittsburgh. He is a member of the American Society of Hematology Scientific Committee on Transplantation Biology and Cellular Therapies.Education
Postdoctoral Research Fellow, University of Michigan School of Medicine
Clinical Fellowship, Pediatric Hematology/Oncology, CS Mott Children’s Hospital
Residency, Pediatrics, CS Mott Children’s Hospital
Internship, Pediatrics, CS Mott Children’s Hospital
MD/PhD, Washington University in St. Louis
BS/BA, Biochemistry and Molecular Biology, Chemistry, and German, University of Minnesota - DuluthSelect Publications
Dolezal JM, Wang H, Kulkarni S, Jackson L, Lu J, Ranganathan S, Goetzman ES, Bharathi S, Beezhold K, Byersdorfer CA, Prochownik EV. Sequential Adaptive Changes in a c-Myc-Driven Model of Hepatocellular Carcinoma. J Biol Chem. 2017 292(24):10068-10086. PMID: 28432125
Tkachev V, Goodell S, Opipari AW, Franchi L, Hao LY, Glick GD, Ferrara JLM, Byersdorfer CA. Programmed death-1 controls T cell survival by regulating oxidative metabolism. J Immunol. 2015 194(12):5789-800. PMID: 25972478
Gleimer M., Li Y, Chang L, Paczesny S, Hanauer DA, Frame DG, Byersdorfer CA, Reddy PR, Braun TM, Choi SW. Baseline body mass index among children and adults undergoing allogeneic hematopoietic cell transplantation: clinical characteristics and outcomes. BMT. 2015 50(3):402-10. PMID: 25531283
Glick GD, Rossignol R, Lyssiotis CA, Wahl D, Lesch C, Sanchez B, Liu X, Hao LY, Taylor C, Hurd A, Ferrara JLM, Tkachev V, Byersdorfer CA, Boros L, Opipari AW. Anaplerotic metabolism of alloreactive T cells provides a metabolic approach to treat graft-versus-host disease. J Pharm Exp Ther. 2014 351(2):298-307. PMID: 25125579
Byersdorfer CA, Tkachev V, Opipari AW, Goodell S, Swanson J, Sandquist S, Glick GD, Ferrara JLM. Effector T cells require fatty acid metabolism during murine graft-versus-host disease. Blood. 2013 122(18):3230-3237.PMID: 24046012