Engineering vaccinia virus as an immunotherapeutic battleship to overcome tumor heterogeneity

Pelin, Adrian; Boulton, Stephen; Tamming, Levi; Bell, John C.; Singaravelu, Ragunath

doi:10.1080/14712598.2020.1757066

Cited by 17 publications

(21 citation statements)

References 165 publications

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“…Infectious disease vaccines were repurposed for cancer immunotherapy owing to their abilities to induce potent antitumor immune responses 44 . Replication-competent oncolytic viruses are among these vaccines and can exert antitumor responses beyond their oncolytic nature, especially when these viruses were armed with genes such as cytokines, chemokines, and costimulatory molecules in order to augment antitumor immunity 5 , 7 , 9 - 11 . Thus, oncolytic virus can be applied as a cancer immunotherapy approach either alone or in combination with other cancer immunotherapies 13 , 14 .…”

Section: Discussionmentioning

confidence: 99%

“…This antitumor immune reactivity results in the infiltration of diverse immune cells, including T lymphocytes, into the TME 5 , 6 . Oncolytic viruses have positive effects on almost every aspect of the cancer-immunity cycle and can be further armed with chemokines, cytokines, or other molecules to modulate the TME so as to harness the immune system to attack and treat tumors 7 - 11 . Thus, oncolytic viral therapy falls into either of the two broad categories of immunotherapy approaches: direct approaches which primarily modify the tumor cells itself; indirect approaches predominately targeting the TME 12 .…”

Section: Introductionmentioning

confidence: 99%

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Intratumoral expression of interleukin 23 variants using oncolytic vaccinia virus elicit potent antitumor effects on multiple tumor models via tumor microenvironment modulation

Chen¹,

Chen²,

Ye³

et al. 2021

Theranostics

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Background: Newly emerging cancer immunotherapy has led to significant progress in cancer treatment; however, its efficacy is limited in solid tumors since the majority of them are “cold” tumors. Oncolytic viruses, especially when properly armed, can directly target tumor cells and indirectly modulate the tumor microenvironment (TME), resulting in “hot” tumors. These viruses can be applied as a cancer immunotherapy approach either alone or in combination with other cancer immunotherapies. Cytokines are good candidates to arm oncolytic viruses. IL-23, an IL-12 cytokine family member, plays many roles in cancer immunity. Here, we used oncolytic vaccinia viruses to deliver IL-23 variants into the tumor bed and explored their activity in cancer treatment on multiple tumor models. Methods: Oncolytic vaccinia viruses expressing IL-23 variants were generated by homologue recombination. The characteristics of these viruses were in vitro evaluated by RT-qPCR, ELISA, flow cytometry and cytotoxicity assay. The antitumor effects of these viruses were evaluated on multiple tumor models in vivo and the mechanisms were investigated by RT-qPCR and flow cytometry. Results: IL-23 prolonged viral persistence, probably mediated by up-regulated IL-10. The sustainable IL-23 expression and viral oncolysis elevated the expression of Th1 chemokines and antitumor factors such as IFN-γ, TNF-α, Perforin, IL-2, Granzyme B and activated T cells in the TME, transforming the TME to be more conducive to antitumor immunity. This leads to a systemic antitumor effect which is dependent on CD8 + and CD4 + T cells and IFN-γ. Oncolytic vaccinia viruses could not deliver stable IL-23A to the tumor, attributed to the elevated tristetraprolin which can destabilize the IL-23A mRNA after the viral treatment; whereas vaccinia viruses could deliver membrane-bound IL-23 to elicit a potent antitumor effect which might avoid the possible toxicity normally associated with systemic cytokine exposure. Conclusion: Either secreted or membrane-bound IL-23-armed vaccinia virus can induce potent antitumor effects and IL-23 is a candidate cytokine to arm oncolytic viruses for cancer immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intratumoral expression of interleukin 23 variants using oncolytic vaccinia virus elicit potent antitumor effects on multiple tumor models via tumor microenvironment modulation

Chen¹,

Chen²,

Ye³

et al. 2021

Theranostics

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“…For example, VSV glycoprotein G has been substituted with a glycoprotein variant of lymphocytic choriomeningitis virus (LCMV) for selective replication in cancer cells [ 76 ]. Similarly, mutation or deletion in the thymidine kinase (TK) gene in HSV-1 and VACV and deleting E1B55K in oncolytic adenovirus ONYX-015 allowed selective replication in cancer cells [ 77 , 78 ]. (iii) Arming OVs with immunostimulatory cytokines and chemokines.…”

Section: Engineered Oncolytic Virusesmentioning

confidence: 99%

Oncolytic Viruses: Newest Frontier for Cancer Immunotherapy

Rahman

McFadden

2021

Cancers

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Cancer remains a leading cause of death worldwide. Despite many signs of progress, currently available cancer treatments often do not provide desired outcomes for too many cancers. Therefore, newer and more effective therapeutic approaches are needed. Oncolytic viruses (OVs) have emerged as a novel cancer treatment modality, which selectively targets and kills cancer cells while sparing normal ones. In the past several decades, many different OV candidates have been developed and tested in both laboratory settings as well as in cancer patient clinical trials. Many approaches have been taken to overcome the limitations of OVs, including engineering OVs to selectively activate anti-tumor immune responses. However, newer approaches like the combination of OVs with current immunotherapies to convert “immune-cold” tumors to “immune-hot” will almost certainly improve the potency of OVs. Here, we discuss strategies that are explored to further improve oncolytic virotherapy.

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“…Incredibly, most of the vaccinia virus genome's products are still yet to be studied in depth to ascertain their function. However, similar to HSV vectors with hinge region deletions, there are VACVs with large core regions of their genome completely removed, allowing multiple arming genes to be inserted (reviewed in [17,18]).…”

Section: Oncolytic Virusesmentioning

confidence: 99%

Immunomodulatory Arming Factors—The Current Paradigm for Oncolytic Vectors Relies on Immune Stimulating Molecules

Peters

Nigim

2021

IJMS

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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.

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Engineering vaccinia virus as an immunotherapeutic battleship to overcome tumor heterogeneity

Cited by 17 publications

References 165 publications

Intratumoral expression of interleukin 23 variants using oncolytic vaccinia virus elicit potent antitumor effects on multiple tumor models via tumor microenvironment modulation

Intratumoral expression of interleukin 23 variants using oncolytic vaccinia virus elicit potent antitumor effects on multiple tumor models via tumor microenvironment modulation

Oncolytic Viruses: Newest Frontier for Cancer Immunotherapy

Immunomodulatory Arming Factors—The Current Paradigm for Oncolytic Vectors Relies on Immune Stimulating Molecules

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