Emerging approaches for preventing cytokine release syndrome in CAR-T cell therapy

Chimeric antigen receptor (CAR) T cells have demonstrated remarkable anti-tumor efficacy against hematological malignancies, such as leukemia and lymphoma. However, patients treated with CAR-T cells frequently experience cytokine release syndrome (CRS), one of the most life-threatening adverse event...

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Published inJournal of materials chemistry. B, Materials for biology and medicine Vol. 1; no. 37; pp. 7491 - 7511
Main Authors Balagopal, Srinivas, Sasaki, Koichi, Kaur, Pooja, Nikolaidi, Maria, Ishihara, Jun
Format Journal Article
LanguageEnglish
Published England Royal Society of Chemistry 28.09.2022
The Royal Society of Chemistry
Subjects
Adaptor proteins
Anticancer properties
Antigens
Cell therapy
Cell- and Tissue-Based Therapy
Chemistry
Chimeric antigen receptors
Cytokine Release Syndrome - etiology
Cytokine Release Syndrome - prevention & control
Cytokines
Hematologic Neoplasms - pathology
Hematologic Neoplasms - therapy
Humans
Immunosuppressive Agents
Inflammation
Leukemia
Lymphocytes
Lymphocytes T
Lymphoma
Macrophages
Neoplasms - therapy
Neutralization
Receptors
Receptors, Chimeric Antigen
Solid tumors
Switches
Therapy
Tumors
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Summary:Chimeric antigen receptor (CAR) T cells have demonstrated remarkable anti-tumor efficacy against hematological malignancies, such as leukemia and lymphoma. However, patients treated with CAR-T cells frequently experience cytokine release syndrome (CRS), one of the most life-threatening adverse events of the therapy induced by systemic concentrations of pro-inflammatory cytokines throughout the body. Immunosuppressants such as tocilizumab are currently administered to treat the onset and progression of CRS symptoms. In order to reduce the risk of CRS, newly designed next-generation CAR-T treatments are being developed for both hematopoietic malignancies and solid tumors. In this review, we discuss six classes of interesting approaches that control cytokine production of CAR-T cell therapy: adaptor-based strategies, orthogonal cytokine-receptor pairs, regulation of macrophage cytokine activity, autonomous neutralization of key cytokines, kill switches and methods of reversible suppression of CARs. With these strategies, future CAR-T cell therapies will be designed to preemptively inhibit CRS, minimize the patients' suffering, and maximize the number of benefiting patients. Strategies for reducing CRS in CAR-T cells capitalize on the specificity between CAR-T cells, cytokines, and their receptors, the role of macrophages in cytokine release, and genetic constructs to ablate CAR-T function reversibly and irreversibly.
Bibliography:Jun Ishihara is an early-career researcher in the field of immunoengineering, with research foci in cancer immunotherapy, autoimmune diseases and regenerative medicine. Trained as a stem cell biologist, immunologist and bioengineer, he employs cell engineering and protein biology methodology to achieve cell manipulation. He has developed novel technologies, and currently focuses on achieving local cancer immunotherapy through targeting the tumor microenvironment. Dr Ishihara spent the period from 2014/5 to 2016/3 in Switzerland as a post-doctoral fellow in the Hubbell laboratory at the Ecole Polytechnique Fédérale de Lausanne (EPFL). He transitioned from the EPFL to the University of Chicago in March 2016 also as a post-doctoral fellow in the Hubbell laboratory, when that laboratory relocated to the Pritzker School of Molecular Engineering. Dr Ishihara became a PI at the Department of Bioengineering, Imperial College London in 2020. He is currently leading a lab of 9 people. Since the establishment of his laboratory, he has been awarded numerous research grants and awards. His goal is to make therapy more "comfortable" and effective long-term for patients.
Koichi Sasaki completed his PhD in 2020 (Supervisor: Prof. Yoshiki Katayama, Kyushu University). He conducted 9 months of research at the University of Chicago (Supervisor: Prof. Jeffrey A Hubbell) as a visiting student during his PhD. He received Chemical Abstract Service (CAS) Future Leaders Award from the American Chemical Society in 2019. After a year of postdoctoral research at Osaka Prefecture University (Supervisors: Prof. Atsushi Harada and Prof. Eiji Yuba), he is currently working on the development of next-generation adoptive cell therapy based on expertise in molecular engineering and drug delivery systems as a member of Ishihara laboratory at Imperial College London.
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These authors contributed equally.
ISSN:2050-750X
2050-7518
DOI:10.1039/d2tb00592a