Minor Histocompatibility Antigen-Specific T Cells

Abstract

Minor Histocompatibility (H) antigens are major histocompatibility complex (MHC)/Human Leukocyte Antigen (HLA)-bound peptides that differ between allogeneic hematopoietic stem cell transplantation (HCT) recipients and their donors as a result of genetic polymorphisms. Some minor H antigens can be used as therapeutic T cell targets to augment the graft-vs.-leukemia (GVL) effect in order to prevent or manage leukemia relapse after HCT. Graft engineering and post-HCT immunotherapies are being developed to optimize delivery of T cells specific for selected minor H antigens. These strategies have the potential to reduce relapse risk and thereby permit implementation of HCT approaches that are associated with less toxicity and fewer late effects, which is particularly important in the growing and developing pediatric patient. Most minor H antigens are expressed ubiquitously, including on epithelial tissues, and can be recognized by donor T cells following HCT, leading to graft-vs.-host disease (GVHD) as well as GVL. However, those minor H antigens that are expressed predominantly on hematopoietic cells can be targeted for selective GVL. Once full donor hematopoietic chimerism is achieved after HCT, hematopoietic-restricted minor H antigens are present only on residual recipient malignant hematopoietic cells, and these minor H antigens serve as tumor-specific antigens for donor T cells. Minor H antigen-specific T cells that are delivered as part of the donor hematopoietic stem cell graft at the time of HCT contribute to relapse prevention. However, in some cases the minor H antigen-specific T cells delivered with the graft may be quantitatively insufficient or become functionally impaired over time, leading to leukemia relapse. Following HCT, adoptive T cell immunotherapy can be used to treat or prevent relapse by delivering large numbers of donor T cells targeting hematopoietic-restricted minor H antigens. In this review, we discuss minor H antigens as T cell targets for augmenting the GVL effect in engineered HCT grafts and for post-HCT immunotherapy. We will highlight the importance of these developments for pediatric HCT.

Keywords: T cell immunotherapy; graft engineering; graft-vs.-leukemia; hematopoietic stem cell transplantation; leukemia; minor histocompatibility antigen; pediatric; polymorphism.

Figure 1

The figure illustrates the GVHD and/or GVL effect in allogeneic HLA-matched donor HCT which is largely attributed to donor T cell responses to recipient cell minor H antigens. When an HCT recipient has a homozygous or heterozygous polymorphism that encodes a minor H antigen and their donor is homozygous negative for the allele, the donor may have T cells in their repertoire that can target the minor H antigen peptide/HLA complex on the recipient's leukemia cell surface leading to an elimination of any residual leukemia following HCT.

Figure 2

The figure illustrates that most minor H antigens are ubiquitously expressed on epithelial tissues and hematopoietic cells. Donor T cell recognition of such antigens leads to GVHD as well as GVL. However, minor H antigens expressed predominantly on hematopoietic cells can be targets of a selective GVL effect.

Figure 3

The schematic illustrates that patient normal hematopoietic and leukemia cells with minor H antigens are eliminated by the transplant conditioning regimen and replaced with donor hematopoietic cells. Once full donor normal hematopoietic cell chimerism is achieved only recipient malignant hematopoietic cells present hematopoietic-restricted minor H antigens if disease persists or recurs following HCT. These minor H antigens serve as tumor-specific antigens for donor T cells.

Figure 4

The schematic depicts the development and potential therapeutic use of donor derived minor H antigen targeting T cell therapy. A patient, with the hematopoietically-restricted minor H antigen target, would undergo allogeneic HCT. The donor, lacking the minor H target, would donate hematopoietic cells for the HCT graft and T cells for the immunotherapy product. The T cells would undergo depletion of the naïve T cell fraction (to reduce GVHD risk) and then undergo modification using a lentiviral construct containing a potent TCR targeting the minor H antigen of interest. Following this modification, the cell product would be expanded to develop a therapeutically active cell dose which could be infused soon after the HCT as a relapse prevention strategy or following relapse detection to treat post-HCT relapse.