Another active-specific immunotherapy with potential antitumor effect in CML relies on the use of intracellular proteins other than p210. In fact a number of self proteins are aberrantly overexpressed in CML and other tumor cells while being expressed at low levels in normal lineages and thus may function as targets for directed immunotherapy of residual disease. As in the case of p210, despite the intracellular location of these proteins, short peptides produced by their cellular processing can be presented on the cell surface within the cleft of HLA molecules and in this form they can be recognized by T cells. Several peptide vaccines derived from such proteins have reached the stage of clinical development in CML patients.
Proteinase-3 (PR3) or myeloblastin is a 26-kd neutral serine protease normally expressed in hematopoietic tissues and highly expressed in myeloid haematologi-cal malignancies. PR1, an HLA-A2.1-restricted nonamer peptide derived from PR3, has been identified as a tumor-specific antigen in myeloid leukemia. Cytotoxic T lymphocytes recognizing PR1 that are capable of lysing fresh leukemia cells have been detected in CML patients and have been implicated in the clearance of malignant cells in patients treated with IFN-a or stem cell transplantation (SCT) (24). Vaccinations of PR1 peptide in Montanide were administered subcutaneously every three weeks for a total of three doses to 10 CML patients not responding to treatment or with relapsed disease (25). Preliminary reports indicate that a significant increase in PR1 CTLs was evident in about 60% of vaccinated patients. Clinical responses included one CCyR and stable disease with some hematologic improvement in three cases. Responses were correlated with the induction of PRl-specific CTLs with a central memory (CCR7+) phenotype, indicative of a self-renewing population (26). However, there is good evidence that imatinib therapy down-regulates PR3 expression in CML cells and this could potentially reduce the antitumor activity of this approach (27). In fact, especially in the context of MRD persisting on prolonged treatment with imatinib, leukemic cells may harbor only minimal amounts of PR3 that are insufficient for proper PR1 peptide HLA presentation. Consequently, PRl-specific CTLs induced with the vaccinations may be unable to recognize and clear residual cells due to an inadequate number of PR-1-HLA complexes on the cell surface. One way to circumvent this problem could be to stop imatinib treatment temporarily after immunization with PR-1 vaccine in order to "restore" the PR3 content of the residual CML cells and allow their recognition and elimination by PR-1 specific CTLs.
Wilm's Tumor Protein-Derived Peptide Vaccines
Another candidate for a peptide vaccine approach in CML is the Wilm's tumor protein (WT-1)—a self protein overexpressed in most human leukemias, including CML and some solid tumors, but rarely present in normal cells (28). Recent studies have identified WT-1-specific CTLs in CML patients (29). Importantly, in vitro models have demonstrated that WT-1-specific CTLs deplete leukemic but not normal CD34+ stem cells (30) suggesting that they may be effective in eradicating the quiescent stem cells present in MRD. Additionally, intravenous injection of human T cells transduced with a WT-1 T-cell receptor into NOD/SCID mice harbouring human leukemia cells resulted in leukemia elimination (31).
Promising clinical results were observed in patients with acute myeloid leukemias and myelodysplastic syndromes after vaccinations with WT-1-derived peptides and Montanide ISA51 or GM-CSF as adjuvants (32). A significant correlation was observed between an increase in the frequencies of WT1-specific CTLs after WT1 vaccination and clinical responses (32). However, similar peptide vaccination studies have not yet been published in CML patients with MRD.
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