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

Theodore W Laetsch, Shannon L Maude, Adriana Balduzzi, Susana Rives, Henrique Bittencourt, Michael W Boyer, Jochen Buechner, Barbara De Moerloose, Muna Qayed, Christine L Phillips, Michael A Pulsipher, Hidefumi Hiramatsu, Ranjan Tiwari, Stephan A Grupp: Tisagenlecleucel in pediatric and young adult patients with Down syndrome-associated relapsed/refractory acute lymphoblastic leukemia. Leukemia 36(6): 1508-1515, June 2022.

Allison Barz Leahy, Kaitlin J Devine, Yimei Li, Hongyan Liu, Regina Myers, Amanda DiNofia, Lisa Wray, Susan R Rheingold, Colleen Callahan, Diane Baniewicz, Maria Patino, Haley Newman, Stephen P Hunger, Stephan A Grupp, David M Barrett, Shannon L Maude: Impact of high-risk cytogenetics on outcomes for children and young adults receiving CD19-directed CAR T-cell therapy. Blood 139(14): 2173-2185, Apr 2022.

Regina M Myers, Agne Taraseviciute, Seth M Steinberg, Adam J Lamble, Jennifer Sheppard, Bonnie Yates, Alexandra E Kovach, Brent 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, Samuel John, Deepa Bhojwani, Patrick A Brown, Theodore W Laetsch, Lia Gore, Rebecca A Gardner, Susan R Rheingold, Michael A Pulsipher, Nirali N Shah: Blinatumomab Nonresponse and High-Disease Burden Are Associated With Inferior Outcomes After CD19-CAR for B-ALL. J Clin Oncol 40(9): 932-944, Mar 2022.

Allison Barz Leahy, Yimei Li, Julie-An Talano, Caitlin W Elgarten, Alix E Seif, Yongping Wang, Bryon Johnson, Dimitri S Monos, Stephan Kadauke, Timothy S Olson, Jason Freedman, Lisa Wray, Stephan A Grupp, Nancy Bunin: Unrelated donor α/β T cell- and B cell-depleted HSCT for the treatment of pediatric acute leukemia. Blood Adv. 6(4): 1175-1185, Feb 2022.

Michael A Pulsipher, Xia Han, Shannon L Maude, Theodore W Laetsch, Muna Qayed, Susana Rives, Michael W Boyer, Hidefumi Hiramatsu, Gregory A Yanik, Tim Driscoll, G Doug Myers, Peter Bader, Andre Baruchel, Jochen Buechner, Heather E Stefanski, Creton Kalfoglou, Kevin Nguyen, Edward R Waldron, Karen Thudium Mueller, Harald J Maier, Gabor Kari, Stephan A Grupp: Next-Generation Sequencing of Minimal Residual Disease for Predicting Relapse after Tisagenlecleucel in Children and Young Adults with Acute Lymphoblastic Leukemia. Blood Cancer Discov. 3(1): 66-81, Jan 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 2022 Notes: Online ahead of print.

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. 2022 Notes: Online ahead of print.

Karen Thudium Mueller, Stephan A Grupp, Shannon L Maude, John E Levine, Michael A Pulsipher, Michael W Boyer, Keith August, G Doug Myers, Constantine S Tam, Ulrich Jaeger, Stephen Ronan Foley, Peter Borchmann, Stephen J Schuster, Edmund K Waller, Rakesh Awasthi, Bernd Potthoff, Andy Warren, Edward Waldron, Fraser McBlane, Andrea Chassot-Agostinho, Theodore W Laetsch: Tisagenlecleucel Immunogenicity in Relapsed/Refractory Acute Lymphoblastic Leukemia and Diffuse Large B-Cell Lymphoma. Blood Adv. 14(5): 4980-4991, Dec 2021.

Makda Getachew Zewde, George Morales, Isha Gandhi, Umut Özbek, Paibel Aguayo-Hiraldo, Francis Ayuk, Janna Baez, Chantiya Chanswangphuwana, Hannah Choe, Zachariah DeFilipp, Aaron Etra, Stephan Grupp, Elizabeth O Hexner, William Hogan, Nora Rebeka Javorniczky, Stelios Kasikis, Carrie L Kitko, Steven Kowalyk, Elisabeth Meedt, Pietro Merli, Ryotaro Nakamura, Muna Qayed, Ran Reshef, Wolf Rösler, Tal Schechter, Daniela Weber, Matthias Wölfl, Gregory Yanik, Rachel Young, John E Levine, James L M Ferrara, Yi-Bin Chen: Evaluation of Elafin as a Prognostic Biomarker in Acute Graft-versus-Host Disease. Transplant Cell Ther. 27(12): 988.e1-988.e7, Dec 2021.

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.

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Last updated: 06/21/2022
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