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NK cell recovery after haploidentical HSCT with post-transplant cyclophosphamide: dynamics and clinical implications

Antonio Russo, Giacomo Oliveira, Sofia Berglund, Raffaella Greco, Valentina Gambacorta, Nicoletta Cieri, Cristina Toffalori, Laura Zito, Francesca Lorentino, Simona Piemontese, Mara Morelli, Fabio Giglio, Andrea Assanelli, Maria Teresa Lupo Stanghellini, Chiara Bonini, Jacopo Peccatori, Fabio Ciceri, Leo Luznik and Luca Vago

Key points

  • Post-transplantation cyclophosphamide eliminates most mature donor NK cells infused with the graft, including alloreactive NK cells.

  • High levels of serum interleukin-15 early after HSCT provide a favorable environment for adoptive infusion of mature donor NK cells.

Abstract

The use of post-transplant cyclophosphamide (PT-Cy) as GvHD prophylaxis has revolutionized haploidentical HSCT, allowing safe infusion of unmanipulated T cell-replete grafts. PT-Cy selectively eliminates proliferating alloreactive T cells, but whether and how it affects NK cells and their alloreactivity is largely unknown. Here we characterized NK cell dynamics in 17 patients who received unmanipulated haploidentical grafts, containing high numbers of mature NK cells, according to PT-Cy-based protocols in two independent centers. In both series we documented robust proliferation of donor-derived NK cells immediately after HSCT. After infusion of Cy, a marked reduction of proliferating NK cells was evident, suggesting selective purging of dividing cells. Supporting this hypothesis, proliferating NK cells did not express aldehyde dehydrogenase and were killed by Cy in vitro. After ablation of mature NK cells, starting from day 15 after HSCT and favored by the high levels of interleukin-15 present in patients' sera, immature NK cells (CD62L+NKG2A+KIR-) became highly prevalent, possibly directly stemming from infused HSCs. Importantly, also putatively alloreactive single KIR+ NK cells were eliminated by PT-Cy, and were thus decreased in numbers and antileukemic potential at day 30 after HSCT. As a consequence, in an extended series of 99 haplo-HSCT with PT-Cy, we found no significant difference in progression-free survival between patients with or without predicted NK alloreactivity (42% vs 52% at 1 year, p=n.s.). Our data suggest that the majority of mature NK cells infused with unmanipulated grafts are lost upon PT-Cy administration, blunting NK cell alloreactivity in this transplantation setting.

  • Submitted May 8, 2017.
  • Accepted September 30, 2017.