A vaccine for chronic Myeloid leukaemia

Abstract

This phase II multicentric trial investigated whether a vaccine targeting the hallmark BCR-ABL derived p210 fusion protein can further reduce persistent residual disease in patients on conventional treatment for chronic myeloid leukaemia (CML) and elicit a tumour-specific immune response. Sixteen patients with CML (with a b3a2 fusion point of p210) with stable residual disease after a minimum of 12 months of imatinib or 24 months of interferon and with no further reduction of residual disease for at least 6 months preceding enrolment were recruited. The vaccination strategy consisted of a biweekly schedule of 6 injections of a peptide vaccine (CMLVAX100) derived from a junction sequence of p210 b3a2 consisting of 4 HLA class I (A11, A3, A3/A11, B8) and one 25-amino acid peptide with HLA class II (DR1, DR4, DR11)-binding motifs, and 100 μg Quillaja saponaria (QS-21; an immunological adjuvant). Also, 50 mg/m² of molgramostim (GM-CSF) was given subcutaneously close to the vaccination site on the day before as well as on the day of vaccination. Patients recruited for the trial were individuals with HLA alleles known to bind the fusion peptide. Peptide-specific immune responses were measured at baseline and after the third and sixth vaccination. Delayed type hypersensitivity was measured by skin tests with intradermal injections of a mixture of 5 mg per peptide in PBS with QS-21 and molgramostim. Unprimed CD4 cell proliferation was measured using standard H3 thymidine incorporation assay. Unprimed interferon-α ELISA spot assay was done to estimate increase in interferon-α secreting cells post-vaccination. Assessment of the disease response was done after the third and sixth vaccination by standard bone marrow cytogenetic analysis for Philadelphia (Ph) chromosome. Patients achieving complete cytogenetic response (CCR: 0% Ph-positive metaphases) were assessed by quantitative real-time PCR. To confirm molecular remission, additional qualitative nested RT-PCR was done. The median age of the patients was 51 (range 45-68) years. Ten patients were on imatinib and 6 on interferon. Nine of 11 patients on imatinib with measurable cytogenetic disease showed a variable degree of progressive reduction of residual Ph-positive metaphases after 3 vaccinations and 5 patients achieved CCR after 6 vaccinations. Three of 5 patients in CCR had undetectable transcripts after 6 vaccinations when assessed by quantitative real-time PCR and qualitative nested RTPCR analysis. One patient in CCR before vaccination showed a half log reduction of residual molecular response after vaccination. Five of 6 patients on interferon showed reduction of their stable disease with 2 reaching CCR. In 1 patient the RT-PCR results were negative. Tolerance to the vaccine was optimum in patients but with some initial symptoms. All 16 patients were negative for delayed type hypersensitivity before vaccination and almost 70% had a positive reaction after vaccination. All but 1 patient with appropriate HLA class II molecules showed varying positive CD4 cell proliferation response after vaccination, and more than half the patients with appropriate HLA class I molecules presented b3a2 peptide-specific interferon-α production after vaccination. These preliminary data suggest that the addition of a b3a2- specific vaccine such as CMLVAX100 to b3a2 CML patients treated with conventional therapy might lead to a further reduction of residual disease and increase the number of patients who reach a molecular response.