Recombinant oncolytic poliovirus, PVSRIPO, has potent cytotoxic and innate inflammatory effects, mediating therapy in human breast and prostate cancer xenograft models

Abstract

Intratumoral inoculation of viruses with tumor-selective cytotoxicity may induce cancer cell death and, thereby, shrink neoplastic lesions. It is unlikely, however, that viral tumor cell killing alone could produce meaningful, durable clinical responses, as clinically suitable ‘oncolytic’ viruses are severely attenuated and their spread and propagation are opposed by host immunity. Thus, a more propitious event in this context is the innate antiviral response to intratumoral virus administration, in particular for recruiting durable adaptive immune effector responses. It may represent a double-edged sword, as innate immune activation may eliminate infected tumor cells early, intercept viral spread and block any meaningful therapeutic response. The innate response to viral infection of tumors may be very different from that in non-malignant target tissues, owing to the unusual composition/tissue properties of tumor stroma. In this work, we report investigations of the innate immune response to the oncolytic poliovirus recombinant, PVSRIPO, in two mouse xenotransplantation models for breast and prostate cancer. Our observations indicate short-term virus persistence in infected tumors and virus recovery indicative of modest intratumoral propagation and persistence. Yet, a powerful innate inflammatory response coincided with chemokine induction and myeloid cell infiltration into tumors that was, interestingly, dominated by neutrophils. The combined effect of PVSRIPO tumor infection and the innate response it elicits was significant tumor regression in both models.

Recombinant Poliovirus for Cancer Immunotherapy

“…This is evident with PVSRIPO infection of SUM149 cells, where at multiplicities of infection of 0.1 (implying multiple rounds of infection in the culture in the presence of an active type 1 IFN response), complete cytolysis as indicated by eIF4G cleavage and decrease in total protein is achieved (Fig. 2) (6). As with other aspects of the poliovirus:host relationship, this phenotype is mostly due to the exceedingly simple (and cytotoxic) viral life cycle.…”

“…A case in point is the SUM149 triple negative inflammatory breast cancer cell line used in our studies (Fig. 2) (6). …”

“…In breast and prostate cancer xenotransplantation models, single intratumoral administration of PVSRIPO led to rapid production of chemokines and cytokines one day after therapy (6). Analysis of tumor immune infiltrates following therapy revealed rampant neutrophil influx 1–2 days after treatment (Fig.…”

“…Analysis of tumor immune infiltrates following therapy revealed rampant neutrophil influx 1–2 days after treatment (Fig. 2) (6). This was reminiscent of immune cell infiltrations that had been described, but not defined, in earlier studies of PVSRIPO treatment in mouse xenotransplantation models with human malignant glioma models (27, 29, 66).…”

“…Lastly, tumor infection with PVSRIPO elicits a range of acute inflammatory events leading to profuse immune cell invasion, resulting in an immune-engaged tumor microenvironment. These events resemble classic cascades of the inflammatory response to pathogen challenge and are highly desirable in the cancer immunotherapy context (6). …”