Allogeneic bone marrow transplantation (BMT) conveys a potent graft-versus-leukemia effect (GVL) that contributes to long-term remission for patients with leukemia. GVL is mediated by cytotoxic T lymphocytes (CTLs) that recognize the minor histocompatibility antigens (mHAs) derived from the genetic differences in the donor and recipient, particularly single nucleotide polymorphisms in the coding regions (cSNPs). Finding more mHAs can help improve BMT and can also be used to develop new adoptive T cell therapies. We propose to identify leukemia mHAs by searching for a statistically significant association between donor-recipient genotyping differences and the reduced rate of leukemia relapse following BMT. This project is made possible by the recently developed large-scale genotyping assays that measure thousands of common cSNPs simultaneously, and will use data from a large transplant tissue bank at MD Anderson Cancer Center. In this project, we will (1) genotype several hundred human leukocyte antigen (HLA)-matched BMT donor-recipient pairs for 13,900 cSNPs;(2) find cSNPs that are donor-negative and recipient-positive that best correlate with long-term remission, using existing and newly developed methods;and (3) experimentally verify mHA-HLA binding by tetramer technique, and verify leukemia-specific lysis by CTL cytotoxicity assay. A potentially legal complication in BMT is graft-versus-host disease (GVHD) which is also caused by recognition of mHAs. To separate mHA that might be targets for GVL from those that are targets for GVHD, we will use a cohort of patients with no GVHD. Using the same data, but by comparing instead with expected SNP distribution in general population (obtained from HapMap), we also identify the mHAs that are GVHD-linked antigens. Our large-scale screening approach will discover immunogenic peptides that are directly applicable to patient care, either to select and expand T cells for adoptive T cell transfer or to vaccinate donors before transplantation to increase the T cells specific for leukemia. These manipulations bring two benefits. First, the immune system being transplanted can be selected for preferential T cell activity against leukemia because the T cells against leukemia-specific antigens could be pre-expanded. Second, the graft-versus-host disease (GVHD) associated with bone marrow transplantation is reduced because the enrichment of leukemia-specific T cells dilutes the T cells with specificities to all other epitopes, including those that cause GVHD. The mHAs are HLA restricted, therefore any additional antigens that we discover will bring the benefit to a wider patient population. We also expect our research to discover more candidates for leukemia vaccines. Because vaccination has few side effects, we can test the effectiveness of potential vaccines by administering them alongside existing therapies.
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