Immune Responses to SARS-CoV-2 Vaccination in Young Patients with Anti-CD19 Chimeric Antigen Receptor T Cell-Induced B Cell Aplasia

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are capable of inducing combined humoral and cellular immunity. Which effect is more relevant for their potent protective effects is unclear, but isolated T cell responses without seroconversion in healthy household members of individuals with Coronavirus disease 19 (COVID-19) suggest that T cell responses effectively protect against clinical infection. Oncologic patients have an outsize risk of unfavorable outcomes after SARS-CoV-2 infection and therefore were prioritized when vaccines first became available, although the quality of their immune response to vaccination was expected to be suboptimal, as has been confirmed in subsequent studies. Inherently, patients with anti-CD19 chimeric antigen receptor (CAR) T cell therapy-mediated B cell aplasia would be incapable of generating humoral responses, so that assessment of the vaccine-induced cellular immunity is all the more important to gauge whether the vaccine can induce meaningful protection. A salient difference between T cell and humoral responses is the former's relative impassiveness to mutations of the antigen, which is more relevant than ever since the advent of the omicron variant. The objective of this study was to assess the immune cell composition and spike protein-specific T cell responses before and after the first and second doses of SARS-CoV-2 mRNA vaccine in a cohort of juvenile CD19 CAR T cell therapy recipients with enduring B cell aplasia. The prospective study included all patients age >12 years diagnosed with multiply relapsed B cell precursor acute lymphoblastic leukemia and treated with anti-CD19 CAR T cell (CAR-T19) therapy in our center. The primary endpoint was the detection of cell-mediated and humoral responses to vaccine (flow cytometry and anti-S immunoglobulin G, respectively). Secondary endpoints included the incidence of vaccine-related grade 3 or 4 adverse events, exacerbation of graft-versus-host disease (GVHD), relapse, and the influence of the vaccine on CAR T cells and lymphocyte subsets. Even though one-half of the patients exhibited subnormal lymphocyte counts and marginal CD4/CD8 ratios, after 2 vaccinations all showed brisk T-cell responsiveness to spike protein, predominantly in the CD4 compartment, which quantitatively was well within the range of healthy controls. No severe vaccine-related grade 3 or 4 adverse events, GVHD exacerbation, or relapse was observed in our cohort. We posit that SARS-CoV-2 mRNA vaccines induce meaningful cellular immunity in patients with isolated B cell deficiency due to CAR-T19 therapy.