Review
State of the CAR-T: Risk of Infections with Chimeric Antigen Receptor T-Cell Therapy and Determinants of SARS-CoV-2 Vaccine Responses

https://doi.org/10.1016/j.jtct.2021.09.016Get rights and content
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open access

Highlights

  • Prolonged B cell aplasia, hypogammaglobulinemia, and cytopenia predispose recipients of chimeric antigen receptor T cell (CAR-T) therapy to severe infections and abrogate the remission success achieved by the living drug.

  • The risk of infections with CAR-T therapy depends on several patient- and disease-related factors, including lymphodepletion chemotherapy regimen, time between cell collection and infusion, bridging therapy, CAR T cell dose, signaling and costimulatory domains, target antigen (eg, CD19 versus BCMA), and duration of lymphopenia and hypogammaglobulinemia.

  • CD28-based CAR T cell constructs may confer a higher risk of or more frequent cytokine release syndrome compared with 4-1BB-based CAR T cell constructs and thus a higher incidence of infections. A prospective comparison of toxicities will determine the infection risk associated with signaling domains.

  • Owing to differential expression patterns on the B cell surface, CAR-T therapy targeting CD19 will likely result in more bacterial infections, whereas viral infections commonly occur following anti-BCMA CAR-T therapy.

  • Data related to COVID-19 outcomes and vaccine responses among CAR-T recipients is evolving and suggests that vaccine responses among CAR-T recipients may even be more diminished than that in allogeneic hematopoietic cell transplantation recipients.

  • In addition to concerns related to suboptimal efficacy, CAR-T recipients could theoretically experience a heightened risk of immune-mediated toxicity.

  • There are no anti-SARS-CoV-2 spike binding (anti-S IgG) and neutralizing antibody titers validated among immunocompromised patients. Further, interassay variability and the level of humoral response that correlates with clinical protection remain unknown.

  • Although the Food and Drug Administration advises against checking vaccine responses, routine serologic assessment to gauge responses to vaccination may be considered in selected CAR-T recipients to determine the number of additional vaccine doses. However, CAR-T recipients should be advised to continue strict precautionary behavior irrespective of the immune responses.

  • Telemedicine should be incorporated at the core of long-term follow-up to minimize exposure of immunosuppressed patients to the hospital and the community.

  • The timing and intensity of corticosteroid use, for both the prevention and treatment of CAR-T therapy toxicities, should be evaluated in the context of potentially diminished immune responses to SARS-CoV-2 vaccines.

  • Given the immunosuppressed milieu as a driver for mutational SARS-CoV-2 variants, antiviral agents and long-acting monoclonal antibodies or small molecules, potentially resistant to current SARS-CoV-2 mutations, merit evaluation in prospective studies to halt the development of mutations and spread to close contacts.

  • The risk of transmission should be minimized by vaccinating all healthcare workers and caregivers, and strict mitigation strategies should remain in place across transplantation and cellular therapy centers.

ABSTRACT

Chimeric antigen receptor T cell (CAR-T) therapy has shown unprecedented response rates in patients with relapsed/refractory (R/R) hematologic malignancies. Although CAR-T therapy gives hope to heavily pretreated patients, the rapid commercialization and cumulative immunosuppression of this therapy predispose patients to infections for a prolonged period. CAR-T therapy poses distinctive short- and long-term toxicities and infection risks among patients who receive CAR T-cells after multiple prior treatments, often including hematopoietic cell transplantation. The acute toxicities include cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. The long-term B cell depletion, hypogammaglobulinemia, and cytopenia further predispose patients to severe infections and abrogate the remission success achieved by the living drug. These on-target-off-tumor toxicities deplete B-cells across the entire lineage and further diminish immune responses to vaccines. Early observational data suggest that patients with hematologic malignancies may not mount adequate humoral and cellular responses to SARS-CoV-2 vaccines. In this review, we summarize the immune compromising factors indigenous to CAR-T recipients. We discuss the immunogenic potential of different SARS-CoV-2 vaccines for CAR-T recipients based on the differences in vaccine manufacturing platforms. Given the lack of data related to the safety and efficacy of SARS-CoV-2 vaccines in this distinctively immunosuppressed cohort, we summarize the infection risks associated with Food and Drug Administration-approved CAR-T constructs and the potential determinants of vaccine responses. The review further highlights the potential need for booster vaccine dosing and the promise for heterologous prime-boosting and other novel vaccine strategies in CAR-T recipients.

© 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Key Words

CAR-T therapy
COVID-19
SARS-CoV-2
mRNA vaccine
Vaccine response
Hematopoietic cell transplantation
Immunocompromised
Humoral immunity
Cellular immunity
Neutralizing antibodies

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Financial disclosure: See Acknowledgments on page 984.