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Cancer Immunology Research
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ONCR-177, an Oncolytic HSV-1 Designed to Potently Activate Systemic Antitumor Immunity

Brian B. Haines, Agnieszka Denslow, Peter Grzesik, Jennifer S. Lee, Terry Farkaly, Jacqueline Hewett, Daniel Wambua, Lingxin Kong, Prajna Behera, Judith Jacques, Caitlin Goshert, Michael Ball, Allison Colthart, Mitchel H. Finer, Melissa W. Hayes, Sonia Feau, Edward M. Kennedy, Lorena Lerner and Christophe Quéva
Brian B. Haines
Oncorus, Inc., Cambridge, Massachusetts.
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  • For correspondence: brian.haines@oncorus.com
Agnieszka Denslow
Oncorus, Inc., Cambridge, Massachusetts.
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Peter Grzesik
Oncorus, Inc., Cambridge, Massachusetts.
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Jennifer S. Lee
Oncorus, Inc., Cambridge, Massachusetts.
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Terry Farkaly
Oncorus, Inc., Cambridge, Massachusetts.
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Jacqueline Hewett
Oncorus, Inc., Cambridge, Massachusetts.
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Daniel Wambua
Oncorus, Inc., Cambridge, Massachusetts.
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Lingxin Kong
Oncorus, Inc., Cambridge, Massachusetts.
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Prajna Behera
Oncorus, Inc., Cambridge, Massachusetts.
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Judith Jacques
Oncorus, Inc., Cambridge, Massachusetts.
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Caitlin Goshert
Oncorus, Inc., Cambridge, Massachusetts.
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Michael Ball
Oncorus, Inc., Cambridge, Massachusetts.
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Allison Colthart
Oncorus, Inc., Cambridge, Massachusetts.
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Mitchel H. Finer
Oncorus, Inc., Cambridge, Massachusetts.
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Melissa W. Hayes
Oncorus, Inc., Cambridge, Massachusetts.
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Sonia Feau
Oncorus, Inc., Cambridge, Massachusetts.
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Edward M. Kennedy
Oncorus, Inc., Cambridge, Massachusetts.
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Lorena Lerner
Oncorus, Inc., Cambridge, Massachusetts.
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Christophe Quéva
Oncorus, Inc., Cambridge, Massachusetts.
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DOI: 10.1158/2326-6066.CIR-20-0609 Published March 2021
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Abstract

ONCR-177 is an engineered recombinant oncolytic herpes simplex virus (HSV) with complementary safety mechanisms, including tissue-specific miRNA attenuation and mutant UL37 to inhibit replication, neuropathic activity, and latency in normal cells. ONCR-177 is armed with five transgenes for IL12, FLT3LG (extracellular domain), CCL4, and antagonists to immune checkpoints PD-1 and CTLA-4. In vitro assays demonstrated that targeted miRNAs could efficiently suppress ONCR-177 replication and transgene expression, as could the HSV-1 standard-of-care therapy acyclovir. Although ONCR-177 was oncolytic across a panel of human cancer cell lines, including in the presence of type I IFN, replication was suppressed in human pluripotent stem cell–derived neurons, cardiomyocytes, and hepatocytes. Dendritic cells activated with ONCR-177 tumor lysates efficiently stimulated tumor antigen–specific CD8+ T-cell responses. In vivo, biodistribution analyses suggested that viral copy number and transgene expression peaked approximately 24 to 72 hours after injection and remained primarily within the injected tumor. Intratumoral administration of ONCR-177 mouse surrogate virus, mONCR-171, was efficacious across a panel of syngeneic bilateral mouse tumor models, resulting in partial or complete tumor regressions that translated into significant survival benefits and to the elicitation of a protective memory response. Antitumor effects correlated with local and distant intratumoral infiltration of several immune effector cell types, consistent with the proposed functions of the transgenes. The addition of systemic anti–PD-1 augmented the efficacy of mONCR-171, particularly for abscopal tumors. Based in part upon these preclinical results, ONCR-177 is being evaluated in patients with metastatic cancer (ONCR-177-101, NCT04348916).

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2021;9:291–308

  • Received July 16, 2020.
  • Revision received September 25, 2020.
  • Accepted December 18, 2020.
  • Published first December 22, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Immunology Research: 9 (3)
March 2021
Volume 9, Issue 3
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ONCR-177, an Oncolytic HSV-1 Designed to Potently Activate Systemic Antitumor Immunity
Brian B. Haines, Agnieszka Denslow, Peter Grzesik, Jennifer S. Lee, Terry Farkaly, Jacqueline Hewett, Daniel Wambua, Lingxin Kong, Prajna Behera, Judith Jacques, Caitlin Goshert, Michael Ball, Allison Colthart, Mitchel H. Finer, Melissa W. Hayes, Sonia Feau, Edward M. Kennedy, Lorena Lerner and Christophe Quéva
Cancer Immunol Res March 1 2021 (9) (3) 291-308; DOI: 10.1158/2326-6066.CIR-20-0609

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ONCR-177, an Oncolytic HSV-1 Designed to Potently Activate Systemic Antitumor Immunity
Brian B. Haines, Agnieszka Denslow, Peter Grzesik, Jennifer S. Lee, Terry Farkaly, Jacqueline Hewett, Daniel Wambua, Lingxin Kong, Prajna Behera, Judith Jacques, Caitlin Goshert, Michael Ball, Allison Colthart, Mitchel H. Finer, Melissa W. Hayes, Sonia Feau, Edward M. Kennedy, Lorena Lerner and Christophe Quéva
Cancer Immunol Res March 1 2021 (9) (3) 291-308; DOI: 10.1158/2326-6066.CIR-20-0609
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