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
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.

Selected Publications

Stephan A Grupp, MD, Selim Corbacioglu, MD, Hyoung Jin Kang, MD, Takanori Teshima, MD, Seong Lin Khaw, MD, Franco Locatelli, MD, Johan Maertens, MD, Matthias Stelljes, MD, Polina Stepensky, MD, Paty Lopez, MD, Vian Amber, PhD, Antonio Pagliuca, MD, Paul G Richardson, MD, Mohamad Mohty, MD: Defibrotide plus best standard of care compared with best standard of care alone for the prevention of sinusoidal obstruction syndrome (HARMONY): a randomised, multicentre, phase 3 trial. The Lancet Hematology March 2023 Notes: DOI:https://doi.org/10.1016/S2352-3026(23)00011-X.

David S. Anderson, Richard S. Hanna, Amir Reza Pashmina Azar, Victoria Collier, Patricia Hankins, Brandon Loudon, Timothy S. Olson, Stephan A. Grupp, Charles A. Phillips, Stephan Kadauke: Automation of Hematopoietic Cell Transplantation Outcomes Reporting Leads to Dramatic Reduction in Errors Reported to Real-World Data Registry. Transplantation and Cellular Therapy 29(3): 207.e1-207.e5, March 2023 Notes: https://doi.org/10.1016/j.jtct.2022.12.026.

Adam Lamble, Regina M Myers, Agne Taraseviciute, Samuel John, Bonnie Yates, Seth M Steinberg, Jennifer Dianne Sheppard, Alexandra Elizabeth Kovach, Brent L Wood, Michael J Borowitz, Maryalice Stetler-Stevenson, Constance M Yuan, Vinodh Pillai, Toni Foley, Perry Chung, Lee Chen, Daniel W Lee, Colleen Annesley, Amanda DiNofia, Stephan A Grupp, Michael R Verneris, Lia Gore, Theodore W Laetsch, Deepa Bhojwani, Patrick A Brown, Michael A Pulsipher, Susan R Rheingold, Rebecca A Gardner, Nirali N Shah: Preinfusion factors impacting relapse immunophenotype following CD19 CAR T cells. Blood Adv. 7(4): 575-585, Feb 2023.

Haley Newman, Yimei Li, Hongyan Liu, Regina M Myers, Vicky Tam, Amanda DiNofia, Lisa Wray, Susan R Rheingold, Colleen Callahan, Claire White, Diane Baniewicz, Lena E Winestone, Stephan Kadauke, Caroline Diorio, Carl H June, Kelly Getz, Richard Aplenc, David T Teachey, Shannon L Maude, Stephan A Grupp, Kira Bona, Allison Barz Leahy: Impact of poverty and neighborhood opportunity on outcomes for children treated with CD19-directed CAR T-cell therapy. Blood 141(6): 609-619, Feb 2023.

Gregory M Chen, Chia-Hui Chen, Jessica Perazzelli, Stephan A Grupp, David M Barrett, Kai Tan: Characterization of Leukemic Resistance to CD19-Targeted CAR T-cell Therapy through Deep Genomic Sequencing. Cancer Immunol Res 11(1): 13-19, Jan 2023.

Theodore W Laetsch, Shannon L Maude, Susana Rives, Hidefumi Hiramatsu, Henrique Bittencourt, Peter Bader, André Baruchel, Michael Boyer, Barbara De Moerloose, Muna Qayed, Jochen Buechner, Michael A Pulsipher, Gary Douglas Myers, Heather E Stefanski, Paul L Martin, Eneida Nemecek, Christina Peters, Gregory Yanik, Seong Lin Khaw, Kara L Davis, Joerg Krueger, Adriana Balduzzi, Nicolas Boissel, Ranjan Tiwari, Darragh O'Donovan, Stephan A Grupp: Three-Year Update of Tisagenlecleucel in Pediatric and Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia in the ELIANA Trial. J Clin Oncol Nov 2022.

Yimei Li, Wei-Ting Hwang, Shannon L Maude, David T Teachey, Noelle V Frey, Regina M Myers, Allison Barz Leahy, Hongyan Liu, David L Porter, Stephan A Grupp, Pamela A Shaw: Statistical Considerations for Analyses of Time-To-Event Endpoints in Oncology Clinical Trials: Illustrations with CAR-T Immunotherapy Studies. Clin Cancer Res 28(18): 3940-3949, Sept 2022.

Alexandra Gyurdieva, Stefan Zajic, Ya-Fang Chang, E Andres Houseman, Shan Zhong, Jaegil Kim, Michael Nathenson, Thomas Faitg, Mary Woessner, David C Turner, Aisha N Hasan, John Glod, Rosandra N Kaplan, Sandra P D'Angelo, Dejka M Araujo, Warren A Chow, Mihaela Druta, George D Demetri, Brian A Van Tine, Stephan A Grupp, Gregg D Fine, Ioanna Eleftheriadou: Biomarker correlates with response to NY-ESO-1 TCR T cells in patients with synovial sarcoma. Nat Commun 13(1), Sept 2022.

Caroline Diorio, Rawan Shraim, Regina Myers, Edward M Behrens, Scott Canna, Hamid Bassiri, Richard Aplenc, Chakkapong Burudpakdee, Fang Chen, Amanda M DiNofia, Saar Gill, Vanessa Gonzalez, Michele P Lambert, Allison Barz Leahy, Bruce L Levine, Robert B Lindell, Shannon L Maude, J Joseph Melenhorst, Haley Newman, Jessica Perazzelli, Alix E Seif, Simon F Lacey, Carl H June, David M Barrett, Stephan A Grupp, David T Teachey: Comprehensive Serum Proteome Profiling of Cytokine Release Syndrome and Immune Effector Cell Associated Neurotoxicity Syndrome in B-Cell ALL Patients Receiving CART19. Clin. Cancer Research 28(17), Sept 2022.

Caroline Diorio, Ryan Murray, Mark Naniong, Luis Alberto Barrera, Adam J Camblin, John A Chukinas, Lindsey Coholan, Aaron Edwards, Tori Fuller, Claudia Gonzales, Stephan A Grupp, Alden Malcolm Ladd, Melissa Buttimer Le, Angelica Messana, Faith Musenge, Haley Newman, Yeh-Chuin Poh, Henry Poulin, Theresa Ryan, Rawan Shraim, Sarah K Tasian, Tiffaney L Vincent, Lauren Young, Yingying Zhang, Giuseppe Ciaramella, Jason Gehrke, David T Teachey: Cytosine Base Editing Enables Quadruple-Edited Allogeneic CAR-T Cells for T-ALL. Blood 140(6), Aug 2022.

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Last updated: 05/02/2023
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