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

Abstract

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.

Identifying SARS‐CoV‐2 ‘memory’ NK cells from COVID‐19 convalescent donors for adoptive cell therapy

“…NK cells and ILC1 differ mainly in their function; while ILC1 is weakly cytotoxic, NK cells are dedicated cytotoxic cells [ 10 ]. Their function is to defend the organism from viral infections [ 11 ], such as Epstein–Barr virus [ 12 ], varicellA−zoster virus [ 13 ], cytomegalovirus (CMV) [ 14 ] or herpesvirus‐6B [ 15 ] as well as fighting against malignant cells [ 16 ]; they have been reported to get to a functional exhaustion level along with disease progression, characterized by elevated expression of regulatory receptors such as PD1 and CD244 [ 17 ], lower levels of CD16 marker [ 18 ] and/or higher levels of NKG2A marker [ 19 ]. Peripheral blood NK cells can be divided in two different subsets regarding the expression of CD56: CD56bright and CD56dim cells [ 20 ].…”

Selective depletion of naïve T cells by targeting CD45RA

“…Indeed, in our institutional cohort of pediatric patients who underwent haplo transplants using CD45RA + depletion followed by NK cell addback, we did not observe a high incidence of HHV-6 encephalitis. In keeping with the in vitro findings and encouraged by the results of our study, the same group of investigators in Spain performed a follow-up study wherein they incorporated a NK-cell infusion within 10 days after a CD45RA +depleted transplant (48). The goal was to infuse a number of NK cells equivalent to at least twice the number of CD4 + T cells infused with the CD45RA + -depleted fraction, as in vitro work showed that NK cells could eliminate HHV-6B CD4 + T cells when present at a ratio of 2:1 (53).…”

Donor selection for adoptive cell therapy with CD45RA− memory T cells for patients with coronavirus disease 2019, and dexamethasone and interleukin-15 effects on the phenotype, proliferation and interferon gamma release

“…4 , 15 We and other authors have shown the antiviral properties of CD45RA − memory T cells in hematopoietic stem cell transplantation and COVID-19 settings. 25 , [38] , [39] , [40] , [41] We have demonstrated the safety and feasibility of adoptive cell therapy using CD45RA − memory T cells containing SARS-CoV-2 specific T cells in hospitalized COVID-19 patients. In this approach, we pursued to increase the pool of lymphocytes in patients with lymphopenia, exerting an antiviral effect on the coronavirus and protecting the patient from other viruses that the donor encountered.…”