Search

•The proportion (efficiency) of peptides that can bind to HLA varies among HLA types.•HLA peptide binding efficiency was calculated for 3242 HLA-matched transplants.•There was no association between peptide-binding efficiency and graft-versus-host disease or relapse.

T-cell responses to minor histocompatibility antigens (mHAs) mediate both antitumor immunity (graft-versus-leukemia [GVL]) and graft-versus-host disease (GVHD) in allogeneic stem cell transplant. Identifying mHAs with high allele frequency, tight binding affinity to common HLA molecules, and narrow tissue restriction could enhance immunotherapy against leukemia. Genotyping and HLA allele data from 101 HLA-matched donor-recipient pairs (DRPs) were computationally analyzed to predict both class I and class II mHAs likely to induce either GVL or GVHD. Roughly twice as many mHAs were predicted in HLA-matched unrelated donor (MUD) stem cell transplantation (SCT) compared with HLA-matched related transplants, an expected result given greater genetic disparity in MUD SCT. Computational analysis predicted 14 of 18 previously identified mHAs, with 2 minor antigen mismatches not being contained in the patient cohort, 1 missed mHA resulting from a noncanonical translation of the peptide antigen, and 1 case of poor binding prediction. A predicted peptide epitope derived from GRK4, a protein expressed in acute myeloid leukemia and testis, was confirmed by targeted differential ion mobility spectrometry-tandem mass spectrometry. T cells specific to UNC-GRK4-V were identified by tetramer analysis both in DRPs where a minor antigen mismatch was predicted and in DRPs where the donor contained the allele encoding UNC-GRK4-V, suggesting that this antigen could be both an mHA and a cancer-testis antigen. Computational analysis of genomic and transcriptomic data can reliably predict leukemia-associated mHA and can be used to guide targeted mHA discovery.

Introduction: Graft-versus-host disease (GVHD) remains a significant complication of allogeneic hematopoietic cell transplant (alloHCT), despite use of HLA-identical donors. Minor histocompatibility antigens presented to donor T-cells by recipient major histocompatibility complexes (MHCs) are central to GVHD pathophysiology, and prediction of GVHD occurrence in HLA-identical transplants remains problematic. Prior data show that informative HLA genotypes bind peptide epitopes with varying degrees of efficiency. Therefore, the cumulative peptide binding efficiency based on HLA-A, -B, and -C in HLA-identical transplants is estimable. We hypothesized that recipients with HLA-genotypes predicting lower cumulative peptide binding will experience lower rates of GVHD and higher rates of relapse following alloHCT.

Background and Rationale:T-cell responses to minor histocompatibility antigens (mHA) mediate both anti-tumor immunity (GvL) and graft versus host disease (GvHD) in allogeneic stem cell transplantation. Clinical trials of cellular immunotherapies that target one or more of these mHA are ongoing, however current laboratory and GWAS methods have thus far produced a limited number of confirmed mHA (Oostvogels et al. BMT2016, PMID: 26501766). Identifying mHA with tight binding affinity to common HLA alleles, narrow tissue restriction, and high population prevalence (GvL mHA) could provide promising immunotherapy targets against leukemia as therapeutic strategies that target these mHA would maximize the number of candidate recipients and may drive a beneficial GvL effect without causing GvHD.

Molldrem: Astellas Pharma: Patents & Royalties.

Background and Rationale:T-cell responses to minor histocompatibility antigens (mHA) are important drivers of the beneficial graft versus leukemia (GvL) effect and harmful graft versus host disease (GvHD) pathology following HLA-matched allogeneic stem cell transplantation (alloSCT). Despite their importance, Genome Wide Association Studies (GWAS) have failed to elicit a prognostic set of individual mHA associated with the clinically observed GvL and GvH effects of alloSCT [Sato-Otsubo et al. Blood2015]. This is likely due to a lack of public mHA shared across the global set of donor/recipient pairs (DRPs). Even an optimally frequent single nucleotide polymorphism (SNP) would result in a recipient restricted genetic variant in only 24% of DRPs with a matched unrelated donor (MUD) or 17% of DRPs with a matched related donor (MRD) [Armistead et al. PLoS One2011]. Moreover, even when DRPs do share a recipient restricted genetic variant, any resulting peptide would have to bind a MHC molecule within the recipient for presentation to T-cells.