Oncolytic vaccinia virus delivering tethered IL-12 enhances antitumor effects with improved safety

Ge, Yan; Wang, Haiyan; Ren, Jinghua; Li, Weilin; Chen, Lingjuan; Chen, Hongqi; Ye, Junjie; Dai, Enyong; Ma, Congrong; Ju, Songguang; Guo, Zong Sheng; Liu, Zuqiang; Bartlett, David L.

doi:10.1136/jitc-2020-000710

Cited by 57 publications

(49 citation statements)

References 30 publications

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“…In this regard, combining PD‐1 blockade with SIRPα‐Fc seems particular promising based on the recent finding that TAMs express high levels of PD‐1 57 . In addition, inserting cytokine genes such as IL‐12 or IL‐15 could change the immunosuppressive tumor microenvironment into a pro‐inflammatory environment bolstering the effect of SIRPα‐Fc 58,59 …”

Section: Discussionmentioning

confidence: 99%

Engineering oncolytic vaccinia virus to redirect macrophages to tumor cells

et al. 2020

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Oncolytic virotherapy has been tested in numerous early phase clinical studies. However, the antitumor activity of oncolytic viruses thus far has been limited. Numerous strategies are being explored to enhance their antitumor activity by activating the adaptive arm of the immune system. We reasoned that it might also be possible to engineer oncolytic viruses to redirect tumor‐associated macrophages to tumor cells for therapeutic benefit. We engineered an oncolytic vaccinia virus (VV) to disrupt the CD47/SIRPα interaction by expressing a chimeric molecule that consists of the ectodomain of SIRPα and the Fc domain of IgG4 (SIRPα‐Fc‐VV). SIRPα‐Fc‐VV readily replicated in tumor cells and redirected M1 as well as M2 macrophages to tumor cells in vitro. In contrast, control VVs that either encoded YFP (YFP‐VV) or SIRPα (SIRPα‐VV) did not. In vivo, SIRPα‐Fc‐VV had greater antitumor activity than YFP‐VV and SIRPα‐VV in an immune competent osteosarcoma model resulting in a significant survival advantage. Pretreatment with cytoxan further augmented the antitumor activity of SIRPα‐Fc‐VV. Thus, arming oncolytic viruses with SIRPα‐Fc may present a promising strategy to enhance their antitumor activity for the virotherapy of solid tumors.

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Section: Discussionmentioning

confidence: 99%

Engineering oncolytic vaccinia virus to redirect macrophages to tumor cells

et al. 2020

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“…38 In addition, studies that augment the OV's function via cytokine and chemokine coexpression have been reported. Ge et al 40 showed that OV delivering tethered IL-12 was able to avoid systemic toxicity and cure all mice with late-stage colon cancer, by facilitating T-cell infiltration, increasing IFN-c and decreasing suppressive factor TGF-b in the tumor.…”

Section: Oncolytic Viruses/bacteriamentioning

confidence: 99%

Therapeutic strategies to remodel immunologically cold tumors

Wang

Desai

et al. 2020

Clin & Trans Imm

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Immune checkpoint inhibitors (ICIs) induce a durable response in a wide range of tumor types, but only a minority of patients outside these ‘responsive’ tumor types respond, with some totally resistant. The primary predictor of intrinsic immune resistance to ICIs is the complete or near‐complete absence of lymphocytes from the tumor, so‐called immunologically cold tumors. Here, we propose two broad approaches to convert ‘cold’ tumors into ‘hot’ tumors. The first is to induce immunogenic tumor cell death, through the use of oncolytic viruses or bacteria, conventional cancer therapies (e.g. chemotherapy or radiation therapy) or small molecule drugs. The second approach is to target the tumor microenvironment, and covers diverse options such as depleting immune suppressive cells; inhibiting transforming growth factor‐beta; remodelling the tumor vasculature or hypoxic environment; strengthening the infiltration and activation of antigen‐presenting cells and/or effector T cells in the tumor microenvironment with immune modulators; and enhancing immunogenicity through personalised cancer vaccines. Strategies that successfully modify cold tumors to overcome their resistance to ICIs represent mechanistically driven approaches that will ultimately result in rational combination therapies to extend the clinical benefits of immunotherapy to a broader cancer cohort.

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“…Consequently, the IL-12-armed oncolytic HSV-1 resulted in better survival compared to the unarmed virus. Ge et al studied the safety and antitumor efficacy of an oncolytic vaccinia virus encoding a membrane-bound version of IL-12 [61]. The virus was found to convert an immunologically "cold" tumor into a "hot" one, and to increase the survival of mice bearing syngeneic colon tumors.…”

Section: Interleukin-12mentioning

confidence: 99%

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

Chaurasiya

Fong

Warner

2020

Cancers

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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.

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Oncolytic vaccinia virus delivering tethered IL-12 enhances antitumor effects with improved safety

Cited by 57 publications

References 30 publications

Engineering oncolytic vaccinia virus to redirect macrophages to tumor cells

Engineering oncolytic vaccinia virus to redirect macrophages to tumor cells

Therapeutic strategies to remodel immunologically cold tumors

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

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