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Proteinase 3, a serine protease stored in azurophilic granules, is a differentiation antigen associated with myeloid granule formation and is overexpressed in a variety of myeloid leukemia types, including CML cells. Therefore, it has been considered a possible target antigen for specific active immunotherapy. CTLs specific for an HLA-A2.1-restricted nonpolymorphic peptide (PR1) derived from proteinase 3 have shown HLA-restricted cytotoxicity, and selectively inhibit CML progenitors over normal marrow cells.67 68 PR1-specific T cells have been identified by HLA-A2-PR1 peptide HLA tetramers in a majority of CML patients who responded to either IFN-a or allogeneic stem cell transplantation.69 PRl-specific CTLs isolated from these patients were capable of lysing fresh leukemia cells. Follow-up studies in patients with relapsed CML revealed a selective loss of the high-avidity PR1-CTL population by tetramer determination. A functional PRl-specific CTL immune response was also lost prior to CML relapse, suggesting a possible therapeutic role for "add back" of high-affinity PR1-CTL.

The results of a phase I vaccine trial using a PRl peptide in patients with HLA A0201 have been reported. This trial included a total of 15 patients: 6 with CML (interferon resistant or relapsed after stem cell transplantation), 8 with AML (smoldering relapse or >second CR), and 1 with MDS with no detectable antibodies to proteinase 3 (antineutrophil cytoplas-mic autoantibody negative). Patients were treated with three dose levels of PR1 peptide in incomplete Freud's adjuvant (Montanide ISA-51) and 70 ^g of GM-CSF every 3 weeks for three injections. Eight of 15 patients (53%) had some evidence of immune response to the peptide vaccine as assessed by tetramer staining and flow cytometric detection of intracellular IFN-7. In this group, five patients experienced a clinical response, including three patients with a molecular response and one with a cytogenetic response. In one patient, tetramer sort-purified PR1-CTL obtained after vaccination showed PR1 specificity

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