Preclinical In Vivo Modeling of Cytokine Release Syndrome Induced by ErbB-Retargeted Human T Cells: Identifying a Window of Therapeutic Opportunity?
Sjoukje J. C. van der Stegen,David M. Davies,Scott Wilkie,Julie Foster,Jane K. Sosabowski,Jerome Burnet,Lynsey M. Whilding,Roseanna Maria Petrovic,Sadaf Ghaem-Maghami,Stephen J. Mather,Jean-Pierre Jeannon,Jean-Pierre Jeannon,Ana C. Parente-Pereira,John Maher,John Maher,John Maher +15 more
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TLDR
These data demonstrate that CAR-induced cytokine release syndrome can be modeled in mice that express target Ag in an appropriate distribution, and argue that ErbB-retargeted T cells can achieve therapeutic benefit in the absence of unacceptable toxicity, providing that route of administration and dose are carefully optimized.Abstract:
The ErbB network is dysregulated in many solid tumors. To exploit this, we have developed a chimeric Ag receptor (CAR) named T1E28z that targets several pathogenetically relevant ErbB dimers. T1E28z is coexpressed with a chimeric cytokine receptor named 4αβ (combination termed T4), enabling the selective expansion of engineered T cells using IL-4. Human T4(+) T cells exhibit antitumor activity against several ErbB(+) cancer types. However, ErbB receptors are also expressed in several healthy tissues, raising concerns about toxic potential. In this study, we have evaluated safety of T4 immunotherapy in vivo using a SCID beige mouse model. We show that the human T1E28z CAR efficiently recognizes mouse ErbB(+) cells, rendering this species suitable to evaluate preclinical toxicity. Administration of T4(+) T cells using the i.v. or intratumoral routes achieves partial tumor regression without clinical or histopathologic toxicity. In contrast, when delivered i.p., tumor reduction is accompanied by dose-dependent side effects. Toxicity mediated by T4(+) T cells results from target recognition in both tumor and healthy tissues, leading to release of both human (IL-2/IFN-γ) and murine (IL-6) cytokines. In extreme cases, outcome is lethal. Both toxicity and IL-6 release can be ameliorated by prior macrophage depletion, consistent with clinical data that implicate IL-6 in this pathogenic event. These data demonstrate that CAR-induced cytokine release syndrome can be modeled in mice that express target Ag in an appropriate distribution. Furthermore, our findings argue that ErbB-retargeted T cells can achieve therapeutic benefit in the absence of unacceptable toxicity, providing that route of administration and dose are carefully optimized.read more
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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
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
Cytokine release syndrome
Alexander Shimabukuro-Vornhagen,Philipp Gödel,Marion Subklewe,Hans Joachim Stemmler,Hans A. Schlößer,Max Schlaak,M. Kochanek,B. Böll,Michael von Bergwelt-Baildon +8 more
TL;DR: This review provides a comprehensive overview of the mechanisms underlying CRS pathophysiology, risk factors, clinical presentation, differential diagnoses, and prognostic factors and gives practical guidance to the management of the cytokine release syndrome.
Journal ArticleDOI
CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade.
Theodoros Giavridis,Sjoukje J. C. van der Stegen,Justin Eyquem,Mohamad Hamieh,Alessandra Piersigilli,Michel Sadelain +5 more
TL;DR: A murine model of CRS is reported that develops within 2–3 d of CAR T cell infusion and that is potentially lethal and responsive to IL-6 receptor blockade, and its severity is mediated not byCAR T cell–derived cytokines, but by IL- 6, IL-1 and nitric oxide produced by recipient macrophages, which enables new therapeutic interventions.
Journal ArticleDOI
CAR exosomes derived from effector CAR-T cells have potent antitumour effects and low toxicity
Wenyan Fu,Changhai Lei,Shuowu Liu,Yingshu Cui,Chuqi Wang,Kewen Qian,Tian Li,Yafeng Shen,Xiaoyan Fan,Fangxing Lin,Min Ding,Mingzhu Pan,Xuting Ye,Yongji Yang,Shi Hu +14 more
TL;DR: CAR-T-cell-derived exosomes are tested as a surrogate for CAR-T cells and it is shown that they can elicit a potent antitumour immune response in preclinical models of breast cancer with reduced signs of cytokine release syndrome compared with Car-T therapy.
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