Vaccinia Virus Shuffling: deVV5, a Novel Chimeric Poxvirus with Improved Oncolytic Potency

Ricordel, Marine; Foloppe, Johann; Antoine, D; Findeli, Annie; Kempf, Juliette; Cordier, Pascale; Gerbaud, Aude; Grellier, Benoit; Lusky, Monika; Quéméneur, Éric; Erbs, Philippe

doi:10.3390/cancers10070231

Cited by 19 publications

(14 citation statements)

References 37 publications

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“…The Copenhagen strain of VACV was originally used as a smallpox vaccine in Denmark and the Netherlands. Probably due to variations in the expression or functionality of different virulence genes between strains, in vitro and in vivo preclinical studies have recently shown that the Copenhagen strain has a more potent oncolytic viral activity against human tumor cells than the Wyeth and the WR strains,46, 47 the original strains of oncolytic VACVs that are currently in clinic. These results suggest that Copenhagen-based VACV should be more effective at controlling tumor growth in the clinic.…”

Section: Discussionmentioning

confidence: 99%

The Enhanced Tumor Specificity of TG6002, an Armed Oncolytic Vaccinia Virus Deleted in Two Genes Involved in Nucleotide Metabolism

Foloppe

Kempf

Futin

et al. 2019

Molecular Therapy - Oncolytics

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103

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Oncolytic vaccinia viruses are currently in clinical development. However, the safety and the tumor selectivity of these oncolytic viruses must be improved. We previously constructed a first-generation oncolytic vaccinia virus by expressing the suicide gene FCU1 inserted in the J2R locus that encodes thymidine kinase. We demonstrated that the combination of this thymidine-kinase-deleted vaccinia virus and the FCU1/5-fluocytosine system is a potent vector for cancer therapy. Here, we developed a second generation of vaccinia virus, named TG6002, expressing FCU1 and with targeted deletions of the J2R gene and the I4L gene, which encodes the large subunit of the ribonucleotide reductase. Compared to the previously used single thymidine-kinase-deleted vaccinia virus, TG6002 is highly attenuated in normal cells, yet it displays tumor-selective replication and tumor cell killing. TG6002 replication is highly dependent on cellular ribonucleotide reductase levels and is less pathogenic than the single-deleted vaccinia virus. Tumor-selective viral replication, prolonged therapeutic levels of 5-fluorouracil in tumors, and significant antitumor effects were observed in multiple human xenograft tumor models after systemic injection of TG6002 and 5-fluorocytosine. TG6002 displays a convincing safety profile and is a promising candidate for treatment of cancer in humans.

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Section: Discussionmentioning

confidence: 99%

The Enhanced Tumor Specificity of TG6002, an Armed Oncolytic Vaccinia Virus Deleted in Two Genes Involved in Nucleotide Metabolism

Foloppe

Kempf

Futin

et al. 2019

Molecular Therapy - Oncolytics

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103

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“…All poxviruses used were wild type and have been described in detail in Ricordel et al (17, 35, 36), except for the vaccinia viruses of Copenhagen strain that were either wild type, doubly deleted of thymidine kinase and ribonucleotide reductase (TK − RR − ), or triply deleted of TK, RR, and M2L (TK − RR − M2L − ). Modified vaccinia virus Ankara (MVA) was also used in some experiments.…”

Section: Methodsmentioning

confidence: 99%

By Binding CD80 and CD86, the Vaccinia Virus M2 Protein Blocks Their Interactions with both CD28 and CTLA4 and Potentiates CD80 Binding to PD-L1

Kleinpeter

Remy-Ziller

Winter

et al. 2019

J Virol

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In this article we report that the M2 protein encoded by the vaccinia virus is secreted as a homo-oligomer by infected cells and binds two central costimulation molecules, CD80 (B7-1) and CD86 (B7-2). These interactions block the ligation of the two B7 proteins to both soluble CD28 and soluble cytotoxic T-lymphocyte associated protein 4 (CTLA4) but favor the binding of soluble PD-L1 to soluble CD80. M2L gene orthologues are found in several other poxviruses, and the B7-CD28/CTLA4 blocking activity has been identified for several culture supernatants of orthopoxvirus-infected cells and for a recombinant myxoma virus M2 protein homolog (i.e., Gp120-like protein, or Gp120LP). Overall, these data indicate that the M2 poxvirus family of proteins may be involved in immunosuppressive activities broader than the NF-κB inhibition already reported (R. Gedey, X. L. Jin, O. Hinthong, and J. L. Shisler, J Virol 80:8676–8685, 2006, https://doi.org/10.1128/JVI.00935-06). A Copenhagen vaccinia virus with a deletion of the nonessential M2L locus was generated and compared with its parental virus. This M2L-deleted vaccinia virus, unlike the parental virus, does not generate interference with the B7-CD28/CTLA4/PD-L1 interactions. Moreover, this deletion did not affect any key features of the virus (in vitro replication, oncolytic activities in vitro and in vivo, and intratumoral expression of a transgene in an immunocompetent murine model). Altogether, these first results suggest that the M2 protein has the potential to be used as a new immunosuppressive biotherapeutic and that the M2L-deleted vaccinia virus represents an attractive new oncolytic platform with an improved immunological profile. IMPORTANCE The vaccinia virus harbors in its genome several genes dedicated to the inhibition of the host immune response. Among them, M2L was reported to inhibit the intracellular NF-κB pathway. We report here several new putative immunosuppressive activities of M2 protein. M2 protein is secreted and binds cornerstone costimulatory molecules (CD80/CD86). M2 binding to CD80/CD86 blocks their interaction with soluble CD28/CTLA4 but also favors the soluble PD-L1-CD80 association. These findings open the way for new investigations deciphering the immune system effects of soluble M2 protein. Moreover, a vaccinia virus with a deletion of its M2L has been generated and characterized as a new oncolytic platform. The replication and oncolytic activities of the M2L-deleted vaccinia virus are indistinguishable from those of the parental virus. More investigations are needed to characterize in detail the immune response triggered against both the tumor and the virus by this M2-defective vaccinia virus.

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“…Another interesting strategy is to generate novel chimeric poxviruses via homologous recombination of different strains of VV or poxviruses or by natural selection in cancer cells themselves. Erbs and associates mixed four strains of VVs and generated deVV5, a novel chimeric poxvirus with improved oncolytic potency in human cancer cells [113]. Chen and colleagues generated another virus, CF189, by mixing different species of poxviruses; yielding a chimeric OV that is therapeutically effective in triple negative breast cancer models, even at low viral doses [114].…”

Section: Biology Of Vaccinia Virusmentioning

confidence: 99%

Vaccinia virus-mediated cancer immunotherapy: cancer vaccines and oncolytics

Guo

et al. 2019

j. immunotherapy cancer

222

170

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Cancer vaccines and oncolytic immunotherapy are promising treatment strategies with potential to provide greater clinical benefit to patients with advanced-stage cancer. In particular, recombinant vaccinia viruses (VV) hold great promise as interventional agents. In this article, we first summarize the current understanding of virus biology and viral genes involved in host-virus interactions to further improve the utility of these agents in therapeutic applications. We then discuss recent findings from basic and clinical studies using VV as cancer vaccines and oncolytic immunotherapies. Despite encouraging results gleaned from translational studies in animal models, clinical trials implementing VV vectors alone as cancer vaccines have yielded largely disappointing results. However, the combination of VV vaccines with alternate forms of standard therapies has resulted in superior clinical efficacy. For instance, combination regimens using TG4010 (MVA-MUC1-IL2) with first-line chemotherapy in advanced-stage non-small cell lung cancer or combining PANVAC with docetaxel in the setting of metastatic breast cancer have clearly provided enhanced clinical benefits to patients. Another novel cancer vaccine approach is to stimulate anti-tumor immunity via STING activation in Batf3-dependent dendritic cells (DC) through the use of replication-attenuated VV vectors. Oncolytic VVs have now been engineered for improved safety and superior therapeutic efficacy by arming them with immune-stimulatory genes or pro-apoptotic molecules to facilitate tumor immunogenic cell death, leading to enhanced DC-mediated cross-priming of T cells recognizing tumor antigens, including neoantigens. Encouraging translational and early phase clinical results with Pexa-Vec have matured into an ongoing global phase III trial for patients with hepatocellular carcinoma. Combinatorial approaches, most notably those using immune checkpoint blockade, have produced exciting pre-clinical results and warrant the development of innovative clinical studies. Finally, we discuss major hurdles that remain in the field and offer some perspectives regarding the development of next generation VV vectors for use as cancer therapeutics.

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Vaccinia Virus Shuffling: deVV5, a Novel Chimeric Poxvirus with Improved Oncolytic Potency

Cited by 19 publications

References 37 publications

The Enhanced Tumor Specificity of TG6002, an Armed Oncolytic Vaccinia Virus Deleted in Two Genes Involved in Nucleotide Metabolism

The Enhanced Tumor Specificity of TG6002, an Armed Oncolytic Vaccinia Virus Deleted in Two Genes Involved in Nucleotide Metabolism

By Binding CD80 and CD86, the Vaccinia Virus M2 Protein Blocks Their Interactions with both CD28 and CTLA4 and Potentiates CD80 Binding to PD-L1

Vaccinia virus-mediated cancer immunotherapy: cancer vaccines and oncolytics

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