SARS-CoV-2 vaccine response in CAR T-cell therapy recipients: A systematic review and preliminary observations.

Evolving data suggest that SARS-CoV-2 vaccine responses are blunted in allogeneic hematopoeitic cell transplant (HCT) recipients. Responses to the vaccine in chimeric antigen receptor T-cell (CAR-T) therapy are unknown and are likely to be even more diminished. We manually searched vital databases and identified 5 studies that have so far reported COVID-19 vaccine response in a total of 70 CAR-T recipients. The cumulative humoral response rate across all 5 studies was 31%. However, the results are not generalizable due to non-standardized units of humoral response measurement and a lack of external validation. Heterogeneity existed in studies regarding the timing of vaccination post-CAR-T, intervals between the vaccine doses, platforms of response assessment, vaccine platforms, and pre-vaccine immune status. CAR-T-related factors that independently impact vaccine response to prevent COVID-19 have further been reviewed. We conclude that the results must be interpreted with caution given the limitations of small sample sizes, differences in immunoassays, lack of standard definitions and clinical correlates of SARS-CoV-2 immune response, and lack of cellular responses. Until large-scale, homogenous prospective data become available, these preliminary observations will help transplant and infectious disease clinicians with their decision-making while providing care to this profoundly immunosuppressed cohort of patients.

Role of Gut Microbiome in COVID-19: An Insight Into Pathogenesis and Therapeutic Potential.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulted in an unprecedented global crisis. Although primarily a respiratory illness, dysregulated immune responses may lead to multi-organ dysfunction. Prior data showed that the resident microbial communities of gastrointestinal and respiratory tracts act as modulators of local and systemic inflammatory activity (the gut-lung axis). Evolving evidence now signals an alteration in the gut microbiome, brought upon either by cytokines from the infected respiratory tract or from direct infection of the gut, or both. Dysbiosis leads to a "leaky gut". The intestinal permeability then allows access to bacterial products and toxins into the circulatory system and further exacerbates the systemic inflammatory response. In this review, we discuss the available data related to the role of the gut microbiome in the development and progression of COVID-19. We provide mechanistic insights into early data with a focus on immunological crosstalk and the microbiome's potential as a biomarker and therapeutic target.

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

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.