Clinical development of CAR T cells—challenges and opportunities in translating innovative treatment concepts
Reads0
Chats0
TLDR
A comprehensive overview of the clinical trials performed so far worldwide and analyze parameters such as targeted antigen and indication, CAR molecular design, CAR T cell manufacturing, anti‐tumor activities, and related toxicities, with a special focus on the European stage.Abstract:
Chimeric antigen receptor (CAR) T cell therapy, together with checkpoint inhibition, has been celebrated as a breakthrough technology due to the substantial benefit observed in clinical trials with patients suffering from relapsed or refractory B-cell malignancies. In this review, we provide a comprehensive overview of the clinical trials performed so far worldwide and analyze parameters such as targeted antigen and indication, CAR molecular design, CAR T cell manufacturing, anti-tumor activities, and related toxicities. More than 200 CAR T cell clinical trials have been initiated so far, most of which aim to treat lymphoma or leukemia patients using CD19-specific CARs. An increasing number of studies address solid tumors as well. Notably, not all clinical trials conducted so far have shown promising results. Indeed, in a few patients CAR T cell therapy resulted in severe adverse events with fatal outcome. Of note, less than 10% of the ongoing CAR T cell clinical trials are performed in Europe. Taking lead from our analysis, we discuss the problems and general hurdles preventing efficient clinical development of CAR T cells as well as opportunities, with a special focus on the European stage.read more
Citations
More filters
Journal ArticleDOI
Chimeric antigen receptor T cell (CAR-T) immunotherapy for solid tumors: lessons learned and strategies for moving forward
TL;DR: The challenges that CAR-T is facing for solid tumor treatment are discussed and potential strategies to improve the efficacy ofCAR-T as promising immunotherapy are proposed.
Journal ArticleDOI
Hematopoietic cell transplantation and cellular therapy survey of the EBMT: monitoring of activities and trends over 30 years
Jakob Passweg,Helen Baldomero,Christian Chabannon,Grzegorz W. Basak,Rafael de la Cámara,Selim Corbacioglu,Harry Dolstra,Rafael F. Duarte,Bertram Glass,Raffaella Greco,Arjan C. Lankester,Mohamad Mohty,Régis Peffault de Latour,John A. Snowden,Ibrahim Yakoub-Agha,Nicolaus Kröger,Marrow Transplantation +16 more
TL;DR: The number of Hematopoietic cell transplantation (HCT) in Europe and collaborating countries continues to rise with 48,512 HCT in 43,581 patients, comprising of 19,798 (41%) allogeneic and 28,714 (59%) autologous, reported by 700 centers in 51 countries during 2019.
Journal ArticleDOI
Development and Clinical Translation of Approved Gene Therapy Products for Genetic Disorders.
Alireza Shahryari,Marie Saghaeian Jazi,Saeed Mohammadi,Hadi Razavi Nikoo,Zahra Nazari,Elaheh Sadat Hosseini,Ingo Burtscher,Seyed Javad Mowla,Heiko Lickert +8 more
TL;DR: The history and development of twenty approved human gene and cell-based gene therapy products that have been approved up-to-now are reviewed in clinic and markets of mainly North America, Europe and Asia.
Journal ArticleDOI
CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy
Michael C. Burger,Congcong Zhang,Patrick N. Harter,Annette Romanski,F Strassheimer,Christian Senft,Torsten Tonn,Joachim P. Steinbach,Winfried S. Wels +8 more
TL;DR: Effects of the GB tumor microenvironment on NK-cell functionality, early treatment attempts with ex vivo activated NK cells, and relevant CAR target antigens validated with CAR-T cells are discussed.
Journal ArticleDOI
Strategies to Address Chimeric Antigen Receptor Tonic Signaling.
Adam Ajina,John Maher +1 more
TL;DR: The mechanisms underpinning CAR tonic signaling are reviewed and the wide variety of effects that can emerge after making subtle structural changes or altering the methodology of CAR transduction are highlighted.
References
More filters
Journal ArticleDOI
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
T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial
Daniel W. Lee,James N. Kochenderfer,Maryalice Stetler-Stevenson,Yongzhi K Cui,Cindy Delbrook,Steven A. Feldman,Terry J. Fry,Rimas J. Orentas,Marianna Sabatino,Nirali N. Shah,Seth M. Steinberg,Dave Stroncek,Nick Tschernia,Constance M. Yuan,Hua Zhang,Ling Zhang,Steven A. Rosenberg,Alan S. Wayne,Crystal L. Mackall +18 more
TL;DR: CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia and non-Hodgkin lymphoma.
Journal ArticleDOI
Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2
Richard A. Morgan,James Chih-Hsin Yang,Mio Kitano,Mark E. Dudley,Carolyn M. Laurencot,Steven A. Rosenberg +5 more
TL;DR: It is speculated that the large number of administered cells localized to the lung immediately following infusion and were triggered to release cytokine by the recognition of low levels of ERBB2 on lung epithelial cells, consistent with a cytokine storm.
Journal ArticleDOI
Efficacy and Toxicity Management of 19-28z CAR T Cell Therapy in B Cell Acute Lymphoblastic Leukemia
Marco L. Davila,Isabelle Riviere,Xiuyan Wang,Shirley Bartido,Jae H. Park,Kevin J. 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 J. Brentjens +31 more
TL;DR: Diagnostic criteria for a severe cytokine release syndrome (sCRS) is defined and serum C-reactive protein, a readily available laboratory study, can serve as a reliable indicator for the severity of the CRS.
Journal ArticleDOI
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 C. Jensen,Stephan A. Grupp,Stephan A. Grupp,Crystal L. Mackall +8 more
TL;DR: A novel system to grade the severity of CRS in individual patients and a treatment algorithm for management of C RS based on severity is presented, to maximize the chance for therapeutic benefit from the immunotherapy while minimizing the risk for life threatening complications of the syndrome.
Related Papers (5)
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
Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia
Shannon L. Maude,Theodore W. Laetsch,Jochen Buechner,S. Rives,Michael Boyer,Henrique Bittencourt,Peter Bader,Michael R. Verneris,Heather E. Stefanski,G.D. Myers,Muna Qayed,B. De Moerloose,Hidefumi Hiramatsu,Krysta Schlis,Kara L. Davis,Paul L. Martin,Eneida R. Nemecek,Gregory A. Yanik,Christina Peters,André Baruchel,Nicolas Boissel,Francoise Mechinaud,Adriana Balduzzi,Joerg Krueger,Carl H. June,Bruce L. Levine,Patricia A. Wood,Tanya Taran,Mimi Leung,Karen Thudium Mueller,Yiyun Zhang,Kapildeb Sen,David Lebwohl,Michael A. Pulsipher,Stephan A. Grupp +34 more
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
T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial
Daniel W. Lee,James N. Kochenderfer,Maryalice Stetler-Stevenson,Yongzhi K Cui,Cindy Delbrook,Steven A. Feldman,Terry J. Fry,Rimas J. Orentas,Marianna Sabatino,Nirali N. Shah,Seth M. Steinberg,Dave Stroncek,Nick Tschernia,Constance M. Yuan,Hua Zhang,Ling Zhang,Steven A. Rosenberg,Alan S. Wayne,Crystal L. Mackall +18 more