126P - Combination of oncolytic viruses, radiation therapy, and immune checkpoint inhibitor treatment in a breast cancer model

Background

Virotherapy is a developing treatment modality with multiple therapeutic mechanisms. Viruses used in this approach can be oncolytic and induce the host immune response against tumor cells. However, oncolytic viruses used as monotherapies are not always effective. We demonstrated that a combination of Echovirus 7, Enterovirus B75, Coxsackievirus A21, and Poliovirus Type 3 with radiation therapy and immune checkpoint inhibitors (ICIs) shows efficacy in in vivo breast cancer models.

Methods

Breast cancer cell line 4T1-PVR (expressing human poliovirus receptor PVR/CD155), were obtained through lentiviral transduction. For the triple combination studies, Balb/c mice were injected subcutaneously with 4T1-PVR cells on day 0. Mice were treated with EnteroMix intravenously on days 7, 12, and 17. An intravenous administration of anti-PD-L1 antibody was done on days 10, 14, and 19. Tumor irradiation was performed on day 24 at a dosage of 5 Gy. CD45+ cells were isolated from the tumors using MagniSort™ Mouse CD45. The cells were stained with anti-mouse CD3, CD4, CD8, CD11b. Flow cytometry analysis was performed on a Fortessa X20. Data analysis was conducted using FlowJo™ v10 software.

Results

The combination of EnteroMix and radiation demonstrated a significant antitumor effect, and the addition of a PD-L1 inhibitor further reduced tumor growth and improved mouse survival. Treatment with the PD-L1 inhibitor alone had no effect on tumor growth, indicating that the tumor was resistant to ICI. Therapeutic responses were associated with increased infiltration of CD45+ immune cells into the tumor, including an increase in CD8+ T cells and a decrease in regulatory T cells.

Conclusions

In a preclinical surrogate model, the triple combination of oncolytic viruses, radiation, and immune checkpoint inhibition resulted in increased tumor infiltration by CD8+ T cells, correlating with reduced tumor volumes and improved animal survival.

Legal entity responsible for the study

The authors.

Funding

Ministry of Science and Higher Education of the Russian Federation (project No.447).

Disclosure

All authors have declared no conflicts of interest.