Intratumoral administration of a single dose of the HEPLISAV-B Vaccine and IL-15 complexes induces tumor regression in Triple Negative Brest Cancer 2259444

Abstract

Abstract Introduction Triple negative breast cancer (TNBC) is a disease with limited treatment options and a poor prognosis, highlighting an urgent need for therapeutic strategies to improve outcomes. Immune checkpoint blockade (ICB) with a PD-1 inhibitor has been an attractive strategy for TNBC treatment; however, the “immune-excluded” tumor microenvironment (TME) often confers resistance. Therefore, a creative solution is needed to turn the immunosuppressive TME into an “immune-inflamed” one with robust CD8+ T cell activity and infiltration. In this study, we determined whether combining IL-15 complexes alone, anti-PD-1 alone, or IL-15 complexes and anti-PD-1 together, with the HEPLISAV-B (HEP B) vaccine, administered intratumorally (i.t.), would enhance tumor immunity in an established 4T1 breast cancer model. Methods For this study female BALB/c mice were injected in the right mammary fat pad with the 4T1-luciferase expressing TNBC cell line, and once tumors developed, either a single dose of HEP-B vaccine or three serial doses of HEP B vaccine was administered i.t., followed by two i.t. injections of IL-15 complexes alone, five doses of anti-PD1 alone (i.p.), or a combination of both IL-15 complexes and anti-PD1 and tumor growth and survival were monitored over 60 days. Tumors were measured using calipers and IVIS imaging. Results We show that, compared with control mice receiving PBS, a single i.t. dose of HEP B induces complete tumor regression in 60% of mice. When HEP B was used with IL-15 complexes and α-PD1, 80% of mice remained tumor-free. Furthermore, when HEP B was combined with IL-15 complexes and +-PD1, tumors regressed and did not recur. CXCL9 expression was downregulated on CD8 T cells in the tumors of mice treated with HEP B alone or with IL-15 and +-PD-1, while CXCR4 was increased. Conclusion Our findings indicate that the HEP B vaccine in combination with IL-15 is an attractive strategy to overcome immune checkpoint inhibitor resistance when added to +PD-1 treatment in TNBC. Funding Source DoD proposal number BC23095 award number HT9425-24-1-0463 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)