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
Citations
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DissertationDOI
Experimental and Modeling Framework for the Production of Cell and Protein-Based Biopharmaceutical Products
TL;DR: This work aims at developing novel experimental and modeling strategies to optimize the production of cell and protein based biotherapeutics with tailored quality attributes through the development of two expansion processes to scale-up the cultivation of human pluripotent stem cells and T cells.
Journal ArticleDOI
Réglementations applicables aux CAR-T cells : comment les établissements de santé français peuvent-ils s’organiser pour participer à la production et permettre la délivrance de ces immunothérapies innovantes ?
TL;DR: The organizational framework for two situations are reviewed: delivery and administration of industry-manufactured CAR-T Cells as well as engineering and distribution of CAR- T Cells produced as investigational drugs to be evaluated in the context of clinical research protocols.
Journal ArticleDOI
Interfacing Biomaterials with Synthetic T Cell Immunity.
TL;DR: In this article, a new generation of biomaterials is being developed to interface with molecular and cellular features of immunity and ultimately shape or control anti-tumor responses, which can improve response rates and safety while lowering costs to expand their use.
Dissertation
Biofunctional iron oxide nanoparticles as vaccine adjuvants for enhanced anti-cancer immunotherapy
Bocanegra Gondan,Ana isabel +1 more
TL;DR: Las nanoparticulas estan biofuncionalizadas con una combinacion de agonistas sinteticos de TLR (Poly(I:C) e imiquimod), que activan de manera sinergica una respuesta inmune innata contra el tumor.
Book ChapterDOI
Components and Design of Chimeric Antigen Receptors
TL;DR: In this chapter, the components and molecular designs of CARs are discussed in detail about the components of chimeric antigen receptors.
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.
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.
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