Efficacy of a multipeptide bcr-abl p210 protein derived vaccine in chronic myeloid leukemia with 5-year follow up

Abstract

Background: Modern treatment modality of chronic myeloid leukemia is dependent on tyrosine kinase inhibitors prototyped by Imatinib and other new TKIs, however it is difficult to eradicate the disease at the molecular level by use of TKIs only. Studies show that deeper molecular response is associated with longer survival. In an attempt to investigate the role of active immunotherapy (vaccination) to reduce the molecular burden at least one-log in patients with detectable molecular disease while receiving and continuing TKI, we designed a small trial of a multipeptide vaccine against bcr-Abl p210 protein junctional peptide on 10 patients with CML-CP receiving Imatinib 400 mg/day or more for at least 12 months and followed them for 5 years. Methods: 10 adults with chronic myeloid leukemia in chronic phase receiving Imatinib of at least 400 mg/day with defined HLA Class I molecules were injected GM-CSF and IL-12 plasmids 100 micrograms intradermally once and eight 3-weekly apart multipeptide injections subcutaneously beginning one day after the adjuvant treatment. The usual TKI dose was continued or changed in the discretion of treating physician. We sampled peripheral blood and bone marrow just before and 2 months after the vaccination trial to compare the molecular burden by bcr-Abl RT-PCR technique. Results: 10 adults with CML-CP were enrolled. There were 9males and one female. They were diagnosed with CML-CP and were taking Imatinib at least 400 mg/day formore than 12 months. All patients had one of theHLA Class I molecules of A02, A03 or B08. At least one of the nine bcr-Abl p210 derived small peptide in the vaccine could adhere to one of the HLA Class Imoleculesmodestly and elicit a cytotoxic T cell response as was published by BIMAS and SYFPEITHI epitope prediction softwares. At the final analysis, 2-months after the last step, laboratory investigation disclosed 1-log decrease in peripheral bloodmolecular burden in 2 of 10 patients. The active immunotherapy was not accompanied by systemic side effects, howevermild local reaction. Long term(5-year) follow up demonstrated undetectable disease in 1 patient and 1-log decrease in 6 others compared to early post-vaccination assay. One of the early responded patient, had discontinued taking Imatinib for 12 months and increased molecular burden that we observedmight be attributed to interruption of TKI treatment and the other one did not participate in follow up study, however he was clinically well.We observed 1-log decrease in molecular burden in six and a case of undetectable disease among eight initially nonresponded patients after 5-years. Conclusions: Active immunotherapy in CML against bcr-Abl derived p210 protein junctional peptide, considering immunology of the peptides and the patients could be an attractive and safe treatment that adds another first to the CML firsts.