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

Brian B Haines1, Agnieszka Denslow2, Peter Grzesik2

  • 1Oncorus, Inc., Cambridge, Massachusetts. brian.haines@oncorus.com.

Cancer Immunology Research
|December 23, 2020
PubMed

Insights

ONCR-177, an engineered oncolytic herpes simplex virus (HSV), demonstrates potent anti-cancer activity and safety in preclinical models. This therapy shows promise for metastatic cancer by stimulating immune responses and tumor regression.

Area of Science:

  • Oncology
  • Virology
  • Immunotherapy

Background:

  • Oncolytic viruses are engineered to selectively infect and kill cancer cells while sparing normal tissues.
  • Herpes simplex virus (HSV) is a common platform for oncolytic virotherapy due to its large genome capacity for genetic modification.
  • Developing oncolytic viruses with enhanced safety profiles and potent anti-tumor immune stimulation is crucial for clinical translation.

Purpose of the Study:

  • To evaluate the safety and efficacy of ONCR-177, an engineered oncolytic HSV, in preclinical cancer models.
  • To assess the immune-stimulating properties and biodistribution of ONCR-177.
  • To investigate the potential of ONCR-177 as a therapeutic agent for metastatic cancer.

Main Methods:

  • ONCR-177 was engineered with safety features including tissue-specific miRNA attenuation and a mutant UL37 gene.
  • Transgenes encoding IL12, FLT3LG, CCL4, and immune checkpoint antagonists (PD-1, CTLA-4) were incorporated into ONCR-177.
  • In vitro studies assessed viral replication in cancer cells and normal cells, as well as immune cell activation.
  • In vivo studies utilized a mouse surrogate virus (mONCR-171) in syngeneic tumor models to evaluate efficacy, survival, and immune responses.

Main Results:

  • ONCR-177 demonstrated oncolytic activity in human cancer cell lines while replication was suppressed in normal cells (neurons, cardiomyocytes, hepatocytes).
  • mONCR-171 treatment led to significant tumor regression, survival benefits, and protective memory responses in mouse models.
  • Antitumor effects correlated with immune cell infiltration, and combination with anti-PD-1 therapy enhanced efficacy, particularly for abscopal tumors.
  • Biodistribution studies showed viral presence primarily within the injected tumor with peak expression at 24-72 hours.

Conclusions:

  • ONCR-177 possesses a favorable safety profile with suppressed replication in normal tissues.
  • The engineered oncolytic virus effectively stimulates anti-tumor immune responses and mediates significant tumor regression.
  • Preclinical data support the ongoing clinical evaluation of ONCR-177 for patients with metastatic cancer.

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