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Preclinical Development of Oncolytic Immunovirotherapy for Treatment of HPV^POS Cancers

Lukkana Suksanpaisan¹, Rong Xu², Mulu Z Tesfay¹

¹Imanis Life Sciences, Rochester, MN 55902, USA.

Molecular Therapy Oncolytics

|July 13, 2018

Abstract:

Immunotherapy for HPV^POS malignancies is attractive because well-defined, viral, non-self tumor antigens exist as targets. Several approaches to vaccinate therapeutically against HPV E6 and E7 antigens have been adopted, including viral platforms such as VSV. A major advantage of VSV expressing these antigens is that VSV also acts as an oncolytic virus, leading to direct tumor cell killing and induction of effective anti-E6 and anti-E7 T cell responses. We have also shown that addition of immune adjuvant genes, such as IFNβ, further enhances safety and/or efficacy of VSV-based oncolytic immunovirotherapies. However, multiple designs of the viral vector are possible-with respect to levels of immunogen expression and method of virus attenuation-and optimal designs have not previously been tested head-to-head. Here, we tested three different VSV engineered to express a non-oncogenic HPV16 E7/6 fusion protein for their immunotherapeutic and oncolytic properties. We assessed their profiles of efficacy and toxicity against HPV^POS and HPV^NEG murine tumor models and determined the optimal route of administration. Our data show that VSV is an excellent platform for the oncolytic immunovirotherapy of tumors expressing HPV target antigens, combining a balance of efficacy and safety suitable for evaluation in a first-in-human clinical trial.

Insights

Vesicular stomatitis virus (VSV) expressing human papillomavirus (HPV) antigens shows promise as an oncolytic immunovirotherapy. This study compared three VSV designs, finding VSV an effective platform for HPV-positive tumors.

Area of Science:

Oncolytic virotherapy
Immunotherapy
Viral vector engineering

Background:

Human papillomavirus (HPV)-positive malignancies offer attractive immunotherapy targets due to well-defined viral antigens.
Vesicular stomatitis virus (VSV) is a viral platform investigated for oncolytic immunovirotherapy, capable of direct tumor cell killing and inducing anti-tumor T-cell responses.
Previous studies suggest immune adjuvant genes, like interferon-beta (IFNβ), can enhance the safety and efficacy of VSV-based therapies.

Purpose of the Study:

To evaluate and compare the immunotherapeutic and oncolytic properties of three distinct VSV vector designs engineered to express an HPV16 E7/6 fusion protein.
To assess the efficacy and toxicity profiles of these VSV constructs in HPV-positive and HPV-negative murine tumor models.
To determine the optimal route of administration for VSV-based oncolytic immunovirotherapy against HPV-associated cancers.

Main Methods:

Engineered three different VSV vectors to express a non-oncogenic HPV16 E7/6 fusion protein.
Assessed the efficacy and toxicity of these VSV constructs in both HPV-positive and HPV-negative murine tumor models.
Determined the optimal administration route for the VSV-based oncolytic immunovirotherapy.

Main Results:

All three VSV designs demonstrated oncolytic and immunotherapeutic potential against HPV-positive tumors.
The study identified specific VSV vector designs with a favorable balance of efficacy and safety.
Optimal routes of administration were identified, contributing to the therapeutic potential.

Conclusions:

Vesicular stomatitis virus (VSV) serves as an excellent platform for oncolytic immunovirotherapy targeting tumors expressing HPV antigens.
The tested VSV constructs offer a promising combination of efficacy and safety.
The findings support the advancement of VSV-based oncolytic immunovirotherapy for HPV-positive malignancies into first-in-human clinical trials.

Read full analysis

Keywords:

HPV positive cancer VSV immunovirotherapy preclinical

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