Abstract P5-16-04: A phase I study of a DNA plasmid based vaccine encoding the HER-2/neu intracellular domain in subjects with HER2+ breast cancer.
Authors: Salazar LG , Slota M , Higgens D , Coveler A , Dang Y , Childs J , Bates N , Guthrie K , Waisman J , Disis ML 
Published: August 2014

Abstract
HER2+ breast cancer (BC) is associated with early disease relapse, usually to distant sites. This would suggest relapse is due to residual microscopic disease. Generation of vaccine-induced HER2-specific CD4+ T helper immunity (Th1) may result in immunologic eradication of residual HER2+ tumor cells and subsequent development of immunologic memory and epitope spreading (ES), which has been associated with a survival benefit in vaccinated BC patients. We have shown HER2 peptide-based vaccines can generate immunity in BC however, more recently we developed a plasmid DNA based vaccine (pNGVL3-hICD) which may have additional advantages over synthetic peptides. DNA vaccines offer a strategy to immunize against multiple tumor antigens and are able to elicit both CTL and Th1 immunity. Plasmid DNA can also remain at the vaccine site, providing a constant source of antigen. Intradermal (i.d.) delivery of DNA vaccines with GM-CSF as adjuvant may enhance immunogenicity due to local influx of dermal Langerhans cells. We have recently completed a phase I trial utilizing pNGVL3-hICD in optimally treated stage III and IV HER2+ BC patients and have defined vaccine safety profile, optimal dose and schedule; and demonstrated vaccine biologic activity.
Methods: A total of 66 subjects with stage III and IV HER2+ BC in complete remission were enrolled sequentially into 1 of 3 pNGVL3-hICD dose arms (22 subjects/arm): Arm 1=10µg, Arm 2=100 µg, and Arm 3 = 500µg. 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 to HER ICD and ECD were assessed with IFN-γ ELISPOT at baseline and serially through week 60 post-vaccination. Linear regression analysis was used to compare differences in immune responses from baseline over the whole study period between dose arms. Vaccine site skin biopsies and peripheral lymphocytes were serially analyzed for plasmid persistence via RT-PCR.
Results: 64 subjects (20 in Arm 1; 22 in Arm 2; 22 in Arm 3) completed 3 vaccines. Age, stage/status, number of previous chemotherapy regimens, and use of bisphosphonate and trastuzumab therapies was similar across dose arms. Vaccine-related toxicity was primarily Grade 1/2 injection site reactions, myalgias, arthralgias and not significantly different between arms; no cardiac or grade IV toxicity was observed. Immune responses to HER2 ICD were significantly better in Arms 2 and 3 vs Arm 1 (p = 0.001 and 0.002, respectively) but not statistically different between Arms 2 and 3. 38 patients had DNA plasmid persistence at the vaccination site with no difference between arms. There has been no detection of DNA plasmid in lymphocytes from patients in all arms. Analyses of survival and ES (HER ECD immune responses) are on-going and will be presented.
Conclusions: pNGVL3-hICD was safe and effectively induced persistent HER2 ICD specific Th1 immunity without increased cardiac toxicity. Moreover, immunity was present more than 1 year after end of vaccination, indicative of vaccine-induced immunologic memory.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-16-04.