Donor Killer Cell Ig-like Receptor B Haplotypes, Recipient HLA-C1, and HLA-C Mismatch Enhance the Clinical Benefit of Unrelated Transplantation for Acute Myelogenous Leukemia

Abstract

Killer cell immunoglobulin-like receptors (KIR) interact with HLA class I ligands to regulate NK cell development and function. These interactions affect the outcome of unrelated donor (URD) hematopoietic cell transplantation (HCT). We have shown previously that donors with KIR B vs. KIR A haplotypes improve the clinical outcome for patients with acute myelogenous leukemia (AML) by reducing the incidence of leukemic relapse and improving leukemia free survival (LFS). Both centromeric and telomeric KIR B genes contribute to the effect, but the centromeric genes are dominant. They include the genes encoding inhibitory KIR that are specific for the C1 and C2 epitopes of HLA-C. We used an expanded cohort of 1532 T-cell replete transplants to examine the interaction between donor KIR B genes and recipient Class I HLA KIR ligands. The relapse protection associated with donor KIR B is enhanced in recipients who have one or two C1-bearing HLA-C allotypes, compared to C2 homozygous recipients, with no effect based on donor HLA. The protective interaction between donors with ≥2 vs. 0–1 KIR B-motifs and recipient C1 was specific to transplants with class I mismatch at HLA-C (RR of LFS 0.57 [0.40–0.79]; P=0.001) irrespective of the KIR ligand mismatch status of the transplant. The survival advantage and relapse protection in C1/x recipients compared to C2/C2 recipients was similar irrespective of the particular donor KIR B genes. Understanding the interactions between donor KIR and recipient HLA class I can be used to inform donor selection to improve outcome of URD HCT for AML.

Neuroblastoma patients with high-affinity FCGR2A, -3A and stimulatory KIR 2DS2 treated by long-term infusion of anti-GD2 antibody ch14.18/CHO show higher ADCC levels and improved event-free survival

“…We first evaluated the impact of two distinct well-established KIR/KIRL combinations, inhibitory genotype A/A and activating genotype B/x, on ADCC and survival of NB patients under ch14.18/CHO immunotherapy. Although a positive impact of B/x genotype on survival has been previously reported in leukemia patients, [23][24][25] the role of A/A and B/x genotypes in NB patients under ch14.18/CHO-based immunotherapy has not been shown yet. Here, we observed a strong tendency toward increased ADCC and improved survival in patients with B/x genotype compared to A/A patients suggesting an important role of activating KIRs in ch14.18/CHO immunotherapy.…”

“…23 In leukemia, transplantation of haematopoietic cells from donors who had haplotype B led to prolonged relapse-free survival. [23][24][25] In contrast, patients that received haematopoietic cells from donors with a set of inhibitory KIRs corresponding to haplotype A showed worse outcome indicating positive impact of activating KIRs on response to therapy.…”

“…Following treatment protocol was used: cytokine IL-2 was given for 5 d (s.c., day 1-5, 6 £ 10 6 IU/m 2 /day), followed by a combined application of IL-2 (s.c., day 8-12, 6 £ 10 6 IU/m 2 / day) with ch14.18/CHO (i.v., day 8-18, 10 mg/m 2 /day) and 13-cis-retinoic acid (p.o., day [22][23][24][25][26][27][28][29][30][31][32][33][34][35]. At initial diagnosis, 46 patients had stage 4, four stage 3, one stage 2 and two stage 1 disease.…”

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

“…Indeed, it is estimated that a significant reduction of relapse after transplantation for acute myeloid leukaemia can be achieved by choosing donors based on their KIR and HLA class I genotype 232, 233. This could be extended in the future to help, for example, sperm donors with the lowest risk of adverse pregnancy outcomes in assisted reproduction.…”

Beyond consolidation: auto-SCT and immunotherapy for plasma cell myeloma

“…This KIR 'mismatch' has been associated with improved outcomes in patients with myeloma and other hematologic malignancies undergoing allo-HCT, presumably due to increased NK cell activity against the tumor cells. [69][70][71] Van Rhee and colleagues attempted to harness this NK cell vs myeloma effect in conjunction with an auto-HCT. Following lymphodepleting conditioning with fludarabine, dexamethasone and melphalan, 10 patients with relapsed myeloma received haplo-identical, KIR-mismatched, IL2-activated NK cell-enriched infusions on days 0 and +2, followed by IL2 administration days +1 to +11, followed by infusion of autologous stem cells on day +14.…”