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A pilot vaccination trial of synthetic analog peptides derived from the BCR-ABL breakpoints in CML patients with minimal disease

Leukemia volume 22, pages 1613–1616 (2008)Cite this article

Previous clinical vaccination trials of BCR-ABL peptides demonstrated that certain amino-acid sequences crossing the p210 breakpoint were immunogenic in patients with chronic myeloid leukemia (CML), with 60–80% of patient's T cells responding to the vaccinating peptides.1, 2, 3, 4 Antileukemic effects were suggested in two of these trials.3, 4 Both trials involved patients with the b3a2 breakpoint. Native peptides from either b3a2 or b2a2 breakpoints demonstrating strong binding to human leukocyte antigen (HLA)-A0201 have not been identified, and CD8 responses to HLA-A0201-restricted peptides have also not been observed in vaccinated patients. We hypothesized that specific CD8 responses could be generated to class I HLA-A0201 peptides by rendering them more immunogenic through selective mutations in their HLA-binding sequences5 and preclinical data have documented the immunogenicity of these sequences to human CD8 T cells. We therefore initiated a clinical trial administering synthetic analog peptide vaccines for either b3a2 or b2a2 breakpoints to CML patients. Eligible patients had obtained either a major or complete cytogenetic remission on a stable treatment regimen of imatinib therapy and were required to have molecular or cytogenetic measurable disease. Patients could not undergo other forms of therapy (exclusive of imatinib) during vaccination. Eleven vaccinations mixed in the immune adjuvant montanide were given: biweekly five doses, then monthly four doses, then at 9 and 12 months. Granulocyte-macrophage CSF (70 μg) was administered subcutaneously with each vaccine at the site of vaccination on days −2 and 0. Responses were evaluated at time 0, after five vaccinations and 2 weeks following the completion of therapy through delayed type hypersensitivity , CD4 T-cell proliferation, CD4 and CD8 T-cell interferon γ ELISPOT, tetramer staining, 51Cr release assay1, 2, 5 as well as bone marrow cytogenetics and PCR (both quantitative and nested assays).

Patients with b3a2 breakpoint received a cocktail of five peptides (American Peptide Company, Sunnyvale, CA, USA) spanning the b3a2 fusion junction: two heteroclitic HLA-A0201-binding peptides, CML-A2-HC (KLLQRPVAV) and CML-HF(YLKALQRPV), and three native sequences: one HLA-A3-binding peptide, CML-A3 (KQSSKALQR) and one HLA-B8-binding peptide, CML-B8, (GFKQSSKAL) and one long class II peptide, B3A2 long (IVHSATGFKQSSKALQRPVASDFE). The additional b3a2 peptide sequences used for testing in vitro were: CML-A2-NC, (KALQRPVAS) and CML-A2-NF, (SSKALQRPV). Patients with b2a2 breakpoint received two peptides spanning the b2a2 fusion junction, which includes one class II peptide, B2A2 long (VHSIPLTINKEEALQRPVASDFE), and an HLA-A0201-binding heteroclitic peptide, B2A2-H (YLINKEEAL). An additional native b2a2 sequence used for testing in vitro was B2A2-N, (LTINKEEAL). Control irrelevant peptides for in vitro testing also included: for HLA-A0201, QLQNPSYDK, ILKEPVHGV; for A0301, VLNYGVCVC; KVYAWVPAH; for HLA-B8, KNKEKALII; GGKKKYKL and for HLA-DR, TEYKLVVVGARGVGKSALTIQ.

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Acknowledgements

We thank Bo Dupont and Alice Yeh, Sloan-Kettering Institute for HLA genomic typing and Seema Gupta for significant contributions to this trial. This work was supported NIH PO1 23766, the Experimental Therapeutics Center and Breakthrough Therapeutics Inc.

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  1. P G Maslak and T Dao: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    P G Maslak, S Chanel, E Berman & D A Scheinberg

  2. Molecular Pharmacology & Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    T Dao, M Gomez, J Packin, T Korontsvit, V Zakhaleva & D A Scheinberg

  3. Hematologic Malignancies Program,

    J Pinilla-Ibarz

  4. Department of Medicine, H Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA

    J Pinilla-Ibarz

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  1. P G Maslak
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Correspondence to P G Maslak.

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Maslak, P., Dao, T., Gomez, M. et al. A pilot vaccination trial of synthetic analog peptides derived from the BCR-ABL breakpoints in CML patients with minimal disease. Leukemia 22, 1613–1616 (2008). https://doi.org/10.1038/leu.2008.7

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