Optimizing Oncolytic Viral Design to Enhance Antitumor Efficacy: Progress and Challenges

Abstract

The field of oncolytic virotherapy has seen remarkable advancements in last two decades, leading to approval of the first oncolytic immuno-virotherapy, Talimogene Laherparepvec, for the treatment of melanoma. A plethora of preclinical and clinical studies have demonstrated excellent safety profiles of other oncolytic viruses. While oncolytic viruses show clinical promise in already immunogenic malignancies, response rates are inconsistent. Response rates are even less consistent in immunosuppressed tumor microenvironments like those found in liver, pancreas, and MSI-stable colon cancers. Therefore, the efficacy of oncolytic viruses needs to be improved for more oncolytic viruses to enter mainstream cancer therapy. One approach to increase the therapeutic efficacy of oncolytic viruses is to use them as primers for other immunotherapeutics. The amenability of oncolytic viruses to transgene-arming provides an immense opportunity for investigators to explore different ways of improving the outcome of oncolytic therapy. In this regard, genes encoding immunomodulatory proteins are the most commonly studied genes for arming oncolytic viruses. Other transgenes used to arm oncolytic viruses include those with the potential to favorably modulate tumor stroma, making it possible to image the virus distribution and increase its suitability for combination with other therapeutics. This review will detail the progress made in arming oncolytic viruses with a focus on immune-modulatory transgenes, and will discuss the challenges that need to be addressed for more armed oncolytic viruses to find widespread clinical use.

Talimogene Laherparepvec (T-VEC): An Intralesional Cancer Immunotherapy for Advanced Melanoma

“…Resistance by local immunosuppression has been shown to be multifactorial and caused by the recruitment of inhibitory cells [regulatory T cells (Tregs) and suppressive myeloid-type cells], the release of inhibitory soluble factors [IL-10, transforming growth factor-beta (TGF-β), and vascular endothelial growth factor (VEGF)], and the expression of inhibitory cell surface receptors (FasL, IFN-γ, PD-L1 and B7-H1) [ 56 , 57 , 58 , 59 , 60 , 61 , 62 ]. Those events are coupled with immunoediting processes occurring at a systemic level and supports the importance of monitoring the local site of tumor growth in addition to peripheral circulation [ 61 ].…”

Mesenchymal stem cells and oncolytic viruses: joining forces against cancer

“…These transgenes can exert diverse functions such as enhancing tumor tropism and penetration, increasing viral potency, promoting cell death, and antiangiogenesis, and modulating antitumor immunity, among others. [2][3][4] To date, engineered OVs from more than 10 different viral families have been evaluated in phase I-III clinical trials, demonstrating favorable safety profiles. However, while local OVs administration has shown promising results in melanoma patients, systemic OVs administration has reported only occasional and transient responses.…”

The Strategy of Conditionally Replicating Adenovirus-Mediated PreS2 Mini-Antibody Expression Has Dual Effects of Inhibiting HBV Infection and Preventing Hepatocellular Carcinoma

“…The advantage of oncolytic viruses is that they can not only dissolve cancer cells but also express therapeutic genes carried by viral vectors more effectively. [15][16][17] Moreover, oncolytic viruses can improve the microenvironment of tumor immunosuppression as a sensitizer to immunotherapy. 18 Therefore, we went with flow cytometry and constructed our conditionally replicating adenovirus with the mPreS2 gene mediated by the human survivin promoter, and its targeting and accuracy were confirmed in previous studies.…”