Stephan A. Grupp, MD, PhD

faculty photo
Professor of Pediatrics
Department: Pediatrics
Graduate Group Affiliations

Contact information
The Children's Hospital of Philadelphia
Colket Translational Research Building, Room 3006
3501 Civic Center Boulevard
Philadelphia, PA 19104
Office: 215-590-5475
Fax: (215) 590-3770
Education:
B.S.
University of Cincinnati (Magna cum laude), 1981.
Ph.D.
University of Cincinnati College of Medicine, 1985.
M.D.
University of Cincinnati College of Medicine, 1987.
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Description of Research Expertise

Research Interests

Role of the B cell receptor complex in B cell signaling and lymphoid development

Research Summary

Basic Science. The primary focus of my lab’s work is the development of targeted cell therapies and study of molecular signaling pathways in ALL. Our group has leveraged studies using primary human ALL xenografts into treatments being tested in a number of clinical trials.

We have demonstrated the importance of the mTOR pathway in leukemia and lymphoma, and demonstrated that inhibitors of mTOR signal transduction (such as sirolimus) are effective agents against pre-B ALL and against the lymphoproliferative disorder ALPS. These findings have direct translational significance in both ALL and ALPS, leading to Phase I, II, III (ASCT0431) and pilot trials in these diseases. We also demonstrated that signaling through the IL-7 receptor is key in the response of early B ALL cells to mTOR inhibitors. IL-7 and a related molecule called TSLP reverse the effect of mTOR inhibitors on pre-B ALL cells, providing insights into the potential mechanisms of the mTOR effect and a further opportunity for signal transduction inhibition in ALL. We are the ALL Xenograft Core Lab for the COG.


Translational. As the CCCR Director of Translational Research, I oversee research into clinical use of hematopoietic stem cells and T cell-based therapies. As an example, we have performed trials to improve outcome in neuroblastoma (NBL), a disease that has <15% long-term survival with chemo and ~35% with single autologous stem cell transplant (SCT). This has also lead to a phase III trial (ANBL0532) in the COG.

More recently, our group has been working with Dr. Carl June and the Penn Translational Research Program on chimeric antigen receptor (CAR)-based engineered T cell therapies. One target is CD19 in ALL, where we have developed chimeric immunoreceptor-armed T cells in an ongoing basic and translational collaboration with the June group. This approach has now been taken into pilot trials at CHOP and Penn. The first three adult patients on this clinical trial experienced remarkable clinical responses and unprecedented persistence and expansion of the therapeutic cells. We are now seeing similar results in pediatric patients with ALL.

Selected Publications

Asnani M, Hayer KE, Naqvi AS, Zheng S, Yang SY, Oldridge D, Ibrahim F, Maragkakis M, Gazzara MR, Black KL, Bagashev A, Taylor D, Mourelatos Z, Grupp SA, Barrett D, Maris JM, Sotillo E, Barash Y, Thomas-Tikhonenko A.: Retention of CD19 intron 2 contributes to CART-19 resistance in leukemias with subclonal frameshift mutations in CD19. Leukemia 34(4): 1202-1207, Apr 2020.

Singh N, Lee YG, Shestova O, Ravikumar P, Hayer KE, Hong SJ, Lu XM, Pajarillo R, Agarwal S, Kuramitsu S, Orlando EJ, Mueller KT, Good CR, Berger SL, Shalem O, Weitzman MD, Frey NV, Maude SL, Grupp SA, June CH, Gill S, Ruella M.: Impaired Death Receptor Signaling in Leukemia Causes Antigen-Independent Resistance by Inducing CAR T-cell Dysfunction. Cancer Discovery 10(4): 552-567, Apr 2020.

Arnold DE, Maude SL, Callahan CA, DiNofia AM, Grupp SA, Heimall JR.: Subcutaneous immunoglobulin replacement following CD19-specific chimeric antigen receptor T-cell therapy for B-cell acute lymphoblastic leukemia in pediatric patients. Pediatr Blood Cancer. 67(3): e28092, Mar 2020.

Tal Schechter-Finkelstein, Evelio Perez-Albuerne, Lin TF, Meredith S. Irwin, Essa M, Desai AV, Frangoul H, Gregory A. Yanik, L. Lee Dupuis, David A. Jacobsohn, Morris Kletzel, Ranalli M, Soni S, Seif AE, Stephan A. Grupp, Christopher C. Dvorak: Veno-occlusive disease after high-dose busulfan-melphalan in neuroblastoma. Bone Marrow Transplantation 55(3): 531-537, Mar 2020.

Nobles CL, Sherrill-Mix S, Everett JK, Reddy S, Fraietta JA, Porter DL, Frey N, Gill SI, Grupp SA, Maude SL, Siegel DL, Levine BL, June CH, Lacey SF, Melenhorst JJ, Bushman FD.: CD19-targeting CAR T cell immunotherapy outcomes correlate with genomic modification by vector integration. J Clin Invest. 130(2): 673-685, Feb 2020.

Hiramatsu H, Adachi S, Umeda K, Kato I, Eldjerou L, Agostinho AC, Natsume K, Tokushige K, Watanabe Y, Grupp SA.: Efficacy and safety of tisagenlecleucel in Japanese pediatric and young adult patients with relapsed/refractory B cell acute lymphoblastic leukemia. Int J Hematol. 111(2): 303-310, Feb 2020.

Frey NV, Shaw PA, Hexner EO, Pequignot E, Gill S, Luger SM, Mangan JK, Loren AW, Perl AE, Maude SL, Grupp SA, Shah NN, Gilmore J, Lacey SF, Melenhorst JJ, Levine BL, June CH, Porter DL.: Optimizing Chimeric Antigen Receptor T-Cell Therapy for Adults With Acute Lymphoblastic Leukemia. J. Clin. Oncol. 38(5): 415-422, Feb 2020.

196. Kevin X Liu, Arlene Naranjo, Fan F Zhang, Steven G DuBois, Steve E Braunstein, Stephan D Voss, Geetika Khanna, Wendy B London, John J Doski, James D Geiger, Susan G Kreissman, Stephan A Grupp, Lisa R Diller, Julie R Park, Daphne A Haas-Kogan. : Prospective Evaluation of Radiation Dose Escalation in Patients With High-Risk Neuroblastoma and Gross Residual Disease After Surgery: A Report From the Children's Oncology Group ANBL0532 Study. Journal of Clinical Oncology 2020 Notes: Epub ahead of print.

Paul G Richardson, Angela R Smith, Nancy A Kernan, Leslie Lehmann, Robert J Soiffer, Robert J Ryan, William Tappe, Stephan Grupp. : Pooled Analysis of Day 100 Survival for Defibrotide-Treated Patients With Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome and Ventilator or Dialysis Dependence Following Haematopoietic Cell Transplantation. British Journal of Haematology 2020 Notes: Epub ahead of print.

Jessica B Foster, Yoav Dori, Stephan A Grupp, David M Barrett.: Thoracic Duct Lymphatic Fluid Harbors Phenotypically Naive T Cells for Use in Adoptive T-cell Therapy. Cytotherapy 2020 Notes: Epub ahead of print.

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Last updated: 09/18/2020
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