Background Of the cancers treated with allogeneic hematopoietic stem-cell transplantation (HSCT), acute myeloid leukemia (AML) is most sensitive to natural killer (NK)–cell reactivity. The activating killer-cell immunoglobulin-like receptor (KIR) 2DS1 has ligand specificity for HLA-C2 antigens and activates NK cells in an HLA-dependent manner. Donor-derived NK reactivity controlled by KIR2DS1 and HLA could have beneficial effects in patients with AML who undergo allogeneic HSCT. Methods We assessed clinical data, HLA genotyping results, and donor cell lines or genomic DNA for 1277 patients with AML who had received hematopoietic stem-cell transplants from unrelated donors matched for HLA-A, B, C, DR, and DQ or with a single mismatch. We performed donor KIR genotyping and evaluated the clinical effect of donor KIR genotype and donor and recipient HLA genotypes. Results Patients with AML who received allografts from donors who were positive for KIR2DS1 had a lower rate of relapse than those with allografts from donors who were negative for KIR2DS1 (26.5% vs. 32.5%; hazard ratio, 0.76; 95% confidence interval [CI], 0.61 to 0.96; P = 0.02). Of allografts from donors with KIR2DS1, those from donors who were homozygous or heterozygous for HLA-C1 antigens could mediate this antileukemic effect, whereas those from donors who were homozygous for HLA-C2 did not provide any advantage (24.9% with homozygosity or heterozygosity for HLA-C1 vs. 37.3% with homozygosity for HLA-C2; hazard ratio, 0.46; 95% CI, 0.28 to 0.75; P = 0.002). Recipients of KIR2DS1-positive allografts mismatched for a single HLA-C locus had a lower relapse rate than recipients of KIR2DS1-negative allografts with a mismatch at the same locus (17.1% vs. 35.6%; hazard ratio, 0.40; 95% CI, 0.20 to 0.78; P = 0.007). KIR3DS1, in positive genetic linkage disequilibrium with KIR2DS1, had no effect on leukemia relapse but was associated with decreased mortality (60.1%, vs. 66.9% without KIR3DS1; hazard ratio, 0.83; 95% CI, 0.71 to 0.96; P = 0.01). Conclusions Activating KIR genes from donors were associated with distinct outcomes of allogeneic HSCT for AML. Donor KIR2DS1 appeared to provide protection against relapse in an HLA-C–dependent manner, and donor KIR3DS1 was associated with reduced mortality. (Funded by the National Institutes of Health and others.)

Survival outcomes for patients with high-risk neuroblastoma (NB) have significantly improved with anti-disialoganglioside GD2 mAb therapy, which promotes NK cell activation through antibody-dependent cell-mediated cytotoxicity. NK cell activation requires an interaction between inhibitory killer cell immunoglobulin-like receptors (KIRs) and HLA class I ligands. NK cells lacking KIRs that are specific for self HLA are therefore "unlicensed" and hyporesponsive. mAb-treated NB patients lacking HLA class I ligands for their inhibitory KIRs have significantly higher survival rates, suggesting that NK cells expressing KIRs for non-self HLA are mediating tumor control in these individuals. We found that, in the presence of mAb, both licensed and unlicensed NK cells are highly activated in vitro. However, HLA class I expression on NB cell lines selectively inhibited licensed NK cell activity, permitting primarily unlicensed NK cells to mediate antibody-dependent cell-mediated cytotoxicity. These results indicate that unlicensed NK cells play a key antitumor role in patients undergoing mAb therapy via antibody-dependent cell-mediated cytotoxicity, thus explaining the potent "missing KIR ligand" benefit in patients with NB.

ANCREATIC TRANSPLANTATION IS a therapeutic option for patients with complicated diabetes mellitus. The American Diabetes Association supports the procedure for patients with diabetes who have had, or need, a kidney transplant. In the absence of kidney failure, pancreas transplantation may be considered for patients with diabetes and severe and frequent metabolic instability (ie, hypoglycemia, ketoacidosis). 1 Despite current controversy, and while the annual number of simultaneous pancreas-kidney transplants remained stable from 1995 to 2002, over that same interval the annual number of solitary pancreas transplants (ie, pancreas transplant alone or pancreas-after-kidney transplant) increased 5-fold (United Network for Organ Sharing/Organ Procurement and Transplantation Network [UNOS/OPTN] data as of May 2, 2003).Specific US transplant numbers document this trend: 910 simultaneous pancreas-kidney transplants were performed in 1995 and 902 were performed in 2002 . In contrast, in 1995

Purpose: Comprehensive genomic profiling (CGP) is of increasing value for patients with metastatic castration-resistant prostate cancer (mCRPC). mCRPC tends to metastasize to bone, making tissue biopsies challenging to obtain. We hypothesized CGP of cell-free circulating tumor DNA (ctDNA) could offer a minimally invasive alternative to detect targetable genomic alterations (GA) that inform clinical care. Experimental Design: Using plasma from 3,334 patients with mCRPC (including 1,674 screening samples from TRITON2/3), we evaluated the landscape of GAs detected in ctDNA and assessed concordance with tissue-based CGP. Results: A total of 3,129 patients (94%) had detectable ctDNA with a median ctDNA fraction of 7.5%; BRCA1/2 was mutated in 295 (8.8%). In concordance analysis, 72 of 837 patients had BRCA1/2 mutations detected in tissue, 67 (93%) of which were also identified using ctDNA, including 100% of predicted germline variants. ctDNA harbored some BRCA1/2 alterations not identified by tissue testing, and ctDNA was enriched in therapy resistance alterations, as well as possible clonal hematopoiesis mutations (e.g., in ATM and CHEK2). Potential androgen receptor resistance alterations were detected in 940 of 2,213 patients (42%), including amplifications, polyclonal and compound mutations, rearrangements, and novel deletions in exon 8. Conclusions: Genomic analysis of ctDNA from patients with mCRPC recapitulates the genomic landscape detected in tissue biopsies, with a high level of agreement in detection of BRCA1/2 mutations, but more acquired resistance alterations detected in ctDNA. CGP of ctDNA is a compelling clinical complement to tissue CGP, with reflex to tissue CGP if negative for actionable variants. See related commentary by Hawkey and Armstrong, p. 2961

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Purpose: NK cells exhibit cytotoxicity against neuroblastoma. Gene polymorphisms governing NK cell function, therefore, may influence prognosis. Two highly polymorphic genetic loci instrumental in determining NK cell responses encode the NK cell killer immunoglobulin-like receptors (KIR) and their class I human leukocyte antigen (HLA) ligands. We hypothesized that patients with a "missing ligand" KIR-HLA compound genotype may uniquely benefit from autologous hematopoietic stem cell transplantation (HSCT). Experimental Design: One hundred sixty-nine patients treated with autologous HSCT for stage IV neuroblastoma underwent KIR and HLA genotyping. Patients were segregated according to the presence or absence of HLA ligands for autologous inhibitory KIR. Univariate and multivariate analyses were done for overall and progression-free survival. Results: Sixty-four percent of patients lacked one or more HLA ligands for inhibitory KIR. Patients lacking a HLA ligand had a 46% lower risk of death [hazard ratio, 0.54; 95% confidence interval (95% CI), 0.35-0.85; P = 0.007] and a 34% lower risk of progression (hazard ratio, 0.66; 95% CI, 0.44-1.0; P = 0.047) at 3 years compared with patients who possessed all ligands for his/her inhibitory KIR. Among all KIR-HLA combinations, 16 patients lacking the HLA-C1 ligand for KIR2DL2/KIR2DL3 experienced the highest 3-year survival rate of 81% (95% CI, 64-100). Survival was more strongly associated with "missing ligand" than with tumor MYCN gene amplification. Conclusion: KIR-HLA immunogenetics represents a novel prognostic marker for patients undergoing autologous HSCT for high-risk neuroblastoma. (Clin Cancer Res 2009;15(23):7330-4) Neuroblastoma is the most frequently diagnosed cancer in infants and is the most common extracranial solid tumor in childhood (1). Prognosis varies, and risk assessment is based on several clinical and biological features, including age, stage at diagnosis, histopathology, and biomarkers of tumor aggressiveness (MYCN status, histology, and DNA ploidy; refs. 2,3). The risk of tumor progression likely depends not only on tumor biology but also on the host immune response. NK cells are capable of inhibiting colony formation of human neuroblastoma cells (4-7), and infusion of NK cells into nonobese diabetic/severe combined immunodeficient mice bearing human metastatic neuroblastoma leads to a significant improvement in overall survival (4). Based on recent advances linking NK cell function to NK cell genetics (8-11), we hypothesized that variations in genes responsible for regulating NK function may affect clinical outcomes for patients with neuroblastoma.The killer immunoglobulin-like receptor (KIR) gene cluster consists of 15 genes that encode both inhibitory and activating NK cell surface receptors instrumental in governing NK cell function. The similarly polymorphic human leukocyte antigen (HLA) class I gene loci encode three ligand groups for inhibitory KIR: HLA for KIR2DL2/KIR2DL3, HLA for KIR2DL1, and HLA for 12KIR3DL1. Ligation of inhi...

Donor Program, we performed donor KIR genotyping for 1087 patients who received an unrelated hematopoietic stem cell transplantation. A total of 33% of donors were KIR3DS1. Compared with KIR3DS1 donors, donor KIR3DS1 was associated with lower-grade II-IV acute graft-versus-host disease (GVHD; odds ratio 0.71; 95% confidence interval, 0.55-0.92; P .009), but not with relapse (hazard ratio 0.97; 95% confidence interval, 0.73-1.29; P .82). Furthermore, grade II-IV acute GVHD, overall mortality, and transplantation-related mortality all decreased as the number of copies of donor KIR3DS1 increased (P .007, P .03, and P .02, respectively), with the lowest failure rate occurring among patients homozygous for donor KIR3DS1. Selection of donors with KIR3DS1 may decrease acute GVHD without compromising relapse-free survival, separating the graft-versus-tumor effect from unwanted GVHD. (Blood. 2010;115(15):3162-3165) Introduction In allogeneic hematopoietic stem cell transplantation (HSCT), natural killer (NK) cells enhance the graft-versus-tumor effect, promote bone marrow engraftment, suppress viral reactivation, and prevent graft-versus-host disease (GVHD). 1 Optimizing NK-cell alloreactivity, therefore, may ultimately favor the desired graft-versus-tumor effect while minimizing the complication of GVHD. With recent advancements demonstrating a link between NK-cell function and NK-cell genetics, 2,3 donor genotyping may be useful for predicting NK activity and for selecting stem cell donors for maximum NK benefit. Identification of the specific genes impacting the salutary effects may facilitate donor selection while offering insight to their biologic functions. The killer Ig-like receptor (KIR) gene locus is a highly polymorphic family of genes encoding activating and inhibitory cell surface receptors expressed on NK cells and a subset of T cells. Previous genetic association studies have identified individual activating KIR, KIR haplotypes, and combinations of inhibitory KIR and their cognate human leukocyte antigen (HLA) class I ligands to be significantly associated with clinical outcomes after HSCT. 4-8 Studies evaluating activating KIR and GVHD have been conflicting. 9-13 To examine the role of activating KIR against GVHD, we evaluated a large cohort of HSCT donor-recipient pairs, hypothesizing that the presence of donor-activating KIR might lead to a lower threshold for NK activation, less GVHD, and improved survival for HSCT recipients. Methods The Center for International Blood and Marrow Transplant Research (CIBMTR) provided clinical data, HLA genotyping, and donor cell lines or genomic DNA for 1087 stem cell donors from 10 of 10 (62%) or 9 of 10 (30% HLA-C; 8% HLA-B) HLA allele-matched unrelated myeloablative transplantations performed from 1995 to 2002 for acute myeloid leukemia (AML; n 306)/myelodysplastic syndrome (MDS; n 154), chronic myelogenous leukemia (n 390), and acute lymphoblastic leukemia (n 237) patients with a median age of 36 years (range, 0.6-65.9 years). Donor KIR genotyping was performed usi...

Programmed death-ligand 1 (PD-L1) and its receptor, programmed cell death-1 (PD-1), are important negative regulators of immune cell activation. Therapeutically targeting PD-1/PD-L1 in diffuse large B-cell lymphoma (DLBCL) patients with a single agent has limited activity, meriting a deeper understanding of this complex biology and of available PD-L1 clinical assays. In this study, we leveraged 2 large de novo DLBCL phase 3 trials (GOYA and MAIN) to better understand the biologic and clinical relevance of PD-L1 in de novo DLBCL. PD-L1 was expressed on myeloid cells in 85% to 95% of DLBCL patients (depending on staining procedure), compared with 10% on tumor cells, and correlated with macrophage gene expression. PD-L1 did not identify high-risk patients in de novo DLBCL; it correlated with STAT3, macrophage gene expression, and improved outcomes among a subset of patients. These results may help identify immunologically distinct DLBCL subsets relevant for checkpoint blockade. GOYA and MAIN trials were registered at www.clinicaltrials.gov as #NCT01287741 and #NCT00486759, respectively.