Immune mediated aplastic anaemia (AA) is a bone marrow failure syndrome characterised by cytotoxic CD8 mediated autoimmune suppression of haematopoietic stem progenitor cells (HSPCs) resulting in varying degrees of peripheral blood cytopenias. Treatment with immunosuppressive therapy and haematopoietic stem cell transplantation are not applicable to all the patients and effective responses occur in a proportion of patients only, highlighting the unmet need for alternative treatments. We have previously shown a reduction in number and function of regulatory T cells (Tregs) in AA patients and their functional restoration following in vitro expansion that laid the foundations for this Phase 1 trial. Required number of Tregs were collected from leukapheresis and expanded under GMP conditions from all 6 patients in the trial who were resistant/refractory to standard form of treatments. The trial design included 2 doses of autologous Tregs (5×106 /kg) administered 2 weeks apart. Mass cytometry, single cell sequencing and cytokine profiling was performed on blood samples collected at various timepoints. Tregs were successfully expanded to required doses from all 6 patients with no adverse or immune related events in any of the patients. Haematological responses were observed in 3 patients. In addition, we were able to track the persistence of the expanded Tregs in vivo, correlate clinical efficacy with the accumulation of clusters of Tregs post-infusion, and identify phenotypic markers in the infusion product that correlate with in vivo expansion. Tregs from AA patients are expandable, safe for infusion, and may help modulate the abnormal immune milieu associated with AA, with induction of clinical response.
Matto et al. (Thu,) studied this question.