Association of Disparities in Known Minor Histocompatibility Antigens with Relapse-Free Survival and Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation

Abstract

Allogeneic stem cell transplantation (allo-SCT) can induce remission in patients with hematological malignancies due to graft-versus-tumor (GVT) responses. This immune-mediated anti-tumor effect, however, is often accompanied by detrimental graft-versus-host disease (GVHD). Both GVT and GVHD are mediated by minor histocompatibility antigen (MiHA)-specific T cells recognizing peptide products from polymorphic genes that differ between recipient and donor. In this study, we evaluated whether mismatches in a panel of seventeen MiHA are associated with clinical outcome after partial T cell-depleted allo-SCT. Comprehensive statistical analysis revealed that DNA mismatches for one or more autosomal-encoded MiHA was associated with increased relapse-free survival in sibling transplants, (P =0.04), particularly in patients suffering from multiple myeloma (P =0.02). Moreover, mismatches for the ubiquitous Y chromosome-derived MiHA resulted in a higher incidence of acute GVHD (grade 3–4; P =0.004), while autosomal MiHA mismatches, ubiquitous or restricted to hematopoietic cells, were not associated with severe GVHD. Finally, we demonstrated considerable differences between MiHA in their capability to induce in vivo T cell responses using dual-color tetramer analysis of peripheral blood samples collected post-SCT. Importantly, detection of MiHA-specific T cell responses was associated with improved relapse-free survival in sibling transplants (P =0.01). Our findings provide a rationale to further boost GVT immunity towards autosomal MiHA with a hematopoietic restriction to improve outcome after HLA-matched allo-SCT.

Immunotherapeutic approaches to treat multiple myeloma

“…Numerous MiHAs have been identified in the past decades and T cell responses against these MiHAs have been associated with improved relapse-free survival. While in some studies the induction of MiHA-specific T cell responses was associated with an increase in the incidence of GVHD and improved relapse-free survival, [18][19][20][21] other studies could not confirm these results. 22,23 Importantly, boosting of T cell responses against MiHAs with a hematopoietic-restricted expression pattern, e.g., HA1, 24 LRH1, 25 ARHGDIB, 26 and UTA2-1 27 has the potential to induce a selective GVM effect with only limited risk of eliciting GVHD.…”

New strategies of DLI in the management of relapse of hematological malignancies after allogeneic hematopoietic SCT

“…[85][86][87] Therefore, it is very important to separate GVL from GVHD. Much current effort is focused on enhancing the GVL effect, or preventing GVHD without impairing the GVL effect through identification and utilization of optimal donors, dose-escalation schemes, CD8+ T-cell depletion 88 and tumor-specific DLI.…”

Selective graft-versus-leukemia depends on magnitude and diversity of the alloreactive T cell response

“…We identified multiple MiHAs by WGAs and demonstrated in several patients that at least 3 to 8 different HLA class I-restricted MiHAs were targeted by donor CD8 T cells after HLA-matched alloSCT and DLI (23)(24)(25). While severe GVHD frequently coincides with the development of T cell responses against ubiquitously expressed MiHAs, relatively selective GVL reactivity was not always associated with T cell responses recognizing MiHAs selectively expressed by hematopoietic cells (23,24,26). Apparently, other factors also determine the balance between GVL reactivity and GVHD.…”