Donor Natural Killer Cell Allorecognition of Missing Self in Haploidentical Hematopoietic Transplantation for Acute Myeloid Leukemia: Challenging Its Predictive Value.

Abstract

In haploidentical transplants that are KIR ligand mismatched in the GvH direction, functional donor NK-cells that express as their sole inhibitory receptor for self, a KIR for the HLA-class-I group which is absent in the recipient, sense the missing expression of the self class-I ligand on allogeneic targets and mediate alloreactions. In a limited series of transplants donor-vs-recipient NK-cell alloreactivity reduced the risk of AML relapse and markedly improved EFS (Ruggeri L, Science 2002). Here, we analyzed 112 AML patients transplanted from NK-alloreactive (n=51) or non-NK-alloreactive (n=61) haploidentical donors. NK-alloreactive donors possessed: HLA-class-I KIR ligand(s) which were missing in the recipients, KIR gene(s) for missing self recognition on recipient targets, and alloreactive NK-clones against recipient targets. Transplantation from NK-alloreactive donors was associated with: significantly lower relapse rate in patients transplanted in CR (3% vs 47%) (P<0.003); decrease infectious mortality which was more evident in patients transplanted in relapse (P=0.1); better EFS in patients transplanted in relapse (34% vs 6%, P=0.04) and in remission (67% vs 18%, P=0.02); reduced risk of relapse or death (relative risk vs non-NK-alloreactive donor: 0.48 [95% CI 0.29–0.78], P<0.001). Recently, an additional algorithm, termed the “missing ligand” model, has been proposed for predicting favorable outcomes not only in haploidentical (Leung W, JI 2004; JI 2005) but also in matched sibling (Hsu KC, Blood 2005) and in unrelated donor transplants (Hsu KC, BBMT 2006). The “missing-ligand” model includes all donor-recipient pairs in whom there is a mismatch between KIR(s) in the donor and HLA molecule(s) in the recipient. Consequently, the model includes all KIR ligand-mismatched transplants because they are all associated with a missing KIR ligand in the recipient, and KIR ligand-matched transplants from donors possessing “extra” KIR(s) for which neither donor nor recipient have HLA ligand(s). Therefore, in the same series of patients we tested the “missing ligand” model. The first step was to divide our 61 non-NK alloreactive (KIR ligand-matched) donor-recipient pairs according to the number of KIR ligands in donor and recipient, i.e., three KIR ligands (29 patients; 15 in remission, 14 in relapse at transplant) vs fewer than three (32 patients; 16 in remission, 16 in relapse at transplant). EFS did not differ in each sub-group. Both curves indicated worse survival than after transplantation from NK-alloreactive donors. The second step was to group the above 32 “missing ligand” transplants and all 51 KIR ligand-mismatched transplants (which corresponded to all our NK-alloreactive transplants). We analyzed EFS in this pool of 83 patients (46 in remission, 37 in relapse at transplant) against EFS in 29 patients with no missing ligand (15 in remission, 14 in relapse at transplant). No significant difference emerged. EFS in the “missing ligand” cohort was worse than after transplantation from NK-alloreactive donors. Therefore, the present analysis leaves no doubt that KIR ligand mismatches, i.e., donor NK cell recognition of “missing self” on recipient targets, are essential for triggering powerful NK cell alloreactions that impact beneficially on transplantation outcomes.

The graft‐versus‐neuroblastoma effect of allogeneic hematopoietic stem cell transplantation, a review of clinical and experimental evidence and a perspective on mechanisms

“…The rationale for using DLI in these trials is derived from the strong GvL responses seen after DLI [62], and the rationale for using adoptive transfer of NK cells is derived from the known sensitivity of neuroblastoma cells to NK cell Cytotoxicity [20][21][22]. Along the same line, haploidentical HSCT is considered of particular interest because of the reported association of strong alloreactive NK cell-mediated GvL responses observed in hematological malignancies [67,[82][83][84][85]. As reviewed by others [86], a KIR-ligand mismatch in the graft-versus-host direction in a donor and transplant recipient pair has been found in several studies to be predictive for a low risk of relapse [67,[82][83][84][85].…”

“…Along the same line, haploidentical HSCT is considered of particular interest because of the reported association of strong alloreactive NK cell-mediated GvL responses observed in hematological malignancies [67,[82][83][84][85]. As reviewed by others [86], a KIR-ligand mismatch in the graft-versus-host direction in a donor and transplant recipient pair has been found in several studies to be predictive for a low risk of relapse [67,[82][83][84][85]. This is a form of anti-host NK cell alloreactivity that extends to the recipient tumor cell and that relies on the key principle of NK cell killing on the basis of missing-self.…”

Human NK receptors: From the molecules to the therapy of high risk leukemias

“…In studies by Velardi's group alloreactive NK cells were detected for up to 1 year after transplantation [54]. Recent studies have confirmed and extended these findings.…”

“…In the second category, all KIR expressed by NK cells recognized the HLA-class I alleles of the patient (lack of KIR/KIRligand mismatch). The presence of alloreactive NK cells has been found to positively correlate with the successful outcome of transplantation either in adults with acute myeloid leukemias (AML) [52,54] or in pediatric patients with high risk lymphoblastic leukemias (ALL) [48,55]. Although the presence of alloreactive NK cells can be predicted by the analysis of the KIR gene profile of the donor and by the HLA class I typing of both donor and recipient, the actual presence and size of the alloreactive cell NK subset can be assessed by cytofluorimetric analysis.…”

Thymosin α1 to harness immunity to pathogens after haploidentical hematopoietic transplantation

“…For almost all leukemia patients who fail to find a matched donor, whether related or unrelated, or a suitable cord blood unit, transplantation from family donors who are matched for one HLA haplotype and fully mismatched at the HLA classes I and II loci of the unshared haplotype (haploidentical) is a viable option. Milestones along the way toward successful haploidentical transplantation were observations that: (1) extensive ex vivo T cell depletion of the graft prevented graft versus host disease (GvHD), in haploidentical transplants for patients with severe combined immunodeficiency; 25 (2) a "megadose" of T cell-depleted stem cells ensured engraftment across major histocompatibility complex (MHC) barriers in mice, 26 and across HLA barriers in clinical transplantation; [27][28][29][30][31] (3) human NK cells exerted alloreactivity; [32][33][34][35][36][37][38][39] (4) transplantation from haploidentical donors that were able to mount donor versus recipient NK cell alloreactions eradicated acute myeloid leukemia (AML), favored engraftment, protected from GvHD and greatly improved survival, as demonstrated by integrating clinical and preclinical data. [32][33][34][35][36][37][38][39] Current conditioning protocols include totalbody irradiation (TBI), fludarabine, thiotepa, and anti-T cell antibodies (anti-thymocyte globulin, ATG) 15,[28][29][30][31] (Fig.…”