Abstract A79: Cancer immunotherapy with recombinant poliovirus induces IFN-dominant activation of antigen-presenting cells and tumor antigen-specific CTLs
Brown, MC; Holl, EK; Boczkowski, D; Dobrikova, E; Mosaheb, M; Chandramohan, V; Bigner, DD; Gromeier, M; Nair, SK
Published in: Cancer Immunology Research
The tumor microenvironment favors tumor immune escape by suppressing production, activation and/or function of antitumor T cells. Our group has developed a recombinant Rhino-Poliovirus chimera, PVSRIPO, currently being evaluated in Phase-II clinical trial against recurrent glioma. PVSRIPO therapy has afforded durable clinical responses in recurrent glioma patients. Clinical and pre-clinical findings suggest that PVSRIPO primarily acts through an immunological mechanism, rather than via cancer selective cytotoxicity. Here we define the immune adjuvant potential of intratumoral-delivered PVSRIPO that ultimately leads to the engagement/production of antitumor T cells. Sub-lethal infection of human dendritic cells (DCs) with PVSRIPO yields potent, sustained type I interferon dominant activation. PVSRIPO infection of macrophages induces similar activation; however, virus translation and the resulting type I Interferon/TNF-α production by macrophages is strongly enhanced in the presence of the Th2 cytokine IL-4. Compared to conventional adjuvants, e.g. poly(I:C) and LPS, PVSRIPO stimulation of APCs withstands tumor-associated immunosuppression, particularly in macrophages, and achieves more durable activation of DCs. Therapy of B16 melanoma tumors with PVSRIPO led to early production of type I interferon, IL-12, and IFN-γ; which was associated with the recruitment of neutrophils to the tumor site. Neutrophil influx was followed by DC and T cell infiltration. Mice treated with PVSRIPO developed tumor-antigen specific, cytotoxic T cells that were present in both tumor draining lymph nodes and spleens. These events correlated with delay in tumor growth and increase in survival following PVSRIPO therapy. Thus, PVSRIPO’s immune adjuvancy stimulates canonical innate inflammatory responses within the tumor microenvironment that culminates in tumor antigen-specific T cell responses.Citation Format: Michael C. Brown, Eda K. Holl, David Boczkowski, Elena Dobrikova, Mubeen Mosaheb, Vidya Chandramohan, Darell D. Bigner, Matthias Gromeier, Smita K. Nair. Cancer immunotherapy with recombinant poliovirus induces IFN-dominant activation of antigen-presenting cells and tumor antigen-specific CTLs [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A79.