Pilot trial of a Wilms tumor-1 (WT1) peptide vaccine in patients with thoracic and myeloid neoplasms

Abstract

3051 Background: The transcription factor, WT1, is overexpressed in several solid tumors and leukemias and has been targeted by investigators for immunotherapy. Using computer prediction analysis we designed analog peptides derived from WT-1 sequences by substituting amino acids at key HLA-A0201 binding positions. One peptide (WT-A1) was capable of stimulating CD8 T-cells for killing of HLA matched tumor cells. A modified version of the protein (WT1–122A1) created by adding flanking amino acids to the core sequence, generated CD4 responses as well. Two additional peptides were generated (WT1–427 & WT1–331) which were capable of recruiting CD4 T-cell response across multiple HLA-DR subtypes. These four peptides administered together with adjuvant Montanide and GM-CSF comprise the vaccine. Methods: The primary objective of the study is to test the safety, activity and immunogenicity of WT1 vaccine in 10 patients with mesothelioma (meso) or non-small cell lung cancer (NSCLC) expressing WT1 protein by immunohistochemistry, and 10 patients with acute myeloid leukemia (AML) or myelodysplastic syndrome with WT1 transcript measured by RQ-PCR. Patients receive up to 12 vaccinations over 9 months. Immune responses are evaluated by delayed-type hypersensitivity, CD4 T-cell proliferation, CD4 and CD8 T-cell interferon release, and WT1 peptide tetramer staining. Results: 12 patients (5 AML, 5 meso, 2 NSCLC) have been enrolled and 2 are currently active. 4 meso patients discontinued the vaccines after 3 or 6 doses because of progression. 1 meso patient has stable disease after 12 vaccinations. 3 AML patients relapsed on the vaccine (after 3rd, 6th, 8th dose) and had evidence of increasing WT-1 transcript. 3 of 10 patients tested developed a DTH skin reaction. 6 of 7 patients evaluated had a CD8 or CD4 immune response to the vaccinating peptides. One AML patient had grade 2 urticaria after the 5th vaccination and was removed from study. No other significant adverse events occurred. Conclusions: This analog WT1 peptide vaccine is well-tolerated and immune responses can be elicited. Future studies will incorporate this vaccine as adjuvant therapy in meso and AML. Supported by NIH PO1 23766, Innovive Pharmaceuticals, MARF, The Experimental Therapeutics Center and the Baker Street Foundation. No significant financial relationships to disclose.