KIR-HLA Interactions Lack Clinical Utility in Matched Unrelated Donor Transplantation for AML: An Analysis of the CIBMTR and DRST Registries

Background: The interaction between donor killer immunoglobulin-like receptor (KIR) and recipient HLA has been postulated to enhance the graft-versus-leukemia effect in allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). Historically, analyses of individual interactions between single KIR and their respective HLA ligands have yielded conflicting findings, and the clinical importance of these interactions in the matched unrelated donor (MUD) setting remains controversial. Here, we applied a systematic approach, studying both a wide range of KIR and class I HLA interactions at the single-receptor level as well as the most prevalent KIR genotypes in a large cohort of AML patients undergoing MUD transplantation. Methods: We included adult AML patients in complete remission transplanted from an 8/8-HLA MUD between 2010 and 2016 and reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Donor-KIR and respective recipient-HLA ligand interactions were assessed in multivariable Cox proportional hazard models for standard transplantation outcomes. To account for the compound effect of simultaneous KIR/HLA interactions, we applied a combinatorial approach to identify aggregate KIR genotypes based on combinations of individual KIR genes. The most frequently observed donor-KIR genotypes, in combination with recipient ligands, were evaluated for association with relapse using multivariable regression. Those associated (p < 0.01) with relapse risk were evaluated for differential relapse in a DRST (German stem-cell registry)/Collaborative Biobank cohort of donors/patients with similar inclusion criteria. Results: A total of 2,036 transplantations from the CIBMTR were included. Most patients were treated in first complete remission (78%) and received myeloablative conditioning (59%). We first studied eight known interactions between donor KIR and their respective HLA ligands (Figure A). Only donor-KIR-2DL2+/recipient-HLA-C1+ was associated with reduced relapse (compared to donor-KIR-2DL2-/recipient-HLA-C1+, hazard ratio [HR] 0.80 [95% confidence interval 0.67-0.94], p=0.008). However, no difference was found when comparing HLA-C group pairs among KIR-2DL2+ recipients, suggesting this finding is confounded by co-occurrence of other receptors. There are hundreds of possible KIR gene combinations (i.e. genotypes), which are typically clustered into two primary haplotypes, A and B. To study the cumulative effect of donor KIR, we investigated nine prevalent KIR genotypes (Figure B) and identified three significantly associated with relapse risk. (1) Donor KIR genotype 5 in all recipients irrespective of their HLA (Figure C, n = 138/2,036) and (2) genotype 3 in HLA-Bw4/x recipients (Figure D, n = 51/1,198) had significantly decreased relapse risk (HR 0.53 [0.37-0.78], p=0.002 and 0.34 [0.15-0.75], p=0.008, respectively). (3) KIR genotype 2 was associated with greater relapse in HLA-C1-homozygous recipients (Figure E, n = 87/836, HR 1.62 [1.14-2.30], p=0.007). These findings were not confirmed in the external European dataset (n = 796, Figure 1C-E); however, this cohort differed in ways that might affect the importance of KIRs, such as the higher frequency of reduced intensity conditioning (74% vs. 41%) and in-vivo T-cell depletion (79% vs. 37%). Conclusion: Our systematic investigation in two large AML cohorts receiving MUD allogenic HCT did not validate any association between individual KIR-HLA interactions and clinical outcomes. A combinatorial approach identified combinations potentially protective against relapse, however these could not be confirmed in a second dataset. Overall, our findings do not support KIR-informed donor selection using the approaches outlined here. Figure 1 Figure 1. Disclosures Shouval: Medexus: Consultancy. Kroeger: AOP Pharma: Honoraria; Gilead/Kite: Honoraria; Riemser: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Novartis: Honoraria. Horowitz: Daiicho Sankyo: Research Funding; Allovir: Consultancy; Miltenyi Biotech: Research Funding; Medac: Research Funding; Kite/Gilead: Research Funding; Genentech: Research Funding; Jazz Pharmaceuticals: Research Funding; Janssen: Research Funding; Kiadis: Research Funding; CSL Behring: Research Funding; Gamida Cell: Research Funding; bluebird bio: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; Astellas: Research Funding; Chimerix: Research Funding; GlaxoSmithKline: Research Funding; Novartis: Research Funding; Magenta: Consultancy, Research Funding; Actinium: Research Funding; Mesoblast: Research Funding; Omeros: Research Funding; Orca Biosystems: Research Funding; Pfizer, Inc: Research Funding; Pharmacyclics: Research Funding; Regeneron: Research Funding; Sanofi: Research Funding; Seattle Genetics: Research Funding; Shire: Research Funding; Sobi: Research Funding; Stemcyte: Research Funding; Takeda: Research Funding; Tscan: Research Funding; Vertex: Research Funding; Vor Biopharma: Research Funding; Xenikos: Research Funding. Malmberg: Merck: Research Funding; Vycellix: Consultancy; Fate Therapeutics: Consultancy, Research Funding. Miller: Sanofi: Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; ONK Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vycellix: Consultancy; GT Biopharma: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics, Inc: Consultancy, Patents & Royalties, Research Funding; Wugen: Membership on an entity's Board of Directors or advisory committees. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria. Romee: Crispr Therapeutics: Research Funding; Glycostem: Membership on an entity's Board of Directors or advisory committees. Schetelig: Roche: Honoraria, Other: lecture fees; Novartis: Honoraria, Other: lecture fees; BMS: Honoraria, Other: lecture fees; Abbvie: Honoraria, Other: lecture fees; AstraZeneca: Honoraria, Other: lecture fees; Gilead: Honoraria, Other: lecture fees; Janssen: Honoraria, Other: lecture fees . Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. Koreth: Biolojic Design: Other: Scientific Advisory Board; Mallinckrodt: Other: Scientific Advisory Board; Cugene: Other: Scientific Advisory Board; Moderna: Consultancy; Amgen: Consultancy; EMD Serono/Merck: Consultancy; Gentibio Inc.: Consultancy; Miltenyi Biotec: Research Funding; BMS: Research Funding; Clinigen Labs: Research Funding; Regeneron: Research Funding; Equillium: Research Funding.

Improving selection of patients with metastatic colorectal cancer to benefit from cetuximab based on KIR genotypes

AimCetuximab is a standard-of-care treatment for KRAS wild-type metastatic colorectal cancer (mCRC), but it may also be effective in a subgroup of KRAS mutant patients by its immunomodulatory activity. Here, we explore if KIR (killer cell immunoglobulin-like receptor) genotyping can provide a significant added value in the clinical outcome of patients with KRAS mutant mCRC based on cetuximab treatment.MethodsWe included 69 patients with histologically confirmed mCRC and KRAS mutation, positive EGFR expression, and Eastern Cooperative Oncology Group performance status ≤2. Based on KIR gene content, haplotype (A or B) was defined and genotypes (AA or Bx) were grouped for each patient.ResultsWe demonstrated with new evidence the immunomodulatory activity of cetuximab in patients with KRAS mutant mCRC. Patients with homozygous genotypes (AA or BB) showed shorter 12-month progression-free survival (PFS12) and poorer overall survival (OS) than those with heterozygotes (AB). Moreover, multivariate analysis confirmed stratification of patients based on genotype was an independent marker of PFS12 (HR 2.16) and the centromeric and telomeric distribution of KIRs was an independent predictor of both PFS12 (HR 2.26) and OS (HR 1.93) in patients with mCRC with KRAS mutation treated with cetuximab.ConclusionsSelection of patients with mCRC based on their KIR genotypes opens a therapeutic opportunity for patients with KRAS mutation, and it should be tested in clinical trials in comparison with other alternatives with scarce benefit.Trial registration numberNCT01450319, EudraCT 2010-023580-18.

Influence of Activating and Inhibitory Killer Immunoglobulin-Like Receptors (KIR) genes on the recurrence rate of ocular toxoplasmosis in Brazil

BackgroundRecurrence is a hallmark of ocular toxoplasmosis (OT), and conditions that influence its occurrence remain a challenge. Natural killer cells (NK) are effectors cells whose primary function is the cytotoxic activity against many parasites, including Toxoplasma gondii. Among the NK cell receptors, immunoglobulin-like receptors (KIR) deserve attention due to their high polymorphism. This study aimed to analyze the influence of KIR gene polymorphism in the course of OT infection and its association with recurrences after an active episode.MethodsNinety-six patients from the Ophthalmologic Clinic of the National Institute of Infectology Evandro Chagas (INI/Fiocruz/RJ, Brazil) were followed for up to five years. After DNA extraction, genotyping of the patients was performed by PCR-SSO utilizing Luminex equipment for reading. During follow-up, 57.4% had a recurrence.ResultsWe identified 25 KIR genotypes and found a higher frequency of genotypes 1 (31.7%) with worldwide distribution. We note that the KIR2DL2 inhibitor gene and the gene activator KIR2DS2 were more frequent in patients without recurrence (P = 0.03 and P = 0.02, respectively). Additionally, we observed one activating gene, KIR2DS1, associated with more than four times faster progression to the development of recurrent ocular toxoplasmosis than individuals without this gene (aRR = 4.6, P = 0.04).ConclusionThe KIR2DL2 and KIR2DS2 are associated as possible protection markers and the KIR2DS1 acting as a possible susceptibility marker. Additionally, the lower proportion of activating genes observed in individuals with recurrence corroborating with the hypothesis that these individuals are more susceptible to ocular toxoplasmosis recurrence (OTR).

The deleterious effect of the HLA-C1/KIR2DL3 receptor-ligand combination on Chinese HIV Patients

Background Among Chinese HIV-infected patients we assessed the impact of different KIR-HLA combinations on the viral set point levels, CD4/CD8 ratios and plasma soluble CD14, all of which are risk factors for the prognosis of HIV patients. Methods Peripheral blood samples were collected from newly diagnosed HIV-infected patients who were treatment naive, and processed according to the study design. Participants were selected according to the inclusive criteria and their clinical data and other demographic information were recorded. The genomic DNA of the host was extracted from the whole blood samples, and the KIR genotyping was performed by sequence specific primer amplification (PCR-SSP); the HLA genotyping was performed by sequence analysis (PCR-SBT); and the HLA-KIR genotyping and combination information were obtained. Results In China, the distribution of KIR genotypes in HIV patients was similar to that of KIR genotypes in people without HIV infection; the baseline HIV level in patients with HLA-C1+/KIR2DL3+ background was significantly higher than that of HLA-C1+/KIR2DL3-(4.34 log10 copies/ml v.s 3.72 log10 copies/ml, P=0.02); the baseline CD4/CD8 ratio of HLA-C1+/KIR2DL3+ was significantly lower than that of HLA-C1+/KIR2DL3-(0.33 v.s 0.56, P=0.02). The plasma soluble CD14 level at baseline was significantly lower in HLA-C1+/KIR2DL3- infected persons than that of HLA-C1+/KIR2DL3+ (P=0.03). Conclusions NK cells may affect the viral set point and host immune status in HIV-infected patients through the combination of KIR molecules and their corresponding ligand HLA, thus affecting the prognosis of HIV infection.