SPECIFIC HUMAN CELLULAR-IMMUNITY TO BCR-ABL ONCOGENE-DERIVED PEPTIDES

Chronic myelogenous leukemia (CML) cells are characterized by a t(9;22 ) translocation, which can encode one of two chimeric P210 bcr-abl fus ion proteins, comprising products of either the b2a2 or the b3a2 exon junction. The junctional sequences represent potentially immunogenic t umor-specific antigens. Despite their intracellular location, the fusi on proteins might be recognized immunologically by T lymphocytes if pe ptides, derived from these unique sequences, are capable of presentati on by the major histocompatibility complex molecules. We previously fo und that four peptides, 9 to 11 amino acids long, spanning the b3a2 CM L breakpoint bind with high or intermediate affinity to purified HLA c lass I molecules A3, A11, B8, or both A3 and A11. We tested the abilit y of these peptides to elicit specific class I restricted cytotoxic T lymphocytes (CTLs) in vitro in HLA-matched healthy donors. In addition , a longer b3a2 CML-breakpoint-derived peptide, 25 aminoacids in lengt h (b3a2-25), was studied for its ability to induce peptide-specific, c lass II-mediated, T-cell proliferation. In four of four HLA-AB donors tested, CML-A3/A11-peptide specific CTLs were induced that killed an a llogeneic HLA-AB-matched peptide pulsed leukemia cell line. In two of three HLA-A3 donors, the CML-A3/A11 peptide was able to induce killing of autologous and allogeneic HLA-matched peptide-pulsed peripheral bl ood mononuclear cells (PBMC). CML-AB peptide induced peptide specific CTLs in one of the four HLA A3 donors tested. No killing was observed in two HLA-BB and two HLA-A11 donors. PBMC from seven donors were also tested for anti b3a2-25 peptide proliferation in a thymidine incorpor ation assay. Specific proliferation was detected in three donors, all of the HLA-DR11 haplotype. These data represent the first evidence of a cytolytic human immune response against CML bcr-abl oncogene-derived peptides and provide a rationale for developing peptide-based vaccine s for this disease. (C) 1996 by The American Society of Hematology.