Journal ArticleDOI
Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells
Margherita Norelli,Barbara Camisa,Giulia Barbiera,Laura Falcone,Ayurzana Purevdorj,Marco Genua,Francesca Sanvito,Maurilio Ponzoni,Claudio Doglioni,Patrizia Cristofori,Catia Traversari,Claudio Bordignon,Claudio Bordignon,Fabio Ciceri,Renato Ostuni,Chiara Bonini,Monica Casucci,Attilio Bondanza +17 more
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TLDR
A mouse model recapitulating key features of CRS and neurotoxicity is described, offering a therapeutic strategy to tackle neurotoxicity and open new avenues to safer CAR T cell therapies.Abstract:
In the clinic, chimeric antigen receptor-modified T (CAR T) cell therapy is frequently associated with life-threatening cytokine-release syndrome (CRS) and neurotoxicity. Understanding the nature of these pathologies and developing treatments for them are hampered by the lack of appropriate animal models. Herein, we describe a mouse model recapitulating key features of CRS and neurotoxicity. In humanized mice with high leukemia burden, CAR T cell-mediated clearance of cancer triggered high fever and elevated IL-6 levels, which are hallmarks of CRS. Human monocytes were the major source of IL-1 and IL-6 during CRS. Accordingly, the syndrome was prevented by monocyte depletion or by blocking IL-6 receptor with tocilizumab. Nonetheless, tocilizumab failed to protect mice from delayed lethal neurotoxicity, characterized by meningeal inflammation. Instead, the IL-1 receptor antagonist anakinra abolished both CRS and neurotoxicity, resulting in substantially extended leukemia-free survival. These findings offer a therapeutic strategy to tackle neurotoxicity and open new avenues to safer CAR T cell therapies.read more
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Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19.
Daniel Blanco-Melo,Benjamin E. Nilsson-Payant,Wen-Chun Liu,Skyler Uhl,Daisy A. Hoagland,Rasmus Møller,Tristan X. Jordan,Kohei Oishi,Maryline Panis,David H. Sachs,Taia T. Wang,Robert E. Schwartz,Jean K. Lim,Randy A. Albrecht,Benjamin R. tenOever +14 more
TL;DR: It is proposed that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.
Journal ArticleDOI
Cytokine Storm.
David C. Fajgenbaum,Carl H. June +1 more
TL;DR: From the Department of Medicine, Division of Translational Medicine and Human Genetics, Center for Cytokine Storm Treatment and Laboratory, and the Center for Cellular Immunotherapies and the Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia.
Journal ArticleDOI
ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells
Daniel W. Lee,Bianca Santomasso,Frederick L. Locke,Armin Ghobadi,Cameron J. Turtle,Jennifer N. Brudno,Marcela V. Maus,Jae H. Park,Elena Mead,Steven Z. Pavletic,William Y. Go,Lamis K. Eldjerou,Rebecca Gardner,Noelle V. Frey,Kevin J. Curran,Karl S. Peggs,Marcelo C. Pasquini,John F. DiPersio,Marcel R.M. van den Brink,Krishna V. Komanduri,Stephan A. Grupp,Sattva S. Neelapu +21 more
TL;DR: The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting.
Journal ArticleDOI
Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality.
TL;DR: Tocilizumab is a blocker of IL-6R, which can effectively block IL- 6 signal transduction pathway, and is likely to become an effective drug for patients with severe COVID-19.
Journal ArticleDOI
Tocilizumab in patients with severe COVID-19: a retrospective cohort study
Giovanni Guaraldi,Marianna Meschiari,Alessandro Cozzi-Lepri,Jovana Milic,Roberto Tonelli,Marianna Menozzi,Erica Franceschini,Gianluca Cuomo,Gabriella Orlando,Vanni Borghi,Antonella Santoro,Margherita Di Gaetano,Cinzia Puzzolante,Federica Carli,Andrea Bedini,Luca Corradi,Riccardo Fantini,Ivana Castaniere,Luca Tabbì,Massimo Girardis,Sara K. Tedeschi,Maddalena Giannella,Michele Bartoletti,Renato Pascale,Giovanni Dolci,Lucio Brugioni,Antonello Pietrangelo,Andrea Cossarizza,Federico Pea,Enrico Clini,Carlo Salvarani,Marco Massari,Pierluigi Viale,Cristina Mussini +33 more
TL;DR: Assessment of the role of tocilizumab in reducing the risk of invasive mechanical ventilation and death in patients with severe COVID-19 pneumonia who received standard of care treatment found it to be associated with a reduced risk.
References
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Massively parallel digital transcriptional profiling of single cells
Grace X.Y. Zheng,Jessica M. Terry,Phillip Belgrader,Paul Ryvkin,Zachary Bent,Ryan Wilson,Solongo B. Ziraldo,Tobias Daniel Wheeler,Geoffrey P. McDermott,Junjie Zhu,Mark T. Gregory,Joe Shuga,Luz Montesclaros,Jason G. Underwood,Donald A. Masquelier,Stefanie Y. Nishimura,Michael Schnall-Levin,Paul Wyatt,Christopher Hindson,Rajiv Bharadwaj,Alexander Wong,Kevin D. Ness,Lan Beppu,H. Joachim Deeg,Christopher McFarland,Keith R. Loeb,Keith R. Loeb,William J. Valente,William J. Valente,Nolan G. Ericson,Emily A. Stevens,Jerald P. Radich,Tarjei S. Mikkelsen,Benjamin J. Hindson,Jason H. Bielas +34 more
TL;DR: A droplet-based system that enables 3′ mRNA counting of tens of thousands of single cells per sample is described and sequence variation in the transcriptome data is used to determine host and donor chimerism at single-cell resolution from bone marrow mononuclear cells isolated from transplant patients.
Journal ArticleDOI
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
TL;DR: Patients with refractory large B‐cell lymphoma who received CAR T‐cell therapy with axi‐cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events.
Journal ArticleDOI
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
TL;DR: In this global study of CAR T‐cell therapy, a single infusion of tisagenlecleucel provided durable remission with long‐term persistence in pediatric and young adult patients with relapsed or refractory B‐cell ALL, with transient high‐grade toxic effects.
Journal ArticleDOI
Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia
TL;DR: A low dose of autologous chimeric antigen receptor-modified T cells reinfused into a patient with refractory chronic lymphocytic leukemia expanded to a level that was more than 1000 times as high as the initial engraftment level in vivo, with delayed development of the tumor lysis syndrome and with complete remission.
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.
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