Strengthening of antitumor effects in breast cancer from a novel B7-H4- and CD3-targeting bispecific antibody by an oncolytic virus.

BACKGROUND

For programmed cell death protein 1/programmed death-ligand 1 (PD-L1)-positive triple-negative breast cancer (TNBC), the addition of immune checkpoint inhibitors (ICIs) to chemotherapy has been shown to increase the objective response rate (ORR) by only 13.4-16.3%. Thus, examining converting tumor immunogenicity and targeting novel pathways may be needed to improve response to immunotherapy. B7-H4 is an emerging target for breast cancer immunotherapy. However, the antitumor effect of B7-H4 is unstable during cell generation and further research is necessary to strengthen the antitumor efficacy of B7-H4.

METHODS

To explore the potential of B7-H4-targeted immunotherapy of breast cancer, current study generated four monoclonal antibodies (mAbs) against B7-H4 through immunization of mice followed by phage display technology. T cell-engaged bispecific antibodies and immunotoxins were created based on these mAbs. To evaluate the anti-tumor activity of B7-H4-targeting bispecific antibody and immunotoxin, the anti-tumor efficacy test and in mice models were performed. Moreover, to boost the efficacy, oncolytic virus herpes simplex virus type 2 (HSV-2) was combined with the bispecific antibody and tested in mice models.

RESULTS

Rigorous cytotoxicity assay showed that both B7-H4 bispecific antibodies and immunotoxins were toxic to B7-H4 positive cells, with the former being more potent. However, studies showed that immunotoxin was slightly more effective in suppressing tumor growth. Further, bispecific antibody combined with oncolytic virus HSV-2 revealed a synergistic effect in suppressing tumor growth without causing obvious adverse effects.

CONCLUSIONS

Collectively, our findings uncover a novel strategy of combining oncolytic virus HSV-2 with bispecific antibody reinforce antitumor immune response, which warranted further translational investigation.