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  • Review Article
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Beyond the storm — subacute toxicities and late effects in children receiving CAR T cells

Nature Reviews Clinical Oncology volume 18, pages 363–378 (2021)Cite this article

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Abstract

As clinical advances with chimeric antigen receptor (CAR) T cells are increasingly described and the potential for extending their therapeutic benefit grows, optimizing the implementation of this therapeutic modality is imperative. The recognition and management of cytokine release syndrome (CRS) marked a milestone in this field; however, beyond the understanding gained in treating CRS, a host of additional toxicities and/or potential late effects of CAR T cell therapy warrant further investigation. A multicentre initiative involving experts in paediatric cell therapy, supportive care and/or study of late effects from cancer and haematopoietic stem cell transplantation was convened to facilitate the comprehensive study of extended CAR T cell-mediated toxicities and establish a framework for new systematic investigations of CAR T cell-related adverse events. Together, this group identified six key focus areas: extended monitoring of neurotoxicity and neurocognitive function, psychosocial considerations, infection and immune reconstitution, other end organ toxicities, evaluation of subsequent neoplasms, and strategies to optimize remission durability. Herein, we present the current understanding, gaps in knowledge and future directions of research addressing these CAR T cell-related outcomes. This systematic framework to study extended toxicities and optimization strategies will facilitate the translation of acquired experience and knowledge for optimal application of CAR T cell therapies.

Key points

  • A host of extended subacute toxicities and/or potential late effects of CAR T cell therapy and cytokine release syndrome (CRS) in children warrant further investigation with a systematic approach and with prospective studies.

  • Herein, we provide a contextual framework for evaluating toxicities of novel CAR T cell constructs, as well as an overview of strategies currently used to optimize responses and assess other long-term outcomes of CAR T cell therapy.

  • Longitudinal neurocognitive evaluations, established time points for and interpretation of neuroimaging, and development of biomarkers for assessment of neurotoxicity risk and quantification of neurological injury across CAR T cell trials are needed to further optimize neurological outcomes.

  • Comprehensive care models that include the patient, family, and referring and primary teams should be embedded into all CAR T cell therapy programmes to provide comfort, address expectations, and understand psychosocial risk factors and educational needs.

  • CAR T cell recipients are at high risk of infection owing to a host of factors and developing optimal guidelines for infection prevention during both acute CRS and longitudinally is necessary to optimize outcomes. Monitoring immune reconstitution after treatment will help identify future risks of infection and how vaccination strategies might be effective in this population.

  • Extending the durability of remission following CAR T cell treatment remains a primary goal, for which the study of late effects remains imperative. The results of ongoing studies of a host of strategies will inform the role of remission consolidation and risk stratification in identifying patients at highest risk of relapse.

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Fig. 1: Comprehensive overview of CAR T cell-related toxicities and subacute effects.
Fig. 2: Risk and timing of infection after CAR T-cell therapy.
Fig. 3: Strategies to prevent relapse after CAR T cell therapy in children.

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Acknowledgements

The initial efforts from the CAR T cell Therapy Beyond the Storm Consortium were presented on 14 May 2020 in a conference jointly sponsored by the National Cancer Institute (NCI), and the Pediatric Transplantation and Cell Therapy Consortium (PTCTC). The authors acknowledge all the speakers and the >200 international participants. The audio recording from the conference can be found on the conference website. The authors acknowledge the NCI and the PTCTC for their support, and specifically L. Schultz for sharing her efforts on CAR T cell Real World consortia studies. PTCTC receives support through a Johnny Crisstopher Children’s Charitable Foundation St. Baldrick’s Consortium Grant and a NHLBI/NCI grant (2UG1HL069254). Additional funding is from National Institute of Neurological Disorders and Stroke Child Neurology Career Development Program K12 (1K12NS098482-02) (Gust). The work of N.N.S. is supported in part by the Intramural Research Program of the NCI and NIH Clinical Center (ZIA BC 011823).

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Authors and Affiliations

  1. Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA

    Haneen Shalabi, Pamela L. Wolters, Carlos Sandi, Lori Wiener & Nirali N. Shah

  2. Seattle Children’s Research Institute, Seattle, WA, USA

    Juliane Gust, Rebecca A. Gardner & Colleen Annesley

  3. Department of Pediatrics, University of Washington Seattle, Seattle, WA, USA

    Juliane Gust, Rebecca A. Gardner & Colleen Annesley

  4. Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, Los Angeles, CA, USA

    Agne Taraseviciute & Michael A. Pulsipher

  5. Division of Oncology, Department of Pediatrics, Children’s Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Allison B. Leahy, Theodore W. Laetsch, Timothy S. Olson & Stephan A. Grupp

  6. St. Baldrick’s Foundation, Monrovia, CA, USA

    Carlos Sandi

  7. Department of Pediatrics and Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA

    Theodore W. Laetsch

  8. National Institute of Allergy and Infectious Disease, Clinical Center, NIH, Bethesda, MD, USA

    Veronique Nussenblatt

  9. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Joshua A. Hill

  10. Department of Medicine, University of Washington, Seattle, WA, USA

    Joshua A. Hill

  11. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Kevin J. Curran

  12. Laboratory of Pathology, NCI, NIH, Bethesda, MD, USA

    Hao-Wei Wang

  13. Oncogenomics Section, Genetics Branch, NCI, NIH, Bethesda, MD, USA

    Javed Khan

  14. Blood and Marrow Transplant and Cellular Therapy Program, Medical College of Wisconsin, Milwaukee, WI, USA

    Marcelo C. Pasquini

  15. Center for International Blood and Marrow Transplant Research, Milwaukee, WI, USA

    Marcelo C. Pasquini

  16. Department of Pediatric Oncology, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA

    Christine N. Duncan

Authors
  1. Haneen Shalabi
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  2. Juliane Gust
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  3. Agne Taraseviciute
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  21. Nirali N. Shah
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Contributions

All authors contributed to the writing of the manuscript, and reviewed and approved the content prior to submission. H.S., J.G., A.T., A.B.L., R.A.G., C.A., C.N.D., S.A.G., M.A.P. and N.N.S. comprised the steering committee leading this effort.

Corresponding author

Correspondence to Nirali N. Shah.

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Competing interests

J.G. is a consultant for Johnson & Johnson. T.W.L. has consulted for Bayer, Cellectis and Novartis; and his institution has research funding from Bayer, Novartis and Pfizer. R.A.G. has received honoraria from Novartis. J.A.H. has consulted for Allogene Therapeutics. K.J.C. has received research support from Juno Therapeutics and Novartis and has consulted and participated in advisory boards or educational seminars for Juno Therapeutics, Mesoblast and Novartis. M.C.P. has received research support from BMS, Kite and Novartis, and has been a consultant for Amgen and BMS. S.A.G. receives research support from Kite, Novartis and Servier; is a consultant for CBMG, GSK, Humanigen, Janssen/Johnson & Johnson, Novartis and Roche; is a study steering committee or scientific advisory board member for Adaptimmune, Allogene, Cellectis, Jazz, Juno, Novartis, TCR2 and Vertex/CRISPR; and has a patent (WO 2014011984 A1) that is managed according to the University of Pennsylvania patent policy. M.A.P. has received fees from Novartis, grants and personal fees from Miltenyi, grants from Adaptive, and personal fees from Mesoblast. The remaining authors declare no competing interests.

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CAR T-Cell Therapy: Beyond The Storm conference: https://ncifrederick.cancer.gov/events/conferences/car-t-cell-therapy-beyond-storm

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Shalabi, H., Gust, J., Taraseviciute, A. et al. Beyond the storm — subacute toxicities and late effects in children receiving CAR T cells. Nat Rev Clin Oncol 18, 363–378 (2021). https://doi.org/10.1038/s41571-020-00456-y

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