CD28 costimulation improves expansion and persistence of chimeric antigen receptor–modified T cells in lymphoma patients
Barbara Savoldo,Carlos A. Ramos,Carlos A. Ramos,Enli Liu,Martha P. Mims,Michael J. Keating,George Carrum,George Carrum,Rammurti T. Kamble,Rammurti T. Kamble,Catherine M. Bollard,Catherine M. Bollard,Adrian P. Gee,Zhuyong Mei,Hao Liu,Bambi Grilley,Bambi Grilley,Cliona M. Rooney,Cliona M. Rooney,Helen E. Heslop,Malcolm K. Brenner,Gianpietro Dotti +21 more
TLDR
The results demonstrate the superiority of CARs with dual signal domains and confirm a method of comparing CAR-modified T cells within individual patients, thereby avoiding patient-to-patient variability and accelerating the development of optimal T cell immunotherapies.Abstract:
Targeted T cell immunotherapies using engineered T lymphocytes expressing tumor-directed chimeric antigen receptors (CARs) are designed to benefit patients with cancer. Although incorporation of costimulatory endodomains within these CARs increases the proliferation of CAR-redirected T lymphocytes, it has proven difficult to draw definitive conclusions about the specific effects of costimulatory endodomains on the expansion, persistence, and antitumor effectiveness of CAR-redirected T cells in human subjects, owing to the lack of side-by-side comparisons with T cells bearing only a single signaling domain. We therefore designed a study that allowed us to directly measure the consequences of adding a costimulatory endodomain to CAR-redirected T cells. Patients with B cell lymphomas were simultaneously infused with 2 autologous T cell products expressing CARs with the same specificity for the CD19 antigen, present on most B cell malignancies. One CAR encoded both the costimulatory CD28 and the ζ-endodomains, while the other encoded only the ζ-endodomain. CAR+ T cells containing the CD28 endodomain showed strikingly enhanced expansion and persistence compared with CAR+ T cells lacking this endodomain. These results demonstrate the superiority of CARs with dual signal domains and confirm a method of comparing CAR-modified T cells within individual patients, thereby avoiding patient-to-patient variability and accelerating the development of optimal T cell immunotherapies.read more
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Chimeric antigen receptor T cells for sustained remissions in leukemia.
Shannon L. Maude,Noelle Frey,Pamela A. Shaw,Richard Aplenc,David M. Barrett,Nancy Bunin,Anne Chew,Vanessa E. Gonzalez,Zhaohui Zheng,Simon F. Lacey,Yolanda D. Mahnke,J. Joseph Melenhorst,Susan R. Rheingold,Angela Shen,David T. Teachey,Bruce L. Levine,Carl H. June,David L. Porter,Stephan A. Grupp +18 more
TL;DR: Chimeric antigen receptor-modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL and was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed.
Journal ArticleDOI
Chimeric antigen receptor-modified T cells for acute lymphoid leukemia.
Stephan A. Grupp,Michael Kalos,David M. 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 +12 more
TL;DR: The emergence of tumor cells that no longer express the target indicates a need to target other molecules in addition to CD19 in some patients with ALL.
Journal ArticleDOI
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 I. Katz,Stephan A. Grupp,Stephan A. Grupp,Adam Bagg,Carl H. June +7 more
TL;DR: It is reported that CAR T cells that target CD19 and contain a costimulatory domain from CD137 and the T cell receptor ζ chain have potent non–cross-resistant clinical activity after infusion in three of three patients treated with advanced chronic lymphocytic leukemia (CLL).
Journal ArticleDOI
CD19-Targeted T Cells Rapidly Induce Molecular Remissions in Adults with Chemotherapy-Refractory Acute Lymphoblastic Leukemia
Renier J. Brentjens,Marco L. Davila,Isabelle Riviere,Jae H. Park,Xiuyan Wang,Lindsay G. Cowell,Shirley Bartido,Jolanta Stefanski,Clare Taylor,Malgorzata Olszewska,Oriana Borquez-Ojeda,Jinrong Qu,Teresa Wasielewska,Qing He,Yvette Bernal,Ivelise Rijo,Cyrus V. Hedvat,Rachel Kobos,Kevin J. Curran,Peter G. Steinherz,Joseph G. Jurcic,Todd L. Rosenblat,Peter Maslak,Mark G. Frattini,Michel Sadelain +24 more
TL;DR: The results demonstrate the marked antitumor efficacy of 19-28z CAR-modified T cells in patients with relapsed/refractory B-ALL and the reliability of this therapy to induce profound molecular remissions, forming a highly effective bridge to potentially curative therapy with subsequent allo-HSCT.
Journal ArticleDOI
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
TL;DR: 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.
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