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Published on: May 25, 2022
Therapeutic potential of oncolytic Newcastle disease virus: a critical review
Shay Tayeb1, Zichria Zakay-Rones2, Amos Panet2
1Department of Biotechnology, Hadassah Academic College, Jerusalem, Israel; Department of Biochemistry and Molecular Biology, The Chanock Center for Virology, Institute of Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Abstract:
Newcastle disease virus (NDV) features a natural preference for replication in many tumor cells compared with normal cells. The observed antitumor effect of NDV appears to be a result of both selective killing of tumor cells and induction of immune responses. Genetic manipulations to change viral tropism and arming the virus with genes encoding for cytokines improved the oncolytic capacity of NDV. Several intracellular proteins in tumor cells, including antiapoptotic proteins (Livin) and oncogenic proteins (H-Ras), are relevant for the oncolytic activity of NDV. Defects in the interferon system, found in some tumor cells, also contribute to the oncolytic selectivity of NDV. Notwithstanding, NDV displays effective oncolytic activity in many tumor types, despite having intact interferon signaling. Taken together, several cellular systems appear to dictate the selective oncolytic activity of NDV. Some barriers, such as neutralizing antibodies elicited during NDV treatment and the extracellular matrix in tumor tissue appear to interfere with spread of NDV and reduce oncolysis. To further understand the oncolytic activity of NDV, we compared two NDV strains, ie, an attenuated virus (NDV-HUJ) and a pathogenic virus (NDV-MTH-68/H). Significant differences in amino acid sequence were noted in several viral proteins, including the fusion precursor (F0) glycoprotein, an important determinant of replication and pathogenicity. However, no difference in the oncolytic activity of the two strains was noted using human tumor tissues maintained as organ cultures or in mouse tumor models. To optimize virotherapy in clinical trials, we describe here a unique organ culture methodology, using a biopsy taken from a patient's tumor before treatment for ex vivo infection with NDV to determine the oncolytic potential on an individual basis. In conclusion, oncolytic NDV is an excellent candidate for cancer therapy, but more knowledge is needed to ensure success in clinical trials.
Insights
Newcastle disease virus (NDV) shows natural tumor-targeting ability, offering potential for cancer therapy. Researchers compared NDV strains and developed an ex vivo method to predict individual patient response to this promising oncolytic virus.
Area of Science:
- Virology
- Oncology
- Immunology
Background:
- Newcastle disease virus (NDV) exhibits selective replication in tumor cells over normal cells, contributing to its antitumor effects through direct cell killing and immune stimulation.
- Genetic modifications and viral protein interactions (e.g., Livin, H-Ras) enhance NDV's oncolytic capacity, while tumor cell interferon defects can increase selectivity.
- Barriers like neutralizing antibodies and the tumor extracellular matrix can impede NDV's spread and efficacy, necessitating further optimization for clinical application.
Purpose of the Study:
- To investigate the factors influencing Newcastle disease virus (NDV) selective oncolytic activity in various tumor types.
- To compare the oncolytic potential of an attenuated NDV strain (NDV-HUJ) and a pathogenic NDV strain (NDV-MTH-68/H).
- To introduce a novel ex vivo organ culture method for predicting individual patient response to NDV virotherapy.
Main Methods:
- Comparison of two NDV strains (attenuated NDV-HUJ and pathogenic NDV-MTH-68/H) for oncolytic activity.
- Utilized human tumor tissues in organ cultures and mouse tumor models to assess viral efficacy.
- Developed and validated an ex vivo organ culture technique using patient tumor biopsies for pre-treatment assessment of NDV's oncolytic potential.
Main Results:
- Despite significant amino acid differences in viral proteins like the F0 glycoprotein between NDV-HUJ and NDV-MTH-68/H, no difference in oncolytic activity was observed in organ cultures or mouse models.
- The study identified cellular systems and barriers that dictate NDV's selective oncolytic activity, highlighting the complexity of its therapeutic application.
- The developed ex vivo organ culture method demonstrated potential for personalized prediction of NDV virotherapy outcomes.
Conclusions:
- Oncolytic Newcastle disease virus (NDV) is a promising candidate for cancer treatment due to its inherent tumor-targeting properties.
- Understanding the interplay between viral strains, cellular factors, and host immune responses is crucial for maximizing NDV's therapeutic success.
- The novel ex vivo organ culture methodology offers a valuable tool for optimizing NDV virotherapy strategies in clinical trials by enabling individualized treatment assessment.
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