Oncolytic poliovirus immunotherapy for triple negative breast cancer
Smita Nair, Eda Holl, Michael Brown, Darell Bigner, Lars Grimm, Jeremy Force, Shelley Hwang and Matthias Gromeier
Duke University School of Medicine, Durham, North Carolina, USA
PVSRIPO is a recombinant polio:rhinovirus chimera that has demonstrated promising responses in patients with recurrent glioblastoma. In addition to cancer cells, PVSRIPO targets antigen-presenting cells (APCs), such as dendritic cells (DCs) and macrophages. PVSRIPO infection of APCs elicits sublethal viral propagation that induces sustained type I interferon (IFN-I) and APC activation, thus engaging both the innate and adaptive immune system (Brown et al, Sci Transl Med 2017 Sep 20; PMID: 28931654).
To develop oncolytic poliovirus immunotherapy for triple negative breast cancer (TNBC), we examined: 1] expression of poliovirus receptor CD155 in primary human TNBC tissue, 2] susceptibility of primary TNBC tissue to PVSRIPO, 3] efficacy of PVSRIPO in an immunocompetent orthotopic mouse breast tumor model.
We demonstrate that primary TNBC tissue expresses CD155. Treatment of primary TNBC tissue with PVSRIPO induces IFN-I and pro-inflammatory cytokines. PVSRIPO-mediated APC activation occurs in the presence of tumor-associated immunosuppression and induces sustained IFN-I in human DCs when compared to poly(I:C) and LPS. Activation of human DCs by PVSRIPO results in upregulation of PDL1. In a murine immunotherapy model, intratumoral injection of PVSRIPO induces IFN-I, IL12 and IFNγ and rapid recruitment of neutrophils into the tumor followed by infiltration of DCs, T cells and B cells. Treatment of orthotopic breast tumors with PVSRIPO results in delayed tumor growth and increased survival.
We continue to examine local and systemic innate and adaptive immune responses and expression of PD1 and PDL1 in tumor-infiltrating immune cells following intratumor PVSRIPO treatment in orthotopic mouse breast cancer model. We are also finalizing a pilot clinical protocol of PVSRIPO in women with TNBC. Women will be treated with PVSRIPO 14-20 days before surgical resection of tumor. We will examine PVSRIPO-mediated bioactivity, inflammation, and PD1/PDL1 expression on tumor infiltrating immune cells in this pilot study. These data will support a phase 1/2 study of PVSRIPO with anti-PD1/PDL1 in women with TNBC.
This study is funded by the Department of Defense Breast Cancer Research Program award W81XWH-16-1-0354 (PI, Smita Nair).