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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Immunomodulatory Arming Factors-The Current Paradigm for Oncolytic Vectors Relies on Immune Stimulating Molecules
Cole W D Peters1, Fares Nigim2,3
1Pediatric Hematology-Oncology, Los Angeles School of Medicine, University of California, Los Angeles, CA 90024, USA.
Abstract:
The dogma of engineering oncolytic viral vectors has shifted from emphasizing the viral lysis of individual cancer cells to the recruitment and coordination of the adaptive immune system to clear the tumor. To accomplish this, researchers have been adding several classes of transgenes to their preferred viral platforms. The most prevalent of these include antibodies and targeting moieties, interleukins and cytokines, and genes which rely on small molecule co-administration for tumor killing. Most current vectors rely exclusively on one of these types of transgenes to elicit the desired immune response to clear tumors, but are not mutually exclusive, with several larger OVs armed with several of these factors. The common theme of emerging armed vectors is to simply initiate or enhance infiltration of effector CD8+ T cells to clear the tumor locally at OV infection sites, and systemically throughout the body where the OV has not infected tumor cells. The precision of oncolytic vectors to target a cell type or tissue remains its key advantage over small-molecule drugs. Unlike chemo- and other drug therapies, viral vectors can be made to specifically infect and grow within tumor cells. This ensures localized expression of the therapeutic transgene to the diseased tissue, thereby limiting systemic toxicity. This review will examine the immunomodulating transgenes of current OVs, describe their general effect on the immune system, and provide the rationale for each vector's use in clearing its targeted tumor.
Insights
Engineered oncolytic viruses (OVs) now focus on immune system coordination, not just cell lysis. These armed OVs use transgenes to enhance CD8+ T cell responses for effective tumor clearance.
Area of Science:
- Oncology
- Immunotherapy
- Viral Vector Engineering
Background:
- The engineering of oncolytic viruses (OVs) has evolved from direct cancer cell lysis to leveraging the adaptive immune system for tumor eradication.
- Current OVs are engineered with transgenes such as antibodies, cytokines, and small molecule-activated genes to stimulate an anti-tumor immune response.
Purpose of the Study:
- To review immunomodulating transgenes used in current oncolytic viruses.
- To describe the immune effects of these transgenes and their rationale for tumor clearance.
- To highlight the advantages of OV precision targeting and localized transgene expression over traditional therapies.
Main Methods:
- Review of current literature on armed oncolytic viruses and their transgene payloads.
- Analysis of the mechanisms by which transgenes modulate the immune system.
- Examination of the strategic use of different transgene classes in OV design.
Main Results:
- Armed OVs commonly incorporate transgenes to enhance effector CD8+ T cell infiltration and activity, both locally and systemically.
- The precision of OVs allows for targeted transgene expression within tumor tissues, minimizing systemic toxicity.
- Various transgene strategies, including antibodies, cytokines, and co-administered drugs, are employed to elicit anti-tumor immunity.
Conclusions:
- Oncolytic viruses engineered with immunomodulating transgenes represent a promising strategy for cancer immunotherapy.
- The targeted delivery and localized expression of therapeutic agents by OVs offer a significant advantage in reducing side effects.
- Future directions involve combining multiple transgene types to optimize immune responses for comprehensive tumor eradication.
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