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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Mentored Quantitative Research Career Development Award (K25)
Project #
5K25CA123344-05
Application #
8217243
Study Section
Subcommittee G - Education (NCI)
Program Officer
Jakowlew, Sonia B
Project Start
2008-03-07
Project End
2013-08-28
Budget Start
2012-03-01
Budget End
2013-08-28
Support Year
5
Fiscal Year
2012
Total Cost
$146,880
Indirect Cost
$10,880
Name
University of Texas MD Anderson Cancer Center
Department
Biostatistics & Other Math Sci
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Tzelepi, Vassiliki; Zhang, Jiexin; Lu, Jing-Fang et al. (2012) Modeling a lethal prostate cancer variant with small-cell carcinoma features. Clin Cancer Res 18:666-77
Challen, Grant A; Sun, Deqiang; Jeong, Mira et al. (2012) Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet 44:23-31
Armistead, Paul M; Liang, Shoudan; Li, Hua et al. (2011) Common minor histocompatibility antigen discovery based upon patient clinical outcomes and genomic data. PLoS One 6:e23217
Chung, Woonbok; Bondaruk, Jolanta; Jelinek, Jaroslav et al. (2011) Detection of bladder cancer using novel DNA methylation biomarkers in urine sediments. Cancer Epidemiol Biomarkers Prev 20:1483-91
Tonthat, Nam Ky; Arold, Stefan T; Pickering, Brian F et al. (2011) Molecular mechanism by which the nucleoid occlusion factor, SlmA, keeps cytokinesis in check. EMBO J 30:154-64
Jelinek, Jaroslav; Gharibyan, Vazganush; Estecio, Marcos R H et al. (2011) Aberrant DNA methylation is associated with disease progression, resistance to imatinib and shortened survival in chronic myelogenous leukemia. PLoS One 6:e22110
Lee, Juhee; Ji, Yuan; Liang, Shoudan et al. (2011) On differential gene expression using RNA-Seq data. Cancer Inform 10:205-15
Estécio, Marcos R H; Gallegos, Juan; Vallot, Céline et al. (2010) Genome architecture marked by retrotransposons modulates predisposition to DNA methylation in cancer. Genome Res 20:1369-82
Maegawa, Shinji; Hinkal, George; Kim, Hyun Soo et al. (2010) Widespread and tissue specific age-related DNA methylation changes in mice. Genome Res 20:332-40
Armistead, Paul M; Wieder, Eric; Akande, Olanike et al. (2010) Cyclic neutropenia associated with T cell immunity to granulocyte proteases and a double de novo mutation in GFI1, a transcriptional regulator of ELANE. Br J Haematol 150:716-9

Showing the most recent 10 out of 12 publications