Gvl mHA Specific T Cell Responses Prevent AML Relapse Following Allogeneic Stem Cell Transplantation.

Abstract We plan to extend the initially proposed work in three ways. First, we will extend our alloantigen identification from considering only antigens derived from germline single-nucleotide polymorphisms (i.e. classical mHAs) to those derived from large structural variants (germline and somatic) along with small somatic variants and tumor-specific transcriptional variants (e.g. alternative splice variants, cancer/testis antigens, endogenous retroviral antigens). Our goal is to capture the full landscape of alloantigens that may be targeted by donor-derived T cells in alloSCT, which will allow us to more comprehensively map the antigen-specific T cell response following HLA-matched alloSCT. This will allow us to evaluate by immunopeptidomics studies and measure T cell responses to as broad a set of antigens as possible, to better understand the landscape of T cell responses following alloSCT (and how these associate with relapse-free survival). We will assess the clonal heterogeneity of antigen expression using long-read single cell sequencing, to test the hypothesis that antigen-specific T cell populations that cover a larger proportion of tumor subclones will be associated with better relapse-free survival. Finally, we will extend our work on testing associations between mHA features and specific mHA with clinical outcomes following alloSCT. Using a large dataset of alloSCT DRP genome and transcriptome being generated by the DISCOVeRY-BMT group, we will integrate genome-wide mHA identifications with KIR/KIR ligand information as predictor variables and test statistical learning and deep learning strategies to improve clinical outcomes prediction. We will accomplish these extensions of the initially proposed work in the following specific aims: Aim 1: Evaluate the contribution of large structural variants to the pool of immunogenic graft-versus-leukemia mHA in the context of HLA-matched allogeneic stem cell transplantation. Aim 2: Comprehensively map the MHC class I-restricted alloantigen landscape of AML in the context of HLA- matched allogeneic stem cell transplantation. Aim 3: Adapt our methods for antigen discovery to identify alloantigens targeted by CD8+ T cells in haploidentical allogeneic stem cell transplantation. Aim 4: Integrate data from mHA profiling with NKc genetics profiling to improve prediction of alloSCT outcomes.