T cells to the rescue?

Abstract

Marasco et al. from Italy prospectively evaluated antibody and T-lymphocyte responses in lymphoid malignancy (LM) patients after messenger RNA (mRNA) severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination. While the successful completion of a broad prospective study of this nature in the context of a pandemic is remarkable, many of the findings are expected. Overall, seroconversion (antibody response) was observed in 64.6%; immune responses were further blunted in those receiving active cancer treatment, and (CD)20 antibody-based treatments were associated with the lowest seroconversion rates (<20%). The lack of antibody responses in individuals following B-cell targeting therapies comes as no surprise. Interruption in Bruton tyrosine kinase (BTK) signalling impairs the humoral response to pneumococcal vaccination.1 Others have previously shown lower seroconversion rates in patients with haematological malignancies compared with patients with solid tumours, where therapy in the latter does not specifically target lymphocytes (Table I). While reduced antibody responses are demonstrated, encouragingly 74% of seronegative patients in the Marasco et al. study achieved a T-cell response. Sadly 13% of cases had no discernible antibody or T-cell response even after two doses of the vaccine. There was a small subset of patients in this cohort who were within 6 months of a haematopoietic stem-cell transplantation and it would be useful to explore if treatment with T-cell immunosuppressive therapies influence immune response. Among solid-organ transplant recipients both reduced humoral and cellular immune responses to SARS-CoV-2 vaccination is evident.5, 6 Additionally, newer targeted therapies used in the management of LM such as duvelisib, an oral dual inhibitor of phosphoinositide 3-kinase-δ (PI3K-δ) and PI3K-γ, may also influence T-cell responsiveness to immunisation. This study was confined to the laboratory evaluation of immune response and does not provide clinical protection data, which is important to confirm because patients with LM are more susceptible to SARS-CoV-2 mortality than immunocompetent individuals.7 Nevertheless, the preservation of T-cell responses is encouraging. Decades of empiric experience in stem cell and organ transplantation provide sufficient confidence that T lymphocytes, and not antibodies, are critically responsible for combating latent herpes viruses. Furthermore, while there is the emergence of SARS-CoV-2 variants harbouring ‘spike’ (S) protein mutations that may evade humoral neutralisation, T-cell anti-viral responses remain intact and these variants do not escape T cell-mediated immunity elicited by the wild-type S protein.8 Careful clinicopathological correlation will be necessary to elucidate the relative importance of induced T-cell immunity in the absence of robust antibody responses. Meanwhile, the evidence in support of a third dose of mRNA vaccine to boost immune responses has widened applicability to immunocompromised individuals such as those with LM undergoing treatment.9-11 No relevant financial conflicts of interest.