Phase II Study of Haploidentical Natural Killer Cell Infusion for Treatment of Relapsed or Persistent Myeloid Malignancies Following Allogeneic Hematopoietic Cell Transplantation

Abstract

We conducted a phase 2 study to determine the efficacy of HLA-haploidentical related donor NK cells following cyclophosphamide based lymphodepletion in patients with relapsed or progressive acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) following allogeneic HCT. Eight patients (2 with MDS, 6 with AML) were treated with cyclophosphamide 50 mg/kg on day −3 and day −2 prior to infusion of NK cells isolated from a haploidentical related donor. One person additionally received fludarabine 25 mg/m2/d × 4. Six doses of 1 million units of interleukin-2 (IL-2) were administered on alternating days beginning on day −1. The median number of infused NK cells was 10.6×106/kg (range 4.3–22.4) and the median number of CD3 cells was 2.1×103/kg (range 1.9–40). NK infusions were well tolerated with a median time to neutrophil recovery of 19 days (range 7-not reached) and no incidence of graft versus host disease after NK infusion. One patient with AML and one patient with MDS achieved a complete response but relapsed at 1.7 and 1.8 months, respectively. One patient with MDS had resolution of dysplastic features but persistence of clonal karyotype abnormalities. This patient remains stable at 65 months post NK cell therapy. The median survival was 12.9 months (range 0.8–65.3 months). Chimerism analysis of CD3−/CD56+ peripheral blood cells did not detect circulating haploidentical NK cells after infusion. NK phenotyping was performed on seven patients during and after IL-2 infusion. We found a slight trend towards greater expression of KIR2DL2/2DL3/2DS2 (5% versus 28%, P = 0.03) at 14 days in patients who survived longer than 6 months from NK cell infusion (N = 4) when compared to those who died within 6 months of NK cell therapy (N=3). In summary, these data support the safety of haploidentical NK cell infusion after allogeneic HCT.

NK cell therapy after hematopoietic stem cell transplantation: can we improve anti-tumor effect?

“…In a small study in AML patients with impending relapse, Uharek et al showed favorable two-year survival (40% vs. 11%) when treated with a haploidentical transplantation in combination with post-transplant NK cell infusion, as compared to haploidentical transplantation alone. Also in multiple myeloma patients, NK cell were infused after both autologous and allogeneic transplantation [37,38] with no safety concerns.…”

Can we make a better match or mismatch with KIR genotyping?

“…As the impact of KIR-ligand mismatch in the transplant setting became evident, the focus of the trials shifted toward the use of allogeneic NK cells either in combination with HSCT or in a non-HSCT setting (Table 3). 71,[141][142][143][144] Allogeneic NK cells are less likely to be subject to the inhibitory response resulting from NK cell recognition of self-MHC molecules, as seen with autologous NK cells. Moreover, several studies have shown that infusion of haploidentical NK cells to exploit the missing-self concept is safe and can mediate impressive clinical activity in some patients with AML.…”

“…71,[130][131][132][133][134][135][136][137][138][139][140][141][142][143][144] Results of the initial trials using ex vivo activated autologous NK cells were mostly unsatisfactory, [130][131][132][133][134][135][136][137][138] likely because of the inhibition of autologous NK cells by self-HLA molecules. As the impact of KIR-ligand mismatch in the transplant setting became evident, the focus of the trials shifted toward the use of allogeneic NK cells either in combination with HSCT or in a non-HSCT setting (Table 3).…”

“…Moreover, several studies have shown that infusion of haploidentical NK cells to exploit the missing-self concept is safe and can mediate impressive clinical activity in some patients with AML. 71,[139][140][141][142][143][144] In those studies, NK cells are activated and expanded ex vivo with a variety of cytokines such as interleukin-2 (IL-2), IL-15, or IL-21 to increase their persistence, enhance their proliferation, and augment their in vivo effector function (Table 3). In a landmark trial of NK cell adoptive therapy in patients with relapsed or refractory AML, Miller et al 71 were among the first to show that adoptive transfer of ex vivo-activated haploidentical NK cells after lymphodepleting chemotherapy followed by IL-2 administration to support their in vivo expansion is safe and can result in NK cell persistence for up to 4 weeks without inducing GVHD.…”

Advances in Immunotherapy for Acute Myeloid Leukemia

“…Haploidentical NK cells are also being investigated for relapsed/refractory AML (RR-AML). Eight patients with AML or MDS following prior alloSCT received lymphodepletion followed by donor NK cell infusion and IL-2 [28]. Although one patient experienced remission, no survival benefit was observed and no donor NK cells were detected in patients.…”