Stephan A. Grupp, MD, PhD

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Professor of Pediatrics (Oncology)
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
University of Cincinnati (Magna cum laude), 1981.
University of Cincinnati College of Medicine, 1985.
University of Cincinnati College of Medicine, 1987.
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Description of Research Expertise

Research Interests

International expert in CAR T and pediatric transplant/cell therapy

I have extensive experience in the development and preclinical testing of engineered cell therapies and signal transduction inhibitors in leukemia, in pediatric trials using both, and in the manufacture and use of cellular therapeutics in preclinical, GMP, and clinical trial settings. I currently lead/have led most of the CTL019 (CD19 CAR) clinical trials at CHOP, in the US, and globally. Our group at CHOP and U Penn has led the field of highly active CAR T cell therapy, culminating in the FDA approval of CTL019/tisagenlecleucel as Kymriah, the first CAR T product ever approved, and the first gene therapy approved in the US. Over the last 10 years, our team has built a one of the most capable cell therapy groups in the world at both CHOP and U Penn, which can implement cell therapy trials with GMP cell manufacturing (Penn CVPF), at registrational level, with full regulatory support, and unmatched clinical implementation. Our work now encompasses engineered cell therapies for non-malignant diseases, including sickle cell disease. I am committed to improving outcomes for children who undergo cell therapies including malignant and non-malignant engineered cell therapies and hematopoietic cell transplantation. The goal - changing the standard of care.

Basic science expertise

The primary focus of my lab’s work is the development of targeted and cell therapies and studies ALL and T cell biology. Our group has leveraged studies using primary human ALL xenografts into treatments tested in a number of clinical trials, including national phase 3 randomized and FDA registration trials. In addition, as the Director of the Cancer Immunotherapy Frontier Program and the Section chief of Cell Therapy and Transplant, I oversee research into clinical use of CAR T cells and hematopoietic stem cells.

1. CAR T cell studies. Most relevant to this grant, 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 CTL019) in an ongoing basic and translational collaboration with the June group. The pediatric data on the ALL trials have been spectacular, leading to 3 NEJM publications and international publicity for the work. CTL019 for pediatric ALL was the 1st CART approved by the FDA, as well as the 1st gene therapy approved in the US, and I led the study steering committees for the global registration trials for CTL019 for ALL. In addition to the clinical trial results with CTL019 in ALL, we have done pioneering work in cytokine release syndrome (CRS). We discovered the link between CRS and macrophage activation syndrome and uncovered the key role that IL-6 plays in the development of severe CRS. Our observation that IL-6 blockade can reverse CRS has transformed the field of highly active cell therapy.

2. Signal transduction studies in ALL. We have demonstrated the importance of the mTOR pathway in B cell cancer and demonstrated that mTOR inhibitors are effective agents against ALL as well as lymphoproliferative disorders (see below). IL-7 and a related molecule called TSLP reverse the effect of mTOR inhibitors on pre-B ALL cells, demonstrating the importance of TSLPR in ALL prior to the work we have participated in defining CRLF (TSLPR) overexpression as a risk factor in ALL. We have recently extended these studies into the JAK2-STAT pathway, which has also led to clinical trials.

3. mTOR inhibitor trials in ALL and transplant. These mTOR pathway findings have had direct translational significance in ALL, leading to Phase I, II, and III (COG ASCT0431 and CTN 0401). These studies have also shown the importance of the GVL effect in ALL (long debated) and demonstrated the power of next-gen sequencing to detect clinically relevant MRD in the transplant setting.

4. Autoimmune lymphoproliferative syndrome (ALPS). In addition to ALL, we have worked with ALPS patients and animal models. ALPS combines lymphoproliferation with life-threatening autoimmunity. We have shown that the autoimmune disorder Evans Syndrome is very often actually ALPS. Leveraging our ALL work, we have also shown the power of mTOR inhibition in ALPS, and out recently published pilot trial of sirolimus in ALPS supports the first-line use of this drug in ALPS

Clinical stem cell transplant

Tandem stem cell transplant in neuroblastoma: As part of my role as Medical Director of the Cell and Gene Therapy lab at CHOP and Transplant Discipline Chair for COG, we have performed trials to improve outcome in neuroblastoma, a disease that had a <15% long-term survival with chemo and ~35% with single autologous stem cell transplant. I developed the tandem transplant approach at CHOP, we piloted it in COG and then work with COG to design the national ANBL0532 phase III trial now published in JAMA. Tandem SCT is now the US standard of care for high risk neuroblastoma.

Description of Clinical Expertise

Pediatric bone marrow/stem cell transplantation, Transplant for high-risk neuroblastoma

Description of Other Expertise

Stem cell engineering and processing, CAR T manufacture

Selected Publications

Haydar Frangoul, Franco Locatelli, Akshay Sharma, Monica Bhatia, Markus Mapara, Lyndsay Molinari, Donna Wall, Robert I. Liem, Paul Telfer, Ami J. Shah, Marina Cavazzana, Selim Corbacioglu, Damiano Rondelli, Roland Meisel, Laurence Dedeke, Stephan Lobitz, Mariane de Montalembert, Martin H. Steinberg, Mark C. Walters, Michael J. Eckrich, Suzan Imren, Laura Bower, Christopher Simard, Weiyu Zhou, Fengjuan Xuan, Phuong Khanh Morrow, William E. Hobbs, and Stephan A. Grupp: Exagamglogene Autotemcel for Severe Sickle Cell Disease. N Engl J Med 390(18): 1649-1662, April 2024.

Franco Locatelli, Peter Lang, Donna Wall, Roland Meisel, Selim Corbacioglu, Amanda M. Li, Josu de la Fuente, Ami J. Shah, Ben Carpenter, Janet L. Kwiatkowski, Markus Mapara, Robert I. Liem, Maria Domenica Cappellini, Mattia Algeri, Antonis Kattamis, Sujit Sheth, Stephan Grupp, Rupert Handgretinger, Puja Kohli, Daoyuan Shi, Leorah Ross, Yael Bobruff, Christopher Simard, Lanju Zhang, Phuong Khanh Morrow, William E. Hobbs, and Haydar Frangoul: Exagamglogene Autotemcel for Transfusion-Dependent β-Thalassemia. N Eng J Med 390(18): 1663-1676, April 2024.

Akahoshi Y, Spyrou N, Hoepting M Dr med, Aguayo-Hiraldo P, Ayuk FA, Chanswangphuwana C, Choe HK, Eder M, Etra AM, Grupp SA, Hexner EO, Hogan WJ, Kitko CL, Kraus S, Al Malki MM, Merli P, Qayed M, Reshef R, Schechter-Finkelstein T, Ullrich E, Vasova I, Wölfl M, Zeiser R, Baez J, Beheshti R, Eng GW, Gleich S, Kasikis S, Katsivelos N, Kowalyk S, Morales G, Young R, DeFilipp Z, Ferrara JLM, Levine JE, Nakamura R.: Flares of Acute Graft-Versus-Host Disease (GVHD): A Mount Sinai Acute GVHD International Consortium (MAGIC) Analysis. Blood Adv February 2024.

Spyrou N, Akahoshi Y, Kowalyk S, Morales G, Beheshti R, Aguayo-Hiraldo P, Malki MMA, Ayuk F, Bader P, Baez J, Capellini A, Choe H, DeFilipp Z, Eder M, Eng G, Etra A, Gleich S, Grupp SA, Hexner E, Hoepting M, Hogan WJ, Kasikis S, Katsivelos N, Khan A, Kitko CL, Kraus S, Kwon D, Merli P, Portelli J, Qayed M, Reshef R, Schechter T, Vasova I, Wölfl M, Wudhikarn K, Young R, Holler E, Chen YB, Nakamura R, Levine JE, Ferrara JLM.: A day 14 endpoint for acute GVHD clinical trials. Transplant Cell Ther February 2024.

Levine BL, Pasquini MC, Connolly JE, Porter DL, Gustafson MP, Boelens JJ, Horwitz EM, Grupp SA, Maus MV, Locke FL, Ciceri F, Ruggeri A, Snowden J, Heslop HE, Mackall CL, June CH, Sureda AM, Perales MA.: Unanswered questions following reports of secondary malignancies after CAR-T cell therapy. Nat Med January 2024.

Alexander E. Doan, Katherine P. Mueller, Andy Y. Chen, Geoffrey T. Rouin, Yingshi Chen, Bence Daniel, John Lattin, Martina Markovska, Brett Mozarsky, Jose Arias-Umana, Robert Hapke, In-Young Jung, Alice Wang, Peng Xu, Dorota Klysz, Gabrielle Zuern, Malek Bashti, Patrick J. Quinn, Zhuang Miao, Katalin Sandor, Wenxi Zhang, Gregory M. Chen, Faith Ryu, Meghan Logun, Junior Hall, Kai Tan, Stephan A. Grupp, Susan E. McClory, Caleb A. Lareau, Joseph A. Fraietta, Elena Sotillo, Ansuman T. Satpathy, Crystal L. Mackall & Evan W. Weber: FOXO1 is a master regulator of memory programming in CAR T cells. Nature 629: 211-218, 2024.

Zhiliang Bai1, Bing Feng, Susan E. McClory, Beatriz Coutinho de Oliveira, Caroline Diorio4, Céline Gregoire, Bo Tao, Luojia Yang, Ziran Zhao, Lei Peng, Giacomo Sferruzza, Liqun Zhou, Xiaolei Zhou, Jessica Kerr, Alev Baysoy, Graham Su, Mingyu Yang, Pablo G. Camara, Sidi Chen8,Li Tang, Carl H. June J.Joseph Melenhorst, Stephan A. Grupp, Rong Fan.: Single-cell multi-omics reveals type-2 function in CAR T cells associated with 8-year leukemia remission. Nature Page: in press, 2024.

Doan A, Mueller KP, Chen A, Rouin GT, Daniel B, Lattin J, Chen Y, Mozarsky B, Markovska M, Arias-Umana J, Hapke R, Jung I, Xu P, Klysz D, Bashti M, Quinn PJ, Sandor K, Zhang W, Hall J, Lareau C, Grupp SA, Fraietta JA, Sotillo E, Satpathy AT, Mackall CL, Weber EW: FOXO1 is a master regulator of CAR T memory programming. Nature November 2023.

Myers RM, Grupp SA.: Driving two chimeric antigen receptors (CARs) in a row to reduce antigen escape in B-cell acute lymphocytic leukaemia. Lancet Oncol October 2023.

Myers RM, Jacoby E, Pulsipher MA, Pasquini MC, Grupp SA, Shah NN, Laetsch TW, Curran KJ, Schultz LM.: INSPIRED Symposium Part 1: Clinical Variables Associated with Improved Outcomes for Children and Young Adults treated with Chimeric Antigen Receptor T cells for B cell Acute Lymphoblastic Leukemia. Transplant Cell Ther October 2023.

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Last updated: 05/13/2024
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