A novel anti Wilms-Tumour-1 (WT1) vaccination strategy in haematological malignancy using DNA fusion vaccines deliv

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Scientific Abstract In patients with chronic myeloid leukaemia (CML), while outcome has improved with novel agents such as tyrosine kinase inhibitors, the only curative approach is with allogeneic transplantation. This exerts its benefit through immune control of the cancer, but is only suitable for a small number of patients. This study intends to examine whether DNA vaccination can exert measurable immune control of CML, by assessing disease with the established, clinically relevant monitoring of BCR-ABL transcripts and correlating reduction in BCR-ABL transcript levels (primary endpoint: molecular response rate at 6 months) with responses in WT1 transcript levels and immunological responses (secondary endpoints). We are in clinical testing with a strategy to raise epitope-specific immunity against cancer using a plasmid-DNA fusion vaccine platform. The unique design encodes an immune alert domain (DOM) from tetanus, linked to a tumour antigen-derived epitope (p-DOM-epitope). In the laboratory this design confers tumour protection, breaks immunological tolerance, and induces strong and durable cytotoxic CD8+ T cell immune responses, superior to peptide vaccines. In patients with prostate cancer, 60% (19/31) developed vaccine induced PSMA (prostate specific membrane antigen) specific T cells with excellent vaccine safety. In this same trial a novel delivery system (intramuscular electroporation) enhanced immune responses to the DNA vaccine. We now wish to show that DNA fusion vaccination can control haematological malignancies, specifically CML. Here, escape from cytotoxic T cell attack by loss of MHC I molecules is less likely and molecular markers are already used to guide clinical management. We intend to exploit the high expression of the WT1 antigen in CML and build on the observation that in spite of inducing only transient immunity, even the suboptimal vaccination with peptide vaccines against WT1 conferred some clinical benefit. Our strategy is to use double DNA vaccination targeting two separate WT1-derived peptides. In this phase I/II study we propose to vaccinate up to 37 HLA A0201+ patients with CML in cytogenetic remission (CCyR), stable on imatinib, with 6x 1-monthly doses of two WT1 vaccines, followed by maintenance vaccination up to 2 years in responders. As the vaccine can only work by stimulating the immune system, we intend to show that molecular clinical responses are related to a CD8+ T cell response induced by vaccination, measured by tetramer and ELISPOT analysis. Synchronously, a consented control group of up to 55 patients will be recruited, who are found to be HLA A2 negative at screening (genetic randomiztion). The generated data will assess the clinical response rate, validate WT1 measurement by qPCR as a biomarker for vaccine responses in CML and inform whether definitive Phase III testing of the vaccine is warranted. We expect to recruit 1-2 HLA A0201+ and 2-3 HLAA2- patients/ month with a follow up of 24 months, allowing completion of the study in the 4 years of funding requested.