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Updated: Jul 28, 2025
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Innovative retargeted oncolytic herpesvirus against nectin4-positive cancers
Andrea Vannini1,2, Federico Parenti1, Cristina Forghieri1
1Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy.
Abstract:
Nectin4 is a recently discovered tumor associated antigen expressed in cancers that constitute relevant unmet clinical needs, including the undruggable triple negative breast cancer, pancreatic ductal carcinoma, bladder/urothelial cancer, cervical cancer, lung carcinoma and melanoma. So far, only one nectin4-specific drug-Enfortumab Vedotin-has been approved and the clinical trials that test novel therapeutics are only five. Here we engineered R-421, an innovative retargeted onco-immunotherapeutic herpesvirus highly specific for nectin4 and unable to infect through the natural herpes receptors, nectin1 or herpesvirus entry mediator. In vitro, R-421 infected and killed human nectin4-positive malignant cells and spared normal cells, e.g., human fibroblasts. Importantly from a safety viewpoint, R-421 failed to infect malignant cells that do not harbor nectin4 gene amplification/overexpression, whose expression level was moderate-to-low. In essence, there was a net threshold value below which cells were spared from infection, irrespective of whether they were malignant or normal; the only cells that R-421 targeted were the malignant overexpressing ones. In vivo, R-421 decreased or abolished the growth of murine tumors made transgenic for human nectin4 and conferred sensitivity to immune checkpoint inhibitors in combination therapies. Its efficacy was augmented by the cyclophosphamide immunomodulator and decreased by depletion of CD8-positive lymphocytes, arguing that it was in part T cell-mediated. R-421 elicited in-situ vaccination that protected from distant challenge tumors. This study provides proof-of-principle specificity and efficacy data justifying nectin4-retargeted onco-immunotherapeutic herpesvirus as an innovative approach against a number of difficult-to-drug clinical indications.
Insights
A novel onco-immunotherapeutic herpesvirus, R-421, specifically targets Nectin4-expressing cancer cells, sparing normal cells. This engineered virus shows promise in reducing tumor growth and enhancing immunotherapy efficacy in preclinical models.
Area of Science:
- Oncology
- Virology
- Immunotherapy
Background:
- Nectin4 is a tumor antigen overexpressed in difficult-to-treat cancers like triple-negative breast cancer and pancreatic cancer.
- Current Nectin4-targeted therapies are limited, with only one approved drug and few ongoing clinical trials.
- There is a significant unmet need for novel therapeutics against Nectin4-positive malignancies.
Purpose of the Study:
- To engineer and evaluate a novel Nectin4-specific onco-immunotherapeutic herpesvirus (R-421).
- To assess the safety and efficacy of R-421 in vitro and in vivo models.
- To determine the therapeutic potential of R-421 as a standalone treatment and in combination therapies.
Main Methods:
- Engineered a herpesvirus (R-421) with high specificity for Nectin4, avoiding natural herpesvirus entry receptors.
- Evaluated R-421's infectivity and cytolytic activity against Nectin4-positive cancer cells versus normal cells in vitro.
- Assessed R-421's anti-tumor efficacy, safety, and immune-mediated effects in murine tumor models.
- Investigated R-421's potential in combination with immune checkpoint inhibitors and cyclophosphamide.
Main Results:
- R-421 selectively infected and killed Nectin4-positive malignant cells in vitro, sparing normal cells and Nectin4-low expressing malignant cells.
- In vivo, R-421 significantly reduced or abolished tumor growth in Nectin4-transgenic murine models.
- R-421 demonstrated synergistic effects with immune checkpoint inhibitors and cyclophosphamide, indicating T cell-mediated activity.
- R-421 induced in situ vaccination, providing protection against distant tumor challenges.
Conclusions:
- R-421 represents a highly specific and effective Nectin4-retargeted onco-immunotherapeutic herpesvirus.
- This approach offers a promising innovative strategy against multiple difficult-to-drug cancers.
- The findings support further development of R-421 for clinical applications in Nectin4-positive cancers.
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