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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo

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Published on: January 7, 2019

Improving cancer immunotherapy by rationally combining oncolytic virus with modulators targeting key signaling

Zhi Zhu^1,2,3, A J Robert McGray⁴, Weijian Jiang⁴

¹UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

Molecular Cancer

|October 11, 2022

Abstract:

Oncolytic viruses (OVs) represent a new class of multi-modal immunotherapies for cancer, with OV-elicited antitumor immunity being key to their overall therapeutic efficacy. Currently, the clinical effectiveness of OV as monotherapy remains limited, and thus investigators have been exploring various combinations with other anti-cancer agents and demonstrated improved therapeutic efficacy. As cancer cells have evolved to alter key signaling pathways for enhanced cell proliferation, cancer progression and metastasis, these cellular and molecular changes offer promising targets for rational cancer therapy design. In this regard, key molecules in relevant signaling pathways for cancer cells or/and immune cells, such as EGFR-KRAS (e.g., KRAS^G12C), PI3K-AKT-mTOR, ERK-MEK, JAK-STAT, p53, PD-1-PD-L1, and epigenetic, or immune pathways (e.g., histone deacetylases, cGAS-STING) are currently under investigation and have the potential to synergize with OV to modulate the immune milieu of the tumor microenvironment (TME), thereby improving and sustaining antitumor immunity. As many small molecule modulators of these signaling pathways have been developed and have shown strong therapeutic potential, here we review key findings related to both OV-mediated immunotherapy and the utility of small molecule modulators of signaling pathways in immuno-oncology. Then, we focus on discussion of the rationales and potential strategies for combining OV with selected modulators targeting key cellular signaling pathways in cancer or/and immune cells to modulate the TME and enhance antitumor immunity and therapeutic efficacy. Finally, we provide perspectives and viewpoints on the application of novel experimental systems and technologies that can propel this exciting branch of medicine into a bright future.

Insights

Oncolytic viruses (OVs) show promise in cancer immunotherapy, but monotherapy is limited. Combining OVs with small molecule pathway modulators can enhance antitumor immunity and improve cancer treatment efficacy.

Area of Science:

Oncology
Immunology
Pharmacology

Background:

Oncolytic viruses (OVs) are a novel class of cancer immunotherapies.
OV therapeutic efficacy relies on eliciting antitumor immunity.
Current OV monotherapy effectiveness is limited, necessitating combination strategies.

Purpose of the Study:

To review OV-mediated immunotherapy and small molecule modulators in immuno-oncology.
To discuss rationales and strategies for combining OVs with signaling pathway modulators.
To explore enhancing antitumor immunity and therapeutic efficacy by modulating the tumor microenvironment (TME).

Main Methods:

Review of key findings on OV immunotherapy.
Analysis of small molecule modulators targeting cancer and immune cell signaling pathways.
Discussion of combination strategies for OV and small molecule modulators.

Main Results:

Cancer cells exploit signaling pathways (e.g., EGFR-KRAS, PI3K-AKT-mTOR, JAK-STAT) for proliferation and metastasis.
Small molecule modulators of these pathways show therapeutic potential.
Combinations of OVs with modulators can synergize to enhance antitumor immunity by modulating the TME.

Conclusions:

Combining oncolytic viruses with targeted small molecule therapies offers a promising strategy to overcome limitations in cancer treatment.
Modulating key cellular signaling pathways can enhance the anti-tumor immune response within the tumor microenvironment.
Future research utilizing novel systems and technologies will advance this field of cancer immunotherapy.

Read full analysis

Keywords:

Antitumor immunity Combination regimen Efficacy Immuno-oncology Inhibitor Oncolytic virus Signaling pathway Small molecule Targeted therapy

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