Abstract P2-02-02: Phase I trial of the safety and immunogenicity of a tri-antigen vaccine targeting HER2, IGFBP-2, and IGF-IR in patients with non-metastatic breast cancer

Background: HER2, IGFBP-2, and IGF-IR are proteins that are overexpressed in breast cancer. These three proteins, when used as immunogens, provide broad antigenic coverage to all molecular breast cancer subtypes. The proteins are also up-regulated in pre-invasive and high-risk breast lesions which are associated with progression to invasive cancer. Therefore, generating protective immunity against these antigens could have the result of preventing cancer development in high risk patients. We identified epitopes derived from these proteins, termed Th1 selective epitopes, that specifically stimulated T-helper 1 immune responses in humans and mice. The tri-antigen vaccine was effective in preventing the development of breast cancer in a transgenic mouse model of neu-expressing mammary cancer. We conducted a dose finding study of a plasmid-based vaccine encoding three extended Th1 selective epitopes derived from these antigens in breast cancer patients. Methods: Patients with non-metastatic, node positive, HER2 negative breast cancer that are in remission and defined as no evidence of disease were enrolled sequentially to one of 3 dose arms: 150, 300, and 600 mcg of the tri-antigen vaccine plasmid with 10 evaluable patients per arm (NCT02780401). Vaccines were given monthly intradermally for three total doses with rhu-GM-CSF (100mcg) as an adjuvant. The primary endpoint was safety through the 6-month follow-up visit and the secondary endpoints were immunogenicity, persistence of the immune response after vaccination, and assessment of potential stimulation of T-regulatory (T-reg) cells or myeloid derived suppressor cells to the overexpressed non-mutated antigens as well as determining the recommended Phase II dose. Results: Thirty-two patients were enrolled and 97% received all three vaccinations. The mean age at enrollment was 51.9 years with 61% of patients being pre-menopausal and 39% post-menopausal. The majority of patients were Stage II/III. Eighty-eight percent of patients had hormone receptor positive tumors and twelve percent were triple negative disease. The majority of adverse events (AE) (>95%) were grade 1 or 2. The most common AE were injection site reactions, flu like symptoms, fatigue, chills, myalgia, and nausea. All doses were immunogenic with the greatest magnitude antigen specific Type I immune responses seen in the low and intermediate doses. Eighty percent of patients at the 300mcg dose retained high levels of antigen specific immunity at 1 and 6 months after immunization as compared to 57% and 50% at the 100 and 600mcg doses respectively. No antigen specific Th2 cells, MDSC or T-reg were generated with vaccination. Immunizations did not upregulate PD-1 on CD4 or CD8 T-cells. Conclusions: A plasmid-based vaccine encoding extended Th1 selective epitopes derived from HER2, IGFBP-2, and IGF-IR could be administered safely and generate high levels of antigen specific interferon gamma secreting T-cells (Th1). The 300mcg dose elicited significant immune responses in the majority of patients which persisted at least 6 months after the end of immunization. A Phase II study of the vaccine given in the neoadjuvant setting to patients with HER2 positive breast cancer is ongoing (NCT04329065). Citation Format: Sasha E. Stanton, Kari B. Wisinski, William R. Gwin, Andrew Coveler, John B. Liao, Mark Burkard, Howard Bailey, KyungMann Kim, Thomas Havinghurst, Katina DeShong, Jennifer S. Childs, Eileen Dimond, Margaret Wojtowicz, Brandy M. Heckman-Stoddard, Denise Cecil, Mary Disis. Phase I trial of the safety and immunogenicity of a tri-antigen vaccine targeting HER2, IGFBP-2, and IGF-IR in patients with non-metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-02-02.