Published Research in Nature Communications: PVSRIPO Leads to Robust, Functional T Cells — Critical for Antitumor Immunity
- Intratumoral PVSRIPO stimulates a specific inflammatory response dominated by type-I/III interferon (IFN)—crucial for effective antitumor T cell priming
- Unique nonlethal infection of dendritic cells by PVSRIPO activates and dramatically increases their ability to present tumor antigens to T cells
- The specific cellular interactions promoted by PVSRIPO lead to generation of functional anticancer CD8+ T cells—the critical component needed to generate systemic cancer immunity
Durham, NC, March 25, 2021 - Istari Oncology, Inc., a clinical-stage biotechnology company, today announced the publication of “Viral infection of cells within the tumor microenvironment mediates antitumor immunotherapy via selective TBK1-IRF3 signaling” in Nature Communications. This mechanistic study found that intratumoral PVSRIPO, via unique activation of antigen presenting cells (APCs) in the tumor microenvironment (TME), stimulates functional CD8+ T cell responses capable of mediating effective, systemic antitumor immunity.<super>1<super>
Research from multiple laboratories has demonstrated the importance of APCs, especially dendritic cells, in stimulating antigen-specific immunity.<super>2,3<super> When activated, these cells produce an inflammatory response marked by type-I/III IFN. The current research demonstrates that nonlethal infection of APCs by PVSRIPO triggers a distinctive pattern of robust, sustained type-I/III IFN secretion, with minimal release of unwanted proinflammatory cytokines, due to PVSRIPO’s selective effect on a specific signaling pathway. The result is effective generation of functional antitumor CD8+ T cells. The functionality of these cells was confirmed by gold-standard methods in which antitumor T cells generated in tumor-bearing mice treated with PVSRIPO could be transferred to untreated tumor-bearing mice, resulting in decreased cancer growth.
“The potential utility of a RNA virus-based immunotherapy like PVSRIPO is its natural ability to prime and activate functional cytotoxic T cell responses,” said Dr. Matthias Gromeier, the senior author of the study. “PVSRIPO is genetically engineered to elicit potent, sustained innate antiviral inflammatory patterns, which yield vigorous CD8+ T cell responses in the TME, without significant toxicity. PVSRIPO’s activation of a specific pattern recognition receptor, MDA5, leads to the optimal cytokine signature — the sustained, type-I/III IFN-dominant response that is required to achieve robust anticancer immunity.”
Dr. Garrett Nichols, Istari Chief Medical Officer added, “Uniquely, PVSRIPO intratumoral replication also triggers CD4-mediated immunologic recall responses made possible by prior polio vaccination, which directly engages the powerful adaptive arm of the immune system. Along with the enduring, nonlethal infection of APCs demonstrated in this report and others,<super>4<super> PVSRIPO triggers the critical steps required for both a direct anticancer effect and establishment of long-term anticancer immunologic memory to help keep cancer at bay. Our upcoming LUMINOS-102 study (NCT04577807) will further evaluate the ability of PVSRIPO to generate a systemic immune response that fights cancer in both injected and noninjected tumors and suppresses cancer growth over time, expanding on the observations in the phase 1 trial in patients with unresectable, advanced, anti–PD-1 refractory melanoma.<super>5<super>”
“To appreciate the importance of these results, you need to consider the approach of other investigational immunotherapies,” commented Matt Stober, President and CEO. “In contrast to PVSRIPO, many viral agents being studied as cancer therapies are based on pathogens that employ strategies to evade the immune system by interfering with or blocking CD8+ T cell responses — the exact responses that are required for systemic anticancer immunity.”
For more information about Istari Oncology and their ongoing clinical trials and research in PVSRIPO, visit istarioncology.com.
About PVSRIPO
PVSRIPO is an investigational immunotherapy based on the live attenuated Sabin type 1 poliovirus vaccine that has been genetically modified for safety. PVSRIPO has a distinct target (the poliovirus receptor, CD155), which is widely expressed in neoplastic cells of most solid tumors. Via CD155, PVSRIPO targets tumors with two primary mechanisms: 1) direct damage to and killing of cancerous cells; and 2) engaging innate and adaptive antitumor immune responses via nonlethal infection of antigen presenting cells in the tumor, which stimulates a specific signaling pathway resulting in a sustained, robust type-I/III IFN-dominant response, with minimal release of unwanted cytokines. Its effects are potentiated by prior vaccination against poliovirus. PVSRIPO has been granted Breakthrough Therapy Designation and Orphan Status by the FDA in recurrent glioblastoma. PVSRIPO has also been granted Orphan Status by the FDA for advanced melanoma.
About Istari Oncology
Istari Oncology, Inc., headquartered in Research Triangle Park, North Carolina, is a privately held clinical-stage biotechnology company focused on novel immuno-oncology and immunotherapy platforms for the treatment of glioblastoma and a wide variety of tumors. The company was founded by Darell Bigner, MD, PhD and Matthias Gromeier, MD, of Duke University Medical Center in 2016. Istari licensed a broad range of patents and patent applications from Duke University and has access to additional intellectual property to continue clinical and commercial development of these technologies. The company’s primary platform currently in clinical development is PVSRIPO. For more information, please visit istarioncology.com.
References
- Brown MC, Mosaheb MM, Mohme M, et al. Viral infection of cells within the tumor microenvironment mediates antitumor immunity via selective TBK1-IRF3 signaling. Nat Commun. 2021;12(1):1858. doi: 10.1038/s41467-021-22088-1
- Wang Y, Swiecki M, Cella M, et al. Timing and magnitude of type I interferon responses by distinct sensors impact CD8 T cell exhaustion and chronic viral infection. Cell Host Microbe.2012;11(6):631-643. doi: 10.1016/j.chom.2012.05.003
- De Giovanni M, Cutillo V, Giladi A, et al. Spatiotemporal regulation of type I interferon expression determines the polarization of CD4+ T cells. Nature Immunol. 2020;21(3):321-330. doi: 10.1038/s41590-020-0596-6
- Brown MC, Holl EK, Boczkowski D, et al. Cancer immunotherapy with recombinant poliovirus induces IFN-dominant activation of dendritic cells and tumor antigen-specific CTLs. Sci Transl Med. 2017;20;9(408):eaan4220. doi: 10.1126/scitranslmed.aan4220
- Beasley GM, Nair SK, Farrow NE, et al. A phase I trial of intertumoral PVSRIPO in patients with unresectable, treatment-refractory melanoma. J Immunother Cancer. 2021 [in press].
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