Chemotherapy-Refractory Diffuse Large B-Cell Lymphoma and Indolent B-Cell Malignancies Can Be Effectively Treated With Autologous T Cells Expressing an Anti-CD19 Chimeric Antigen Receptor
James N. Kochenderfer,Mark E. Dudley,Sadik H. Kassim,Robert Somerville,Robert O. Carpenter,Maryalice Stetler-Stevenson,James Chih-Hsin Yang,Giao Q. Phan,Michael S. Hughes,Richard M. Sherry,Mark Raffeld,Steven R. Feldman,Lily Lu,Yong F. Li,Lien T. Ngo,Andre Goy,Tatyana Feldman,David Spaner,Michael L. Wang,Clara C. Chen,Sarah M. Kranick,Avindra Nath,Debbie-Ann N. Nathan,Kathleen E. Morton,Mary Ann Toomey,Steven A. Rosenberg +25 more
TLDR
The results demonstrate the feasibility and effectiveness of treating chemotherapy-refractory B-cell malignancies with anti-CD19 CAR T cells and provide strong support for further development of this approach.Abstract:
Purpose T cells can be genetically modified to express an anti-CD19 chimeric antigen receptor (CAR). We assessed the safety and efficacy of administering autologous anti-CD19 CAR T cells to patients with advanced CD19 B-cell malignancies. Patients and Methods We treated 15 patients with advanced B-cell malignancies. Nine patients had diffuse large B-cell lymphoma (DLBCL), two had indolent lymphomas, and four had chronic lymphocytic leukemia. Patients received a conditioning chemotherapy regimen of cyclophosphamide and fludarabine followed by a single infusion of anti-CD19 CAR T cells. Results Of 15 patients, eight achieved complete remissions (CRs), four achieved partial remissions, one had stable lymphoma, and two were not evaluable for response. CRs were obtained by four of seven evaluable patients with chemotherapy-refractory DLBCL; three of these four CRs are ongoing, with durations ranging from 9 to 22 months. Acute toxicities including fever, hypotension, delirium, and other neurologic toxicities occurred in some patients after infusion of anti-CD19 CAR T cells; these toxicities resolved within 3 weeks after cell infusion. One patient died suddenly as a result of an unknown cause 16 days after cell infusion. CAR T cells were detected in the blood of patients at peak levels, ranging from nine to 777 CAR-positive T cells/L.read more
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Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma
Sattva S. Neelapu,Frederick L. Locke,Nancy L. Bartlett,Lazaros J. Lekakis,David B. Miklos,Caron A. Jacobson,Ira Braunschweig,Olalekan O. Oluwole,Tanya Siddiqi,Yi Lin,John M. Timmerman,Patrick J. Stiff,Jonathan W. Friedberg,Ian W. Flinn,Andre Goy,Brian T. Hill,Mitchell R. Smith,Abhinav Deol,Umar Farooq,Peter A. McSweeney,Javier Munoz,Irit Avivi,Januario E. Castro,Jason R. Westin,Julio C. Chavez,Armin Ghobadi,Krishna V. Komanduri,Ronald Levy,Eric D. Jacobsen,Thomas E. Witzig,Patrick M. Reagan,Adrian Bot,John J. Rossi,Lynn Navale,Yizhou Jiang,Jeff Aycock,Meg Elias,David Z. Chang,Jeff Wiezorek,William Y. Go +39 more
TL;DR: Patients with refractory large B‐cell lymphoma who received CAR T‐cell therapy with axi‐cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events.
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Adoptive cell transfer as personalized immunotherapy for human cancer.
TL;DR: The ability to genetically engineer lymphocytes to express conventional T cell receptors or chimeric antigen receptors has further extended the successful application of ACT for cancer treatment.
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CD19 CAR–T cells of defined CD4+:CD8+ composition in adult B cell ALL patients
Cameron J. Turtle,Laïla Aïcha Hanafi,Carolina Berger,Ted Gooley,Sindhu Cherian,Michael Hudecek,Daniel Sommermeyer,Katherine Melville,Barbara S. Pender,Tanya M Budiarto,Emily Robinson,Natalia N Steevens,Colette Chaney,Lorinda Soma,Xueyan Chen,Cecilia Yeung,Brent L. Wood,Daniel Li,Jianhong Cao,Shelly Heimfeld,Michael C. Jensen,Stanley R. Riddell,David G. Maloney +22 more
TL;DR: It is established that high CAR-T cell doses and tumor burden increase the risks of severe cytokine release syndrome and neurotoxicity, and serum biomarkers that allow testing of early intervention strategies in patients at the highest risk of toxicity are identified.
Journal ArticleDOI
Chimeric antigen receptor T-cell therapy — assessment and management of toxicities
Sattva S. Neelapu,Sudhakar Tummala,Partow Kebriaei,William G. Wierda,Cristina Gutierrez,Frederick L. Locke,Krishna V. Komanduri,Yi Lin,Nitin Jain,Naval Daver,Jason R. Westin,Alison M. Gulbis,Monica Loghin,John de Groot,Sherry Adkins,Suzanne E. Davis,Katayoun Rezvani,Patrick Hwu,Elizabeth J. Shpall +18 more
TL;DR: The multidisciplinary approach adopted at institutions is described, and recommendations for monitoring, grading, and managing the acute toxicities that can occur in patients treated with CAR-T-cell therapy are provided.
Journal ArticleDOI
Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia
David L. Porter,Wei-Ting Hwang,Noelle V. Frey,Simon F. Lacey,Pamela A. Shaw,Alison W. Loren,Adam Bagg,Katherine T. Marcucci,Angela Shen,Vanessa E. Gonzalez,David E Ambrose,Stephan A. Grupp,Anne Chew,Zhaohui Zheng,Michael C. Milone,Bruce L. Levine,J. Joseph Melenhorst,Carl H. June +17 more
TL;DR: The in vivo expansion of theCAR T cells correlated with clinical responses, and the CAR T cells persisted and remained functional beyond 4 years in the first two patients achieving CR, suggesting that disease eradication may be possible in some patients with advanced CLL.
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