A phase I study of a DNA plasmid based vaccine encoding the HER2/neu (HER2) intracellular domain (ICD) in subjects with HER2+ breast cancer

Abstract

3054 Background: HER2 is overexpressed in 25% of breast cancers and plays a role in the malignant transformation of cells. Vaccine-induced immunity against the HER2 ICD correlates with antitumor responses in animal models. DNA-based vaccines offer a strategy to immunize against multiple tumor antigens and are able to elicit both CTL and T helper immune responses. Plasmid DNA can also remain at the vaccine site, providing a constant source of antigen. However, DNA vaccines have been poorly immunogenic due in part to inefficient APC transfection. Intradermal (i.d.) delivery of DNA vaccines with GM-CSF as adjuvant may enhance immunogenicity due to local influx of dermal Langerhans cells. A phase I study was conducted to evaluate the safety and immunogenicity of a DNA-based vaccine encoding the HER2 ICD. Methods: 44 subjects with stage III and IV HER2+ breast cancer in complete remission were enrolled sequentially into 2 vaccine arms (22 subjects/arm) and received 10μg pNGVL3-hICD (Arm 1) or 100μg pNGVL3-hICD (Arm 2). All vaccines were admixed with 100μg GM-CSF and given i.d. monthly for a total of 3 vaccines. Toxicity was assessed at baseline, during vaccination, and at follow-up. Immune responses were assessed with IFN-γ ELISPOT at baseline and post-vaccination. Vaccine site biopsies were analyzed for plasmid persistence via RT-PCR, 1 and 6 months after vaccination. Results: 43 subjects (21 in Arm 1; 22 in Arm 2) completed 3 vaccines. Vaccine-related toxicity in both arms was primarily grade I/II; no cardiac or grade IV toxicity was observed. 13/21 (62%) subjects in Arm 1 developed T-cell immunity, defined as HER2-specific T cell precursors:PBMC, to the HER2 protein (median 1:5,972, range 1:717–1:3,000,000) and to p776, a HER2 pan DR binding epitope (median 1:3,150, range 1:543–1:108,696). 13/19 (68%) subjects in Arm 1 had persistent plasmid DNA at the vaccine site. ELISPOT and RT-PCR analysis for Arm 2 are on-going. Conclusions: Immunization with a DNA plasmid-based HER2 vaccine is safe and immunogenic. Moreover, plasmid DNA persists at the vaccine site post-immunization and HER2+ cancer patients are able to develop immunity to the HER2 ICD. No significant financial relationships to disclose.