Clinical development of CAR T cells—challenges and opportunities in translating innovative treatment concepts
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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
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The use of ICU resources in CAR-T cell recipients: a hospital-wide study
Sandrine Valade,Michael Darmon,Lara Zafrani,Eric Mariotte,Virginie Lemiale,Swann Bredin,Guillaume Dumas,Nicolas Boissel,Florence Rabian,André Baruchel,Isabelle Madelaine,Jérôme Larghero,Anne Brignier,Etienne Lengliné,Stephanie Harel,Bertrand Arnulf,Roberta Di Blasi,Catherine Thieblemont,Elie Azoulay +18 more
TL;DR: In this paper , the authors describe and assess outcomes in critically ill CAR-T cell recipients, using a hospital-wide retrospective study, and show that the severity of organ dysfunction is a major determinant of death, especially in patients with altered performance status or disease progression.
Journal ArticleDOI
Transcriptional states of CAR-T infusion relate to neurotoxicity – lessons from high-resolution single-cell SOM expression portraying
H. Loeffler-Wirth,Michael Rade,Arsen Arakelyan,Markus Kreuz,Markus Loeffler,Ulrike Koehl,Kristin Reiche,Hans Binder +7 more
TL;DR: This study provides molecular details of the transcriptomic landscape with possible impact to overcome neurotoxicity as well as capabilities of single-cell data portraying to disentangle transcriptional states using intuitive visualization, functional mining, molecular cell stratification, and variability analyses.
Journal ArticleDOI
Touch-free optical technologies to streamline the production of T cell therapies.
TL;DR: In this article , the authors discuss emerging label-free optical imaging and sensing methods, along with machine learning techniques that could enable in-line feedback to optimize T cell quality at multiple stages during manufacturing.
Journal ArticleDOI
CAR T-cell Therapy as a Modern Method for the Treatment of Oncological Diseases
TL;DR: The article presents the results of the analysis of modern literature sources devoted to CAR T–cell therapy, which has become a breakthrough trend in the treatment of a number of hematological tumors.
Journal ArticleDOI
The Shared Ethical Responsibility of Medically and Non-medically Qualified Experts in Human Drug Development Teams.
Sandor Kerpel-Fronius,Sander Becker,Jane Barrett,Johan Brun,Roberto Carlesi,Anthony A.W. Chan,Luis Francisco Collia,David Dubois,Peter Kleist,Greg Koski,Chieko Kurihara,Luís Filipe Laranjeira,Johanna Schenk,Honorio Silva +13 more
TL;DR: It is argued that all members of such multidisciplinary teams must share the scientific and ethical responsibilities since they all influence directly or indirectly both the outcome of the various phases of the medicines development projects and the safety of the research subjects involved.
References
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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.
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Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2
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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.
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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.
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