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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Review of cancer treatment with immune checkpoint inhibitors : Current concepts, expectations, limitations and pitfalls.
Christiane Thallinger,Thorsten Füreder,Matthias Preusser,Gerwin Heller,Leonhard Müllauer,Christoph Höller,Helmut Prosch,Natalija Frank,Rafal Swierzewski,Walter Berger,Ulrich Jäger,Christoph C. Zielinski +11 more
TL;DR: The current overview summarizes current knowledge on immune checkpoint inhibitor treatment in malignancies, its outlook and limitations, diagnostic means and, finally, side effect management.
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Gamma-Delta CAR-T Cells Show CAR-Directed and Independent Activity Against Leukemia.
Meir Rozenbaum,Meir Rozenbaum,Amilia Meir,Yarden Aharony,Orit Itzhaki,Jacob Schachter,Ilan Bank,Elad Jacoby,Elad Jacoby,Michal J. Besser,Michal J. Besser +10 more
TL;DR: In this paper, a 14-day production process initiated from peripheral-blood mononuclear cells was described, leading to a median 185-fold expansion of γδ T cells with high purity (>98% CD3+ and >99% TCR+).
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Multispecific anti-HIV duoCAR-T cells display broad in vitro antiviral activity and potent in vivo elimination of HIV-infected cells in a humanized mouse model.
Kim Anthony-Gonda,Ariola Bardhi,Alex K. Ray,Nina C. Flerin,Mengyan Li,Weizao Chen,Christina Ochsenbauer,John C. Kappes,John C. Kappes,Winfried Krueger,Andrew Worden,Dina Schneider,Zhongyu Zhu,Rimas Orentas,Dimiter S. Dimitrov,Harris Goldstein,Boro Dropulic +16 more
TL;DR: It is shown that transduction with lentiviral vectors encoding multispecific anti-HIV duoCARs confer primary T cells with the capacity to potently reduce cellular HIV infection by up to 99% in vitro and >97% in vivo, and this data suggest that mult ispecificAnti-Hiv duoCAR-T cells could be an effective approach for the treatment of patients with HIV-1 infection.
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In vivo generation of human CD19‐CAR T cells results in B‐cell depletion and signs of cytokine release syndrome
Anett Pfeiffer,Frederic B. Thalheimer,Sylvia Hartmann,Annika M. Frank,Ruben R. Bender,Simon Danisch,Caroline Costa,Winfried S. Wels,Winfried S. Wels,Ute Modlich,Renata Stripecke,Els Verhoeyen,Els Verhoeyen,Christian J. Buchholz,Christian J. Buchholz +14 more
TL;DR: Evidence is provided that human CD19‐CAR T cells can be generated directly in vivo using the lentiviral vector CD8‐LV specifically targeting human CD8+ cells, yet with similar adverse effects currently notorious in the clinical practice.
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Bispecific T-Cell Redirection versus Chimeric Antigen Receptor (CAR)-T Cells as Approaches to Kill Cancer Cells.
William R. Strohl,Michael Naso +1 more
TL;DR: New formats and dosing paradigms for TRBAs and CAR-T cells are being developed in efforts to maximize efficacy and minimize toxicity, as well as to optimize use with both solid and hematologic tumors, both of which present significant challenges such as target heterogeneity and the immunosuppressive tumor microenvironment.
References
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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
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T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial
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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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