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Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia.
Literature Information
| DOI | 10.1126/scitranslmed.3008226 |
|---|---|
| PMID | 24553386 |
| Journal | Science translational medicine |
| Impact Factor | 14.6 |
| JCR Quartile | Q1 |
| Publication Year | 2014 |
| Times Cited | 1351 |
| Keywords | CAR T cell therapy, B cell acute lymphoblastic leukemia, cytokine release syndrome |
| Literature Type | Journal Article, Research Support, Non-U.S. Gov't |
| ISSN | 1946-6234 |
| Pages | 224ra25 |
| Issue | 6(224) |
| Authors | Marco L Davila, Isabelle Riviere, Xiuyan Wang, Shirley Bartido, Jae Park, Kevin Curran, Stephen S Chung, Jolanta Stefanski, Oriana Borquez-Ojeda, Malgorzata Olszewska, Jinrong Qu, Teresa Wasielewska, Qing He, Mitsu Fink, Himaly Shinglot, Maher Youssif, Mark Satter, Yongzeng Wang, James Hosey, Hilda Quintanilla, Elizabeth Halton, Yvette Bernal, Diana C G Bouhassira, Maria E Arcila, Mithat Gonen, Gail J Roboz, Peter Maslak, Dan Douer, Mark G Frattini, Sergio Giralt, Michel Sadelain, Renier Brentjens |
TL;DR
This study reports on 16 patients with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL) treated with autologous T cells expressing the 19-28z chimeric antigen receptor targeting CD19, achieving an 88% complete response rate, including in high-risk Philadelphia chromosome-positive cases. Additionally, the research identifies diagnostic criteria for severe cytokine release syndrome and highlights serum C-reactive protein as a reliable severity indicator, supporting the need for a multicenter phase 2 study to further evaluate this CAR T cell therapy approach.
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CAR T cell therapy · B cell acute lymphoblastic leukemia · cytokine release syndrome
Abstract
We report on 16 patients with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL) that we treated with autologous T cells expressing the 19-28z chimeric antigen receptor (CAR) specific to the CD19 antigen. The overall complete response rate was 88%, which allowed us to transition most of these patients to a standard-of-care allogeneic hematopoietic stem cell transplant (allo-SCT). This therapy was as effective in high-risk patients with Philadelphia chromosome-positive (Ph(+)) disease as in those with relapsed disease after previous allo-SCT. Through systematic analysis of clinical data and serum cytokine levels over the first 21 days after T cell infusion, we have defined diagnostic criteria for a severe cytokine release syndrome (sCRS), with the goal of better identifying the subset of patients who will likely require therapeutic intervention with corticosteroids or interleukin-6 receptor blockade to curb the sCRS. Additionally, we found that serum C-reactive protein, a readily available laboratory study, can serve as a reliable indicator for the severity of the CRS. Together, our data provide strong support for conducting a multicenter phase 2 study to further evaluate 19-28z CAR T cells in B-ALL and a road map for patient management at centers now contemplating the use of CAR T cell therapy.
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Primary Questions Addressed
- What are the long-term outcomes and survival rates for patients who achieve a complete response with 19-28z CAR T cell therapy in B-ALL?
- How does the efficacy of 19-28z CAR T cell therapy compare to other CAR T cell therapies targeting CD19 in terms of response rates and safety profiles?
- What specific factors contribute to the development of severe cytokine release syndrome in patients receiving 19-28z CAR T cell therapy, and how can these be mitigated?
- How do the clinical characteristics of Philadelphia chromosome-positive B-ALL patients influence their response to 19-28z CAR T cell therapy compared to those with standard risk?
- What are the implications of using serum C-reactive protein as a biomarker for managing cytokine release syndrome in the context of CAR T cell therapies?
Key Findings
Research Background and Purpose
The study investigates the efficacy and toxicity management of 19-28z CAR T cell therapy in patients with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL). Given the poor prognosis of B-ALL, especially in adults, this research aims to evaluate the therapeutic potential of CAR T cells targeting the CD19 antigen, aiming for improved patient outcomes and establishing management protocols for associated toxicities.
Main Methods/Materials/Experimental Design
The study involved a phase 1 clinical trial where 16 patients with relapsed or refractory B-ALL were treated with autologous T cells expressing the 19-28z CAR. The process is summarized in the flowchart below:
- Patient Selection: Adults with relapsed or refractory B-ALL, with some having Philadelphia chromosome-positive (Ph+) disease.
- Intervention: Patients received a conditioning regimen followed by infusion of 19-28z CAR T cells.
- Monitoring: Clinical outcomes, cytokine levels, and potential toxicities were systematically analyzed over 21 days post-infusion.
Key Results and Findings
- Efficacy: The overall complete response (CR) rate was 88%, with a significant number of patients achieving molecular complete remission (CRm).
- Cytokine Release Syndrome (CRS): A severe form of CRS (sCRS) was diagnosed based on specific clinical and laboratory criteria, including elevated C-reactive protein (CRP) levels.
- Toxicity Management: High-dose steroids and tocilizumab were used to manage sCRS, with tocilizumab showing less impact on CAR T cell expansion compared to steroids.
- Transplantation Outcomes: 44% of patients successfully transitioned to allogeneic stem cell transplant post-therapy, with no relapses observed in those who underwent the procedure.
Main Conclusions/Significance/Innovation
The study provides strong evidence supporting the use of 19-28z CAR T cell therapy as an effective treatment for relapsed or refractory B-ALL. The high CR rate and successful transition to allogeneic stem cell transplant highlight its potential as a bridge to curative therapy. Furthermore, the establishment of diagnostic criteria for sCRS and the role of CRP as a monitoring tool represent significant advancements in managing CAR T cell therapy-related toxicities.
Research Limitations and Future Directions
- Limitations: The study is limited by its small sample size and single-center design, which may affect the generalizability of the results.
- Future Directions: The authors propose conducting a multicenter phase 2 clinical trial to validate the findings and further explore the efficacy and safety of 19-28z CAR T cells in a broader patient population. Additionally, optimizing toxicity management protocols will be crucial as CAR T cell therapies become more widely implemented.
Summary Table of Key Findings
| Characteristic | Findings |
|---|---|
| Overall CR Rate | 88% |
| CRm Rate | 75% |
| sCRS Management | High-dose steroids and tocilizumab |
| Patients Transitioned to allo-SCT | 44% |
| Toxicity Monitoring Indicator | C-reactive protein (CRP) |
This structured approach emphasizes the importance of CAR T cell therapy in B-ALL and lays the groundwork for future studies and clinical applications.
References
- High-dose vincristine sulfate liposome injection for advanced, relapsed, and refractory adult Philadelphia chromosome-negative acute lymphoblastic leukemia. - Susan O'Brien;Gary Schiller;John Lister;Lloyd Damon;Stuart Goldberg;Walter Aulitzky;Dina Ben-Yehuda;Wendy Stock;Steven Coutre;Dan Douer;Leonard T Heffner;Melissa Larson;Karen Seiter;Scott Smith;Sarit Assouline;Philip Kuriakose;Lori Maness;Arnon Nagler;Jacob Rowe;Markus Schaich;Ofer Shpilberg;Karen Yee;Guenter Schmieder;Jeffrey A Silverman;Deborah Thomas;Steven R Deitcher;Hagop Kantarjian - Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2013)
- Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. - David L Porter;Bruce L Levine;Michael Kalos;Adam Bagg;Carl H June - The New England journal of medicine (2011)
- Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. - Michael C Milone;Jonathan D Fish;Carmine Carpenito;Richard G Carroll;Gwendolyn K Binder;David Teachey;Minu Samanta;Mehdi Lakhal;Brian Gloss;Gwenn Danet-Desnoyers;Dario Campana;James L Riley;Stephan A Grupp;Carl H June - Molecular therapy : the journal of the American Society of Gene Therapy (2009)
- T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. - Michael Kalos;Bruce L Levine;David L Porter;Sharyn Katz;Stephan A Grupp;Adam Bagg;Carl H June - Science translational medicine (2011)
- Development of a new intensive therapy for acute lymphoblastic leukemia in children at increased risk of early relapse. The Memorial Sloan-Kettering-New York-II protocol. - P G Steinherz;A Redner;L Steinherz;P Meyers;C Tan;G Heller - Cancer (1993)
- Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. - Nicola Gökbuget;Daniel Stanze;Joachim Beck;Helmut Diedrich;Heinz-August Horst;Andreas Hüttmann;Guido Kobbe;Karl-Anton Kreuzer;Lothar Leimer;Albrecht Reichle;Markus Schaich;Stefan Schwartz;Hubert Serve;Michael Starck;Matthias Stelljes;Reingard Stuhlmann;Andreas Viardot;Knut Wendelin;Mathias Freund;Dieter Hoelzer; - Blood (2012)
- How do CARs work?: Early insights from recent clinical studies targeting CD19. - Marco L Davila;Renier Brentjens;Xiuyan Wang;Isabelle Rivière;Michel Sadelain - Oncoimmunology (2012)
- Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. - Stephan A Grupp;Michael Kalos;David Barrett;Richard Aplenc;David L Porter;Susan R Rheingold;David T Teachey;Anne Chew;Bernd Hauck;J Fraser Wright;Michael C Milone;Bruce L Levine;Carl H June - The New England journal of medicine (2013)
- Primary refractory and relapsed adult acute lymphoblastic leukemia: characteristics, treatment results, and prognosis with salvage therapy. - D A Thomas;H Kantarjian;T L Smith;C Koller;J Cortes;S O'Brien;F J Giles;J Gajewski;S Pierce;M J Keating - Cancer (1999)
- Adolescent and adult acute lymphoblastic leukemia: prognostic features and outcome of therapy. A study of 293 patients. - M Baccarani;G Corbelli;S Amadori;A Drenthe-Schonk;R Willemze;G Meloni;P L Cardozo;C Haanen;F Mandelli;S Tura - Blood (1982)
Literatures Citing This Work
- Novel approaches to enhance the specificity and safety of engineered T cells. - Victor D Fedorov;Michel Sadelain;Christopher C Kloss - Cancer journal (Sudbury, Mass.) (2014)
- How do we prepare ourselves for a new paradigm of medicine to advance the treatment of pediatric acute lymphoblastic leukemia? - Kyung Duk Park - Blood research (2014)
- Nature Biotechnology's academic spinouts of 2013. - Aaron Bouchie;Malorye Allison;Sarah Webb;Laura DeFrancesco - Nature biotechnology (2014)
- Gene therapy: charting a future course--summary of a National Institutes of Health Workshop, April 12, 2013. - Marina O'Reilly;Howard J Federoff;Yuman Fong;Donald B Kohn;Amy P Patterson;Nabil Ahmed;Aravind Asokan;Shannon E Boye;Ronald G Crystal;Satiro De Oliveira;Linda Gargiulo;Scott Q Harper;Yasuhiro Ikeda;Robert Jambou;Maureen Montgomery;Lawrence Prograis;Eugene Rosenthal;Daniel H Sterman;Luk H Vandenberghe;Laurie Zoloth;Mehrdad Abedi;Jennifer Adair;Prasad S Adusumilli;William F Goins;Jhanelle Gray;Paul Monahan;Leslie Popplewell;Miguel Sena-Esteves;Bakhos Tannous;Thomas Weber;William Wierda;Rashmi Gopal-Srivastava;Cheryl L McDonald;Daniel Rosenblum;Jacqueline Corrigan-Curay - Human gene therapy (2014)
- Antibody therapy for pediatric leukemia. - Aditi Vedi;David S Ziegler - Frontiers in oncology (2014)
- Current concepts in the diagnosis and management of cytokine release syndrome. - Daniel W Lee;Rebecca Gardner;David L Porter;Chrystal U Louis;Nabil Ahmed;Michael Jensen;Stephan A Grupp;Crystal L Mackall - Blood (2014)
- Progress and prospects for engineered T cell therapies. - Waseem Qasim;Adrian J Thrasher - British journal of haematology (2014)
- Engineered T cells for cancer therapy. - Carl H June;Marcela V Maus;Gabriela Plesa;Laura A Johnson;Yangbing Zhao;Bruce L Levine;Stephan A Grupp;David L Porter - Cancer immunology, immunotherapy : CII (2014)
- CAR-T cell therapy seeks strategies to harness cytokine storm. - Laura DeFrancesco - Nature biotechnology (2014)
- Hyperinflammation, rather than hemophagocytosis, is the common link between macrophage activation syndrome and hemophagocytic lymphohistiocytosis. - Lehn K Weaver;Edward M Behrens - Current opinion in rheumatology (2014)
... (1341 more literatures)
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