Selected memory T cells infused post haploidentical hematopoietic stem cell transplantation persist and hyper-expand

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with post-transplant cyclophosphamide is a curative treatment for many hematological malignancies, yet a majority of patients still suffers from recurrent infections. Post-transplant infusion of memory T cells could potentially enhance immunological protection without increasing the risk of eliciting acute graft-versus-host disease, which is mainly induced by naïve T cells. Here, we performed longitudinal analysis of the lymphocyte compartment in 19 haplo-HSCT patients previously enrolled in a phase II prospective clinical trial (ClinicalTrials.gov Identifier: NCT04687982), in which they received post-transplant CD45RA-depleted donor lymphocyte infusions (DLI). T cell receptor sequencing analysis showed that, surprisingly, CD45RA-depleted DLI do not increase T cell clonal diversity, but lead to prominent expansion of a selected number of infused memory T cell clones, suggestive of recruitment of these cells in the immune response. Pathogen-specific memory T cells, including cytomegalovirus (CMV)-specific cells, engrafted and were able to persist for at least one month. Deep immunophenotyping revealed strong polyfunctional effector CMV-specific T cell responses in the majority of patients, with their expansion correlating with the frequency of CMV-specific cells in the donor. These findings provide a rationale behind the suggested improved protection against viral infections for patients receiving CD45RA-depleted DLI.