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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Virotherapy, gene transfer and immunostimulatory monoclonal antibodies
José I Quetglas1, Liza B John, Michael H Kershaw
1Division of Hepatology and Gene Therapy; Center for Applied Medical Research; University of Navarra; Pamplona, Spain.
Abstract:
Malignant cells are susceptible to viral infection and consequent cell death. Virus-induced cell death is endowed with features that are known to stimulate innate and adaptive immune responses. Thus danger signals emitted by cells succumbing to viral infection as well as viral nucleic acids are detected by specific receptors, and tumor cell antigens can be routed to professional antigen-presenting cells. The anticancer immune response triggered by viral infection is frequently insufficient to eradicate malignancy but may be further amplified. For this purpose, transgenes encoding cytokines as co-stimulatory molecules can be genetically engineered into viral vectors. Alternatively, or in addition, it is possible to use monoclonal antibodies that either block inhibitory receptors of immune effector cells, or act as agonists for co-stimulatory receptors. Combined strategies are based on the ignition of a local immune response at the malignant site plus systemic immune boosting. We have recently reported examples of this approach involving the Vaccinia virus or Semliki Forest virus, interleukin-12 and anti-CD137 monoclonal antibodies.
Insights
Viruses can trigger immune responses against cancer by inducing cell death and danger signals. Combining viral therapy with immune-boosting agents like cytokines and antibodies enhances anti-tumor immunity.
Area of Science:
- Oncology
- Immunology
- Virology
Background:
- Malignant cells can be targeted by viral infections, leading to cell death.
- Virus-induced cell death releases danger signals and tumor antigens, activating innate and adaptive immune responses.
- Current viral oncolytic strategies often require amplification to effectively eradicate tumors.
Purpose of the Study:
- To explore strategies for amplifying virus-induced anticancer immune responses.
- To investigate the potential of genetically engineered viral vectors and monoclonal antibodies in cancer immunotherapy.
- To combine local immune stimulation with systemic immune boosting for enhanced anti-tumor effects.
Main Methods:
- Utilizing viral vectors engineered with transgenes encoding cytokines (e.g., interleukin-12) for co-stimulation.
- Employing monoclonal antibodies to modulate immune effector cells by blocking inhibitory receptors or activating co-stimulatory receptors (e.g., anti-CD137).
- Implementing combined strategies involving oncolytic viruses (Vaccinia virus, Semliki Forest virus) and immunomodulatory agents.
Main Results:
- Virus infection of malignant cells initiates immune responses through danger signals and antigen presentation.
- Genetically engineered viral vectors can enhance immune responses by delivering co-stimulatory molecules.
- Monoclonal antibodies targeting immune checkpoints or co-stimulatory receptors can further augment anti-tumor immunity.
- Combined approaches involving oncolytic viruses and immunotherapy show promise in amplifying local and systemic anti-cancer immunity.
Conclusions:
- Virus-mediated oncolysis can be harnessed to stimulate anticancer immune responses.
- Genetic engineering of viral vectors and use of immunomodulatory antibodies are effective strategies to amplify these responses.
- Combined therapeutic approaches integrating oncolysis, cytokine delivery, and immune checkpoint modulation offer a promising avenue for cancer immunotherapy.
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