The role of early natural killer cell adoptive infusion before engraftment in protecting against human herpesvirus-6B encephalitis after naïve T-cell-depleted allogeneic stem cell transplantation.

BACKGROUND: Naïve T-cell-depleted grafts have been employed as an ex vivo T-cell depletion (TCD) platform to prevent graft-versus-host disease (GvHD) and improve immune reconstitution by providing rapid donor memory T-cell reconstitution after allogenic hematopoietic stem cell transplantation (allo-HSCT). CD45RA- memory T cells confer protection against viruses such as cytomegalovirus, Epstein-Barr virus, and adenovirus; however, reports have shown an unexpectedly high incidence of human herpesvirus (HHV)-6B encephalitis among pediatric allo-HSCT patients. METHODS: We report the first 18 consecutive allo-HSCT, 16 haplo-HSCT, and two human leukocyte antigen-matched related donors implanted with naïve TCD grafts. All donors were administered three cell products: first, a CD34+ stem cell product; second, a CD45RA+ TCD graft, followed by an adoptive natural killer (NK) cell infusion within 10 days after HSCT. The study's primary endpoint was the incidence of HHV-6B encephalitis. RESULTS: Engraftment was achieved in 94.5% of cases; 2-year overall survival, event-free survival, and GvHD/relapse-free survival were 87.2% (95% CI 78.6-95.8), 67.3% (95% CI 53.1-81.5), and 64% (95% CI 50.5-78.1), respectively. HHV-6B reactivation occurred in 7 of the haplo-HSCT patients, six of who received a cell infusion with an NK/CD4 ratio <2. None of the patients developed encephalitis. CONCLUSIONS: In this clinical study, we show that early adoptive NK cell infusion after a 45RA+ TCD allo-HSCT graft is safe and can prevent HHV-6B encephalitis. We recommend infusing adoptive NK cells after allo-HSCT using CD45RA+ TCD grafts.

Selective T-cell depletion targeting CD45RA as a novel approach for HLA-mismatched hematopoietic stem cell transplantation in pediatric nonmalignant hematological diseases.

Severe aplastic anemia and congenital amegakaryocytic thrombocytopenia are rare bone marrow failure syndromes. Treatment for aplastic anemia consists of hematopoietic stem cell transplantation (HSCT) from a matched sibling donor or immunosuppressant drugs if there is no donor available. Congenital amegakaryocytic thrombocytopenia is a rare autosomal recessive disease that causes bone marrow failure and has limited treatment options, except for transfusion support and HSCT. In the absence of a suitable matched sibling donor, matched-unrelated, haploidentical, or mismatched donors may be considered. A 2-step partial T-cell-depletion strategy can remove CD45RA+ naïve T cells responsible for graft-versus-host disease (GvHD) while preserving memory T cells. Five patients underwent transplantation using this strategy with rapid neutrophil and platelet recovery. Acute and chronic GvHD ≥ grade 2 appeared in two and one patient, respectively. No severe infections were observed before day + 100. A high (60%) incidence of transplant-associated microangiopathy was observed. Three patients (60%) remain alive, with a median follow-up of 881 (range 323-1248) days. CD45RA-depleted HSCT is a novel approach for patients lacking a suitable matched donor; however, further improvements are needed.