Prevention and Therapy of Metastatic HER-2+ Mammary Carcinoma with a Human Candidate HER-2 Virus-like Particle Vaccine

Abstract

Vaccines are a promising therapeutic alternative to monoclonal antibodies against HER-2+ breast cancer. We present the preclinical activity of an ES2B-C001, a VLP-based vaccine being developed for human breast cancer therapy. FVB mice challenged with HER-2+ mammary carcinoma cells QD developed progressive tumors, whereas all mice vaccinated with ES2B-C001+Montanide ISA 51, and 70% of mice vaccinated without adjuvant, remained tumor-free. ES2B-C001 completely inhibited lung metastases in mice challenged intravenously. HER-2 transgenic Delta16 mice developed mammary carcinomas by 4–8 months of age; two administrations of ES2B-C001+Montanide prevented tumor onset for >1 year. Young Delta16 mice challenged intravenously with QD cells developed a mean of 68 lung nodules in 13 weeks, whereas all mice vaccinated with ES2B-C001+Montanide, and 73% of mice vaccinated without adjuvant, remained metastasis-free. ES2B-C001 in adjuvant elicited strong anti-HER-2 antibody responses comprising all Ig isotypes; titers ranging from 1–10 mg/mL persisted for many months. Antibodies inhibited the 3D growth of human HER-2+ trastuzumab-sensitive and -resistant breast cancer cells. Vaccination did not induce cytokine storms; however, it increased the ELISpot frequency of IFN-γ secreting HER-2-specific splenocytes. ES2B-C001 is a promising candidate vaccine for the therapy of tumors expressing HER-2. Preclinical results warrant further development towards human clinical studies.

Virus-like Particle (VLP) Vaccines for Cancer Immunotherapy

“…Commonly used expression systems include bacteria (e.g., Escherichia coli ) [ 23 ], yeasts (e.g., Pichia pastoris ) [ 24 ], insect cells (e.g., Drosophila melanogaster S2 cells) [ 25 , 26 ], mammalian cells (e.g., human embryonic kidney (HEK) cells) [ 27 , 28 ], and even plant cells [ 29 ]. Each system has distinct characteristics that can affect both the yield of VLP production, a crucial factor considering the large quantities needed for vaccine development, and their immunogenicity [ 21 ].…”

“…In this HER-2-tolerant mouse model, the vaccine confirmed its therapeutic efficacy on metastasis treatment by removing lung nodules in the treated mice. Additionally, the strong antitumoral activity was accompanied by a copious induction of anti-HER-2 antibodies of all IgG subclasses in both mouse models (ranging 1–10 mg/mL in FVB mice and 0.1–1 mg/mL in Delta16 mice) that remained stable for around one year after the last vaccination, suggesting the induction of a persistent B memory response [ 26 ].…”