Recombinant oncolytic poliovirus, PVSRIPO, has potent cytotoxic and innate inflammatory effects, mediating therapy in human breast and prostate cancer xenograft models.
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.
Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA.
Eda K
EK
Holl
Department of Neurosurgery, Duke University School of Medicine, Durham, NC 27710, USA.
Michael C
MC
Brown
Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA.
David
D
Boczkowski
Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
Megan A
MA
McNamara
Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
Daniel J
DJ
George
Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA.
Darell D
DD
Bigner
Department of Neurosurgery, Duke University School of Medicine, Durham, NC 27710, USA.
Matthias
M
Gromeier
Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA.|Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA.
Smita K
SK
Nair
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology / Q000821:virology; D058922:Inflammatory Breast Neoplasms / Q000276:immunology / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics; D017955:Poliovirus / Q000235:genetics / Q000276:immunology; D011471:Prostatic Neoplasms / Q000276:immunology / Q000628:therapy*; D019076:Transgenes; D023041:Xenograft Model Antitumor Assays
PVSRIPO; inflammation; innate immunity; oncolytic poliovirus