Shared graft-versus-leukemia minor histocompatibility antigens in DISCOVeRY-BMT

Area of Science:

• Immunology
• Transplantation Science
• Genomics

Background:

• T-cell responses to minor histocompatibility antigens (mHAs) are crucial for graft-versus-leukemia (GVL) and graft-versus-host disease (GVHD) in allogeneic hematopoietic cell transplantation (alloHCT).
• Current therapies enhancing T-cell responses for alloHCT efficacy often increase GVHD incidence and severity.
• Minor histocompatibility antigens restricted to hematopoietic tissue (GVL mHAs) offer a promising avenue for GVL-specific targeting without inducing GVHD.

Purpose of the Study:

• To discover a comprehensive set of novel GVL mHAs.
• To identify shared mHAs that can be targeted for immunotherapy in allogeneic hematopoietic cell transplantation.
• To develop strategies for maximizing GVL effects while minimizing GVHD.

Main Methods:

• Utilized the DISCOVeRY-BMT dataset of 3231 alloHCT donor-recipient pairs (DRPs).
• Employed computational prediction of mHA immunogenicity, tissue expression, and DRP sharing.
• Validated predicted novel GVL mHAs using mass spectrometry for common HLA alleles and confirmed immunogenicity via T-cell coculture.

Main Results:

• Discovered a large set of novel GVL mHAs, with numbers varying by HLA allele and recipient genomic ancestry.
• Identified minimal sets of GVL mHAs to cover 100% of DRPs for specific HLA alleles.
• Validated 24 novel GVL mHAs, cumulatively present in a high percentage of DRPs for HLA-A∗02:01, HLA-B∗35:01, and HLA-C∗07:02.

Conclusions:

• The identification and validation of shared GVL mHAs represent a feasible and promising strategy for expanding mHA-targeting immunotherapeutics.
• This approach holds potential for enhancing GVL effects and improving alloHCT outcomes.
• Further development of mHA-based therapies could lead to more targeted and effective treatments for leukemia.