Survivin (BIRC5) peptide vaccine in the 4T1 murine mammary tumor model: a potential neoadjuvant T-cell immunotherapy for triple negative breast cancer

Abstract

Background Triple negative breast cancer (TNBC) cells are, by definition, estrogen and progesterone receptor negative and do not produce high levels of the HER2 protein. Checkpoint inhibitor immunotherapy has been approved for patients with TNBC, but the prognosis for these patients is poor compared with patients presenting with other common forms of breast cancer. Survivin (BIRC5) is a tumor-associated antigen (TAA) previously described to be overexpressed in triple negative breast cancer, but not expressed, or expressed at very low levels, in normal tissue, representing targets for cytotoxic T lymphocyte (CTL) immunotherapy. Study Design A BALB/c TNBC mouse model using the 4T1 cell line was used to explore the effect of an adjuvanted microsphere synthetic vaccine containing survivin peptides on tumor growth rate. After conducting a 4T1 tumor cell inoculation dose ranging study, adjuvanted peptide vaccine microspheres were studied for their effect on tumor growth using 250 4T1 cells in one group and 500 4T1 cells in the other. The vaccine was administered via intraperitoneal injection at study start with a second dose given 14 days later. An orthotopic injection of 4T1 cells into mammary tissue was performed on the same day as the administration of the second vaccine dose. The mice were followed for up to 41 days with subcutaneous measurements of tumor volume made every three days (Figure 1). Results Vaccination with survivin peptide antigens resulted in a statistically significant diminution of tumor-takes and a deceleration of primary tumor growth volume in BALB/c mice challenged with 4T1 cells versus control. This effect was seen in both the 250 4T1 cell and the 500 4T1 cell challenge groups. The mice produced an ELISpot immune response to one of the survivin peptide antigens used in the vaccine and this response was only seen after the adjuvanted microsphere vaccine was administered. Conclusion The synthetic, adjuvanted microsphere peptide vaccine given 14 days before challenge, and on the day of challenge, was able to diminish tumor-takes and decelerate tumor growth in BALB/c mice challenged with 250 or 500 4T1 cells injected into mammary tissue. This model suggests that T-cell immunotherapy specifically targeting survivin might be an applicable neoadjuvant immunotherapy therapy for triple negative breast cancer. More pre-clinical studies and clinical trials will be needed to explore this concept further.