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Immune effector cell associated neurotoxicity syndrome in chimeric antigen receptor-T cell therapy. ​

Literature Information ​

DOI10.3389/fimmu.2022.879608
PMID36081506
JournalFrontiers in immunology
Impact Factor5.9
JCR QuartileQ1
Publication Year2022
Times Cited42
KeywordsCAR-T cell, ICANS, chimeric antigen receptor-T cell (CAR-T cell) therapy, cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS)
Literature TypeJournal Article, Review
ISSN1664-3224
Pages879608
Issue13()
AuthorsRobert C Sterner, Rosalie M Sterner

TL;DR ​

This paper discusses Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS), a serious neurotoxic side effect of chimeric antigen receptor (CAR)-T cell therapy, which, despite its effectiveness against certain hematological malignancies, limits the therapy's broader application due to associated toxicities. The authors emphasize the need for further research to understand ICANS mechanisms and develop effective treatments, aiming to enhance the safety and accessibility of CAR-T cell therapy.

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CAR-T cell · ICANS · chimeric antigen receptor-T cell (CAR-T cell) therapy · cytokine release syndrome (CRS) · immune effector cell associated neurotoxicity syndrome (ICANS)

Abstract ​

Chimeric antigen receptor (CAR)-T cell therapy is an emerging staple in the treatment of certain hematological malignancies. While CAR-T cells have produced robust responses in certain hematological malignancies, toxicities associated with the therapy have limited their use. Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) is a potentially life-threatening neurotoxicity that commonly occurs with CAR-T cell therapy. Here we will discuss ICANS, its treatment, possible mechanisms, and potential solutions to this critical limitation of CAR-T cell therapy. As the field of CAR-T cell therapy evolves, improved treatments and methods to circumvent or overcome ICANS are necessary to improve morbidity, mortality, and decrease the cost of CAR-T cell therapy. This serious, life-threatening side effect needs to be studied to better understand its mechanisms and develop treatments and alternative strategies.

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Primary Questions Addressed ​

  1. What are the long-term effects of ICANS on patients undergoing CAR-T cell therapy?
  2. How do different patient demographics influence the incidence and severity of ICANS?
  3. What role do pre-existing neurological conditions play in the development of ICANS during CAR-T cell therapy?
  4. How can biomarkers be utilized to predict the onset of ICANS in patients receiving CAR-T cell therapy?
  5. What advancements in CAR-T cell design could potentially reduce the risk of neurotoxicity associated with the therapy?

Key Findings ​

Research Background and Purpose ​

Chimeric antigen receptor (CAR)-T cell therapy has emerged as a significant treatment for certain hematological malignancies, demonstrating substantial clinical success. However, the therapy is associated with severe toxicities, notably Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS), which poses serious risks, including morbidity and mortality. This review aims to discuss ICANS, its underlying mechanisms, treatment options, and potential strategies to mitigate this critical limitation of CAR-T cell therapy.

Main Methods/Materials/Experimental Design ​

The authors utilized a comprehensive review approach to gather and synthesize current knowledge on ICANS, focusing on its clinical presentation, mechanisms, and management strategies.

Mermaid diagram

Key Results and Findings ​

  1. Prevalence and Symptoms: ICANS affects 20-70% of patients undergoing CAR-T cell therapy, with symptoms ranging from confusion and headaches to severe cases involving cerebral edema and seizures.
  2. Grading of ICANS: The grading system categorizes ICANS from Grade 1 (mild) to Grade 4 (severe), with variability in grading based on the system used.
  3. Mechanisms: Key mechanisms identified include:
    • Cytokine release and increased levels of inflammatory markers.
    • Disruption of the blood-brain barrier, leading to neuroinflammation.
    • Endothelial activation and capillary leak syndrome.
  4. Treatment Challenges: While corticosteroids are the mainstay of treatment, their optimal use remains unclear, and no specific prophylactic therapies exist.

Main Conclusions/Significance/Innovation ​

The review highlights the critical nature of ICANS as a life-threatening complication of CAR-T cell therapy, emphasizing the need for further research into its mechanisms and management strategies. Innovative approaches, such as modifying CAR structures and utilizing "off switches" or suicide genes, may offer potential solutions to mitigate ICANS and enhance the safety profile of CAR-T therapies.

Research Limitations and Future Directions ​

  1. Limited Understanding: The exact pathophysiology of ICANS is not fully understood, necessitating more extensive research.
  2. Lack of Animal Models: There is a scarcity of suitable animal models to study ICANS, which hampers the development of effective treatments.
  3. Future Research: Future studies should focus on identifying specific cytokine networks involved in ICANS and developing targeted therapies. Additionally, structural modifications of CARs to reduce toxicity while maintaining efficacy should be explored.

In summary, this review provides a thorough overview of ICANS associated with CAR-T cell therapy, outlining its clinical implications and the urgent need for advancements in understanding and managing this complex syndrome.

References ​

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  2. A Graduate-Level Interdisciplinary Curriculum in CAR-T Cell Therapy. - Rosalie M Sterner;Karen E Hedin;Richard E Hayden;Grzegorz S Nowakowski;Saranya P Wyles;Alexandra J Greenberg-Worisek;Andre Terzic;Saad S Kenderian - Mayo Clinic proceedings. Innovations, quality & outcomes (2020)
  3. Modulation of chimeric antigen receptor surface expression by a small molecule switch. - Alexandre Juillerat;Diane Tkach;Brian W Busser;Sonal Temburni;Julien Valton;Aymeric Duclert;Laurent Poirot;Stéphane Depil;Philippe Duchateau - BMC biotechnology (2019)
  4. A Versatile Safeguard for Chimeric Antigen Receptor T-Cell Immunotherapies. - Julien Valton;Valerie Guyot;Bijan Boldajipour;Cesar Sommer;Thomas Pertel;Alexandre Juillerat;Aymeric Duclert;Barbra Johnson Sasu;Philippe Duchateau;Laurent Poirot - Scientific reports (2018)
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  6. Brain capillary obstruction during neurotoxicity in a mouse model of anti-CD19 chimeric antigen receptor T-cell therapy. - Lila D Faulhaber;Anthea Q Phuong;Kendra Jae Hartsuyker;Yeheun Cho;Katie K Mand;Stuart D Harper;Aaron K Olson;Gwenn A Garden;Andy Y Shih;Juliane Gust - Brain communications (2022)
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  9. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. - Shannon L Maude;Theodore W Laetsch;Jochen Buechner;Susana Rives;Michael Boyer;Henrique Bittencourt;Peter Bader;Michael R Verneris;Heather E Stefanski;Gary D Myers;Muna Qayed;Barbara De Moerloose;Hidefumi Hiramatsu;Krysta Schlis;Kara L Davis;Paul L Martin;Eneida R Nemecek;Gregory A Yanik;Christina Peters;Andre Baruchel;Nicolas Boissel;Francoise Mechinaud;Adriana Balduzzi;Joerg Krueger;Carl H June;Bruce L Levine;Patricia Wood;Tetiana Taran;Mimi Leung;Karen T Mueller;Yiyun Zhang;Kapildeb Sen;David Lebwohl;Michael A Pulsipher;Stephan A Grupp - The New England journal of medicine (2018)
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Literatures Citing This Work ​

  1. Neurological Complications of Conventional and Novel Anticancer Treatments. - Paola Alberti;Alessandro Salvalaggio;Andreas A Argyriou;Jordi Bruna;Andrea Visentin;Guido Cavaletti;Chiara Briani - Cancers (2022)
  2. Neoantigen-directed therapeutics in the clinic: where are we? - Lien Lybaert;Kris Thielemans;Steven A Feldman;Sjoerd H van der Burg;Cedric Bogaert;Patrick A Ott - Trends in cancer (2023)
  3. CAR T-cell-associated neurotoxicity in central nervous system hematologic disease: Is it still a concern? - Roser Velasco;Alberto Mussetti;Macarena Villagrán-García;Anna Sureda - Frontiers in neurology (2023)
  4. IRF4 downregulation improves sensitivity and endurance of CAR T cell functional capacities. - Dennis Christoph Harrer;Valerie Bezler;Jordan Hartley;Wolfgang Herr;Hinrich Abken - Frontiers in immunology (2023)
  5. Early and Late Toxicities of Chimeric Antigen Receptor T-Cells. - Rebecca Epperly;Victoria M Giordani;Lekha Mikkilineni;Nirali N Shah - Hematology/oncology clinics of North America (2023)
  6. Toxicity Profile of Chimeric Antigen Receptor T-Cell and Bispecific Antibody Therapies in Multiple Myeloma: Pathogenesis, Prevention and Management. - Mariam Markouli;Fauzia Ullah;Serhan Unlu;Najiullah Omar;Nerea Lopetegui-Lia;Marissa Duco;Faiz Anwer;Shahzad Raza;Danai Dima - Current oncology (Toronto, Ont.) (2023)
  7. CAR-T State of the Art and Future Challenges, A Regulatory Perspective. - Lorenzo Giorgioni;Alessandra Ambrosone;Maria Francesca Cometa;Anna Laura Salvati;Armando Magrelli - International journal of molecular sciences (2023)
  8. A Pharmacovigilance Study on the Safety of Axicabtagene Ciloleucel Based on Spontaneous Reports from the EudraVigilance Database. - Concetta Rafaniello;Valerio Liguori;Alessia Zinzi;Mario Gaio;Angela Falco;Luigi Di Costanzo;Francesca Gargano;Valentina Trimarco;Mauro Cataldi;Annalisa Capuano - Biomedicines (2023)
  9. Outcomes of Chimeric Antigen Receptor (CAR) T-Cell Therapy in Patients with Large B-Cell Lymphoma (LBCL): A Single-Institution Experience. - Aaron Trando;Anna Ter-Zakarian;Phillip Yeung;Aaron M Goodman;Ayad Hamdan;Michael Hurley;Ah-Reum Jeong;Dimitrios Tzachanis - Cancers (2023)
  10. CD44v6 specific CAR-NK cells for targeted immunotherapy of head and neck squamous cell carcinoma. - Ioana Sonya Ciulean;Joe Fischer;Andrea Quaiser;Christoph Bach;Hinrich Abken;Uta Sandy Tretbar;Stephan Fricke;Ulrike Koehl;Dominik Schmiedel;Thomas Grunwald - Frontiers in immunology (2023)

... (32 more literatures)

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