The current studies evaluate granulocyte-macrophage colony-stimulating factor (GM-CSF) as a vaccine adjuvant. An important issue for developing vaccine therapy for human malignancy is identifying adjuvants that can elicit T-cell responses to proteins and peptides derived from “self” tumor antigens. GM-CSF, in vitro, stimulates the growth of antigen-presenting cells such as dendritic cells and macrophages. Initial experiments examined whether GM-CSF injected into the skin of rats could affect the number or character of antigen presenting cells, measured as class II major histocompatability complex expressing cells, in lymph nodes draining the injection site. Intradermal (id) inoculation of GM-CSF every 24 hours for a total of five inoculations resulted in an increase of class II+ fluorescing cells that peaked at the fourth inoculation. Subcutaneous (sq) inoculation resulted in an increase of class II+ fluorescing cells that peaked following the second inoculation, then decreased over time. Using this schema for “conditioning” the inoculation site, GM-CSF was administered id or sq for five injections and a foreign antigen, tetanus toxoid (tt), was given at the beginning or the end of the immunization cycle. Id immunization was more effective than sq at eliciting tt specific immunity. In addition, GM-CSF id, administered as a single dose with antigen, compared favorably with complete Freund's adjuvant (CFA) and alum in eliciting tt specific antibody and cellular immunity. We have shown that immunity to rat neu (c-erbB-2) protein, an oncogenic self protein, can be generated in rats by immunization with peptides derived from the normal rat neu sequence plus CFA. The current study demonstrates that rat neu peptides inoculated with GM-CSF could elicit a strong delayed type hypersensitivity reaction (DTH) response, whereas peptides alone were non-immunogenic. GM-CSF was as effective as CFA in generating rat neu specific DTH responses after immunization with a neu peptide based vaccine. Soluble GM-CSF is a potent adjuvant for the generation of immune responses to foreign proteins as well as peptides derived from a self tumor antigen.
Background: Three proteins insulin like growth factor binding protein 2 (IGFBP2), human epidermal growth factor receptor 2 (HER2), and insulin like growth factor receptor-1 (IGF1R) are overexpressed in in pre-invasive and high risk breast lesions and are associated with progression to invasive breast cancer. These proteins are immunogenic and elicit both humoral and cellular immunity in breast cancer patients. It is hypothesized that immunization with a plasmid vaccine (WOKVAC) targeting antigens from these proteins will be safe and immunogenic. WOKVAC has been designed to include extended sequences of the immunizing antigens that are predominantly associated with eliciting Type I immune responses. Type I immunity results in immune cells called T-cells secreting high levels of inflammatory cytokines (called Th1) that stimulate tumor destruction as well as the generation of cytotoxic T-cells that can directly kill the tumors. Trial design: Phase I dose escalation study of 3 doses of WOKVAC admixed with 100mcg of GM-CSF. Patients will be assigned sequentially to one of three arms (10 patients/arm): Arm 1=150mcg, Arm 2=300mcg, Arm 3=600mcg. Each dose arm will have a staggered enrollment to assess toxicity. If the Arm 1 dose is determined to be safe, Arm 2 patients can be enrolled. If the Arm 2 dose is safe and immunologically more efficacious than Arm 1 then Arm 3 patients can be enrolled. Study treatment includes 3 monthly vaccines, two evaluations at 1 and 6 months post vaccine and a 5 year follow-up to collect reports from the patient's primary oncologist. Toxicity is assessed at baseline through the end of the study. Serial blood draws for immunologic monitoring is done. Eligibility criteria: Patients with non-metastatic, node positive, HER2 negative breast cancer that is in remission and defined as no evidence of disease. Patients must have a good performance status, be at least 28 days from last cytotoxic chemotherapy and/or radiotherapy and 28 days from any use of systemic steroids. Specific aims: (1) Determine safety of 3 escalating doses of WOKVAC, (2) Determine the most immunogenic dose, (3) Determine whether a WOKVAC Th1 polyepitope plasmid based vaccine elicits a persistent memory T-cell and (4) Determine whether WOKVAC vaccination modulates T regulatory cells and myeloid derived suppressor cells. Statistical methods: (1) Safety will be assessed per NCI CTCAE v. 4.0, (2) Immunogenicity will be defined by the magnitude of the Th1 IFN-gamma antigen specific immune response. Successful immunization is a protein specific IFN-g precursor frequency greater than 1:20,000 PBMC for each antigen or 2 fold increase if baseline immune response (3) The IGFBP2, HER2, and IGF1R specific IFN-g/IL-10 ratios by ELISPOT will be evaluated to determine that a predominantly Th1 immune response is stimulated, and (4) Humoral immune response will be measured by ELISA and serum antibody avidity for IGFBP2, HER2, and IGF1R to determine an avidity index (AI) before and after vaccination. Targeted Accrual: 30 patients Contact information: University of Washington: 866-392-8588/TrialTVG@uw.edu University of Wisconsin: 608-265-2493/prevention@uwcarbone.wisc.edu. Citation Format: Childs JS, Higgins DM, DeShong K, Heckman-Stoddard BM, Wojtowicz ME, Stanton SE, Bailey HH, Wisinski KB, Disis ML. A phase I trial of the safety and immunogenicity of a DNA plasmid based vaccine (WOKVAC) encoding epitopes derived from three breast cancer antigens (IGFBP2, HER2, and IGF1R) in patients with breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-01-03.
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