Randomized phase II study of proteinase 3-derived PR1 vaccine and GM-CSF with or without peg-interferon alfa-2b to eradicate minimal residual disease in chronic myeloid leukemia

Abstract

22043 Background: Imatinib (IM) induces complete molecular responses in a minority of patients (pts) with chronic myeloid leukemia (CML). CML is responsive to T-cell-mediated immunity. The PR1 peptide (VLQELNVTV) is a leukemia-associated antigen presented on HLA-A2 to cytotoxic T lymphocytes (CTL) that preferentially kills leukemia progenitors. Methods: We evaluated the activity of PR1 vaccine (2 mg) with GM-CSF (0.6 mg) and Montanide ISA-51 given subcutaneously to pts with CML on IM in complete cytogenetic response with stable residual molecular disease. Pts were randomized to receive pegylated interferon alfa (PEG-IFN-α; 0.5 μg/kg) with each vaccination. PR1 was administered on weeks 0, 3, 6, and 18. Immune responses were assessed by PR1/HLA-A2 tetramer staining and molecular responses by quantitative PCR in peripheral blood before study entry, prior to each vaccination, and every 3 months thereafter. Results: 4 of the 20 planned HLA-A2+ pts have been accrued. Pt 1 (on IM 600 mg/d for 85 months) and 2 (on IM 800 mg/d for 72 months) received PR1 vaccine+PEG-IFN-α and Pts 3 and 4 (both on IM 400 mg/d, for 43 and 37 months, respectively) received PR1 vaccine alone. BCR- ABL1/ABL1 ratios prior to vaccination were 0.99, 0.79, 0.52, and 0.10, respectively. The median follow-up is 8.5 months (range, 4–11). All pts had mild elevations of BCR-ABL1 transcripts after the first vaccine, followed by steady decline in transcript levels in Pt 1 (>1- log), Pt 2 (<1-log) and Pt 3 (<1-log). Toxicity was limited to grade 1–2 injection site reactions except for Pt 2, in whom PEG-IFN-α was discontinued after 4 mos due to behavioral changes. Immune responses were elicited in Pts 1 (PR1 vaccine+PEG-IFN-α), and 3 (PR1 vaccine). Data on differentiation phenotype, T cell receptor (TCR-alpha-beta) gene usage, TCR avidity, and peptide-induced CTL cytokine secretion profile of PR1-CTLs compared to overall CTL population and CTL with specificity for the HLA-A2-restricted NLV peptide from CMV at each time point after PR1 will be presented. Conclusions: PR1 vaccine in pts with CML in CCyR with stable or rising levels of BCR-ABL1 transcripts on IM induces specific immune responses and ongoing improvement of molecular response. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration The Vaccine Company The Vaccine Company The Vaccine Company