Stephan A. Grupp, MD, PhD

faculty photo
Professor of Pediatrics
Attending Physician, Pediatrics, Oncology/Bone Marrow Transplant Service, Children's Hospital of Philadelphia
Medical Director, Cell and Gene Therapy Laboratory, Children's Hospital of Philadelphia, University of Pennsylvania
Director, Cancer Immunotherapy Program, Children's Hospital of Philadelphia, University of Pennsylvania
Section Chief, Cellular Therapy and Transplant Section (CTTS), Children's Hospital of Philadelphia, University of Pennsylvania
Co-leader, Pediatric Cancer Program, Abramson Cancer Center, Children's Hospital of Philadelphia, University of Pennsylvania
Cell and Gene Therapy Collaborative (CGTC), Children's Hospital of Philadelphia
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

Stelios Kasikis, Janna Baez, Isha Gandhi, Stephan Grupp, Carrie L Kitko, Steven Kowalyk, Pietro Merli, George Morales, Michael A Pulsipher, Muna Qayed, Matthias Wölfl, Gregory Yanik, Fiona See, Jack Hayes, Fred Grossman, Elizabeth Burke, Rachel Young, John E Levine, James L M Ferrara: Mesenchymal stromal cell therapy induces high responses and survival in children with steroid refractory GVHD and poor risk biomarkers. Bone Marrow Transplant 56(11): 2869-2870, Nov 2021.

Allison Barz Leahy, Haley Newman, Yimei Li, Hongyan Liu, Regina Myers, Amanda DiNofia, Joseph G Dolan, Colleen Callahan, Diane Baniewicz, Kaitlin Devine, Lisa Wray, Richard Aplenc, Carl H June, Stephan A Grupp, Susan R Rheingold, Shannon L Maude: CD19-targeted chimeric antigen receptor T-cell therapy for CNS relapsed or refractory acute lymphocytic leukaemia: a post-hoc analysis of pooled data from five clinical trials. Lancet Haematol. 8(10), Oct 2021 Notes: doi: 10.1016/S2352-3026(21)00238-6.

John E Levine, Stephan A Grupp, Michael A Pulsipher, Andrew C Dietz, Susana Rives, G Douglas Myers, Keith J August, Michael R Verneris, Jochen Buechner, Theodore W Laetsch, Henrique Bittencourt, Andre Baruchel1, Michael W Boyer, Barbara De Moerloose, Muna Qayed, Stella M Davies, Christine L Phillips, Timothy A Driscoll, Peter Bader, Krysta Schlis, Patricia A Wood, Rajen Mody, Lan Yi, Mimi Leung, Lamis K Eldjerou, Carl H June and Shannon L Maude: A Pooled Safety Analysis of Tisagenlecleucel in Children and Young Adults With B-Cell Acute Lymphoblastic Leukemia. Journal for ImmunoTherapy of Cancer 9(8), Aug 2021.

Priya Khurana, Chakkapong Burudpakdee, Stephan A. Grupp, Ulf H. Beier, David M. Barrett and Hamid Bassiri: Distinct Bioenergetic Features of Human Invariant Natural Killer T Cells Enable Retained Functions in Nutrient-Deprived States. Frontiers in Immunology Aug 2021.

Nathan Singh, Noelle V. Frey, Boris Engels, David M. Barrett, Olga Shestova, Pranali Ravikumar, Katherine D. Cummins, Yong Gu Lee, Raymone Pajarillo, Inkook Chun, Amy Shyu, Steven L. Highfill, Andrew Price, Linlin Zhao, Liaomin Peng, Brian Granda, Melissa Ramones, Xueqing Maggie Lu, David A. Christian, Jessica Perazzelli, Simon F. Lacey, Nathan H. Roy, Janis K. Burkhardt, Florent Colomb, Mohammad Damra, Mohamed Abdel-Mohsen, Ting Liu, Dongfang Liu, Daron M. Standley, Regina M. Young, Jennifer L. Brogdon, Stephan A. Grupp, Carl H. June, Shannon L. Maude, Saar Gill, Marco Ruella: Antigen-independent activation enhances the efficacy of 4-1BB-costimulated CD22 CAR T cells. Nature Medicine Apr 2021 Notes:

Sophia Faude, Jane Wei, Kavitha Muralidharan, Xiaoming Xu, Gerald Wertheim, Michele Paessler, Vijay G Bhoj, Stephan A Grupp, Shannon L Maude, Susan R Rheingold, Vinodh Pillai: Absolute lymphocyte count proliferation kinetics after CAR T-cell infusion impact response and relapse. Blood Advances 5(8): 2128-2136, Apr 2021.

Kadauke, S, RM Myers, Y Li, R Aplenc, D Baniewicz, DM Barrett, AB Leahy, C Callahan, JG Dolan, JC Fitzgerald, W Gladney, SF Lacey, H Liu, SL Maude, R McGuire, LS Motley, DT Teachey, G Wertheim, L Wray, AM DiNofia, SA Grupp. : Risk-Adapted Preemptive Tocilizumab to Prevent Severe Cytokine Release Syndrome after CTL019 for Pediatric B-Cell Acute Lymphoblastic Leukemia: A Prospective Clinical Trial. J Clin Oncol 39(8): 920-930, Mar 2021.

Rahul Arya, David M Barrett, Stephan A Grupp, Jan Joseph Melenhorst: Improving and Maintaining Responses in Pediatric B-Cell Acute Lymphoblastic Leukemia Chimeric Antigen Receptor-T Cell Therapy. Cancer 27(2): 151-158, Mar-Apr 2021.

Haydar Frangoul, M.D., David Altshuler, M.D., Ph.D., M. Domenica Cappellini, M.D., Yi-Shan Chen, Ph.D., Jennifer Domm, M.D., Brenda K. Eustace, Ph.D., Juergen Foell, M.D., Josu de la Fuente, M.D., Ph.D., Stephan Grupp, M.D., Ph.D., Rupert Handgretinger, M.D., Tony W. Ho, M.D., Antonis Kattamis, M.D., Andrew Kernytsky, Ph.D., Julie Lekstrom-Himes, M.D., Amanda M. Li, M.D., Franco Locatelli, M.D., Markus Y. Mapara, M.D., Ph.D., Mariane de Montalembert, M.D., Damiano Rondelli, M.D., Akshay Sharma, M.B., B.S., Sujit Sheth, M.D., Sandeep Soni, M.D., Martin H. Steinberg, M.D., Donna Wall, M.D., Angela Yen, Ph.D., and Selim Corbacioglu, M.D.: CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. The New England Journal of Medicine 384(3): 252-260, Jan 2021.

Haneen Shalabi, Juliane Gust, Agne Taraseviciute, Pamela L Wolters, Allison B Leahy, Carlos Sandi, Theodore W Laetsch, Lori Wiener, Rebecca A Gardner, Veronique Nussenblatt, Joshua A Hill, Kevin J Curran, Timothy S Olson, Colleen Annesley, Hao-Wei Wang, Javed Khan, Marcelo C Pasquini, Christine N Duncan, Stephan A Grupp, Michael A Pulsipher, Nirali N Shah: Beyond the storm - subacute toxicities and late effects in children receiving CAR T cells. Nat Rev Clin Oncol Jan 2021 Notes: Epub ahead of print.

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Last updated: 12/10/2021
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