Chronic myelogenous leukemia (CML) cells are characterized by a t(9;22) translocation, which can encode one of two chimeric P210
bcr-abl fusion proteins, comprising products of either the b2a2 or the b3a2 exon junction. The junctional sequences represent potentially immunogenic
tumor-specific
antigens. Despite their intracellular location, the fusion
proteins might be recognized immunologically by T lymphocytes if
peptides, derived from these unique sequences, are capable of presentation by the major histocompatibility complex molecules. We previously found that four
peptides, 9 to 11
amino acids long, spanning the b3a2 CML breakpoint bind with high or intermediate affinity to purified HLA class I molecules A3, A11, B8, or both A3 and A11. We tested the ability 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 length (b3a2-25), was studied for its ability to induce
peptide-specific, class II-mediated, T-cell proliferation. In four of four
HLA-A3 donors tested, CML-A3/A11-
peptide specific CTLs were induced that killed an allogeneic HLA-A3-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 blood mononuclear cells (PBMC). CML-A3
peptide induced
peptide specific CTLs in one of the four HLA A3 donors tested. No killing was observed in two
HLA-B8 and two
HLA-A11 donors. PBMC from seven donors were also tested for anti b3a2-25
peptide proliferation in a
thymidine incorporation 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
vaccines for this disease.