UPMC Children's Hospital of Pittsburgh BMT-CT Division News
December 6, 2019
The Blood and Marrow Transplantation and Cellular Therapies Division at UPMC Children’s Hospital of Pittsburgh is one of the leading centers in the United States and globally advancing new and safer treatment approaches for numerous medical conditions. Below are recent updates from the Division: speaking engagements, new grants, awards, and recent publications.
Speaking Engagements
Division Chief Paul Szabolcs, MD, was invited to give numerous lectures and presentations in 2019. Among his invited speaking engagements were the following:
- “A Longitudinal Analysis of TCRß Repertoire Diversity in Immune Tolerance of Pediatric Patients Post-UCBT: T Cell Clonal Deletion Over Clonal Anergy.” Presented at the 45th European Society for Blood and Marrow Transplantation annual meeting in Frankfurt, Germany, on March 25, 2019.
- “Induction of Immune Tolerance by Allogeneic Transplantation.” Delivered at the Children’s University Hospital Tubingen in Tubingen, Germany, on March 28, 2019.
- “New Challenge of Immunotherapy: Tolerance and Immunity, Mechanisms and Proposals.” Presented at the Universidad Autonoma de Madrid in Madrid, Spain, on June 17-19, 2019.
- “Combined Lung + Bone Marrow Transplant: Progress and Challenges.” Lecture delivered at the Major Complications of Dyskeratosis Congenita/Telomere Biology Disorders meeting in Boston, Massachusetts, on September 12-13, 2019.
New Grants
In September, Craig Byersdorfer, MD, PhD, was awarded a Hyundai Hope on Wheels® Scholar Grant for a project on “Minimizing Cell Therapy-Associated Cytokine Release Syndrome.” The $300,000 grant is one of 24 given to researchers across the country. The Scholar Senior Research Grants fund research projects designed to improve the treatment and quality of life for children with cancer. The ultimate goal of the Scholar Senior Research Grant program is to find cures for childhood cancers once and for all. Since 1998, the program has funded $115 million in research to Children’s Oncology Group (COG) member institutions nationwide. UPMC Children’s Division of Pediatric Hematology/Oncology researcher Kelly Bailey, MD, PhD, also was a recipient of one of the awards for her work with Ewing’s sarcoma.
Dr. Byersdorfer also received a U.S. Department of Defense (DOD) grant for a new study called “Leveraging T Cell Metabolism to Improve Anticancer Immunotherapies.” In this study, Dr. Byersdorfer and colleagues will be investigating metabolic pathways that may be able to augment and increase in vivo persistence of tumor-reactive lymphocytes, specifically T cells involved in antitumor responses against acute myelogenous and acute lymphoblastic leukemia. Immune cell targeting of tumor antigens offer hope for these difficult cases, but the full potential of adoptive immunotherapy remains unrealized. The innovation for this project comes from taking a recognized clinical problem (a lack of immune cell persistence) and addressing it by metabolically reprogramming an established treatment, making this innovation both conceptual and technical.
The first aim of Dr. Byersdorfer’s study will elucidate metabolic changes in human T cells following constitutive activation of AMPK or expression of PPAR-δ. His laboratory has recently generated lentiviral constructs bearing either mutant AMPKγ2 sequences, which drive AMPK activation, or full-length human PPAR-δ cDNA. Lentiviral genes will be transduced into human T cells and T cell metabolism assessed following in vitro and in vivo stimulation. The second aim of the study will determine the in vivo impact of constitutive AMPK activation or PPAR-δ expression on T cell persistence and subsequent antitumor responses. CAR T cells targeting human CD19 will be transduced with a second lentivirus bearing PPAR-δ or mutant AMPKγ2. CAR T cells, with or without metabolic manipulation, will then be injected with CD19+ leukemia cells into immunodeficient mice where both T cell persistence and antitumor responses will be measured. In a second model, cytotoxic lymphocytes (CTLs) will be generated against the antigen PR-1. PR1-reactive CTLs will then be transduced with metabolic lentiviral constructs and injected into immuno-deficient mice, followed by assessment of CTL persistence and the ability to clear a PR1-presenting tumor cell line. In a final series of experiments, primary human T cells will be expanded in vitro against primary human AML blasts, transduced with AMPK or PPAR-δ lentiviral constructs, and then tested for the ability to eliminate primary AML cells in vivo in an immunodeficient mouse model.
These studies seek to positively impact the wider field of immunotherapy by determining whether metabolic changes, such as constitutive activation of AMPK, can improve T cell responses by prolonging their survival and thereby lessening overall disease burden. These studies also are important for cancer research in general, as the ability to modulate immune responses is likely to be a cardinal feature in multiple treatment regimens.
Other Division News
Elizabeth Stenger, MD, MSc, was elected to the Board of Directors of the International Society for Cell & Gene Therapy (ISCT).
Recent Peer-Reviewed Publications and Abstracts
Hsu AP, Donkó A, Arrington ME, Swamydas M, Fink D, Das A, Escobedo O, Bonagura V, Szabolcs P, Steinberg HN, Bergerson J, Skoskiewicz A, Makhija M, Davis J, Foruraghi L, Palmer C, Fuleihan RL, Church JA, Bhandoola A, Lionakis MS, Campbell S, Leto TL, Kuhns DB, Holland SM. Dominant Activating RAC2 Mutation With Lymphopenia, Immunodeficiency, and Cytoskeletal Defects. Blood. 2019 May 2; 133(18): 1977-1988.
Dreyzin A, Michaels MG, Vander Lugt MT, Szabolcs P. Oral Ribavirin for Paramyxovirus Infection After Alemtuzumab-Containing Reduced-Intensity Conditioning HCT Regimen. Pediatr Transplant. 2019 Mar; 23(2): e13358.
Burk CM, Coffey KE, Mace EM, Bostwick BL, Chinn IK, Coban-Akdemir ZH, Jhangiani SN, Lupski JR, Ortiz D, Barnum JL, Allen SW, Robertson LM, Orange JS, Chong HJ. Immunodeficiency, Centromeric Instability, and Facial Anomalies (ICF) Syndrome With NK Dysfunction and EBV-Driven Malignancy Treated With Stem Cell Transplantation. J Allergy Clin Immunol Pract. 2019 Sep 11.
pii: S2213-2198(19)30765-2. doi: 10.1016/j.jaip.2019.08.040. Epub ahead of print.
