Elucidating mechanisms of antitumor immunity mediated by live oncolytic vaccinia and heat-inactivated vaccinia

Wang, Weiyi; Liu, Shuaitong; Dai, Peihong; Yang, Ning; Wang, Yi; Giese, Rachel; Merghoub, Taha; Wolchok, Jedd D.; Deng, Liang

doi:10.1136/jitc-2021-002569

Cited by 14 publications

(12 citation statements)

References 54 publications

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“…The resulting vector, though, did not increase antitumor activity, 42 and the massive deletion of clusters of fifteen immunomodulatory genes did not improve the immunogenicity of the resulting MVAs 43 . However, recent reports underlined that reinforcement of the type I IFN responses could be a set screw to improve antitumor immune responses 15,44,45 . These findings supported retrospectively our approach to select PCPV based on its capacity to stimulate IFN‐α secretion in human cells.…”

Section: Discussionsupporting

confidence: 70%

“…43 However, recent reports underlined that reinforcement of the type I IFN responses could be a set screw to improve antitumor immune responses. 15,44,45 These findings supported retrospectively our approach to select PCPV based on its capacity to stimulate IFN-a secretion in human cells. It distinguishes between MVA and VACV by its higher capacity to induce secretion of IFN-a in PBMCs not only from healthy donors but also from cancer patients.…”

Section: Discussionsupporting

confidence: 63%

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Pseudocowpox virus, a novel vector to enhance the therapeutic efficacy of antitumor vaccination

et al. 2022

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Objective. Antitumor viral vaccines, and more particularly poxviral vaccines, represent an active field for clinical development and translational research. To improve the efficacy and treatment outcome, new viral vectors are sought, with emphasis on their abilities to stimulate innate immunity, to display tumor antigens and to induce a specific T-cell response. Methods. We screened for a new poxviral backbone with improved innate and adaptive immune stimulation using IFN-a secretion levels in infected PBMC cultures as selection criteria. Assessment of virus effectiveness was made in vitro and in vivo. Results. The bovine pseudocowpox virus (PCPV) stood out among several poxviruses for its ability to induce significant secretion of IFN-a. PCPV produced efficient activation of human monocytes and dendritic cells, degranulation of NK cells and reversed MDSC-induced T-cell suppression, without being offensive to activated T cells. A PCPV-based vaccine, encoding the HPV16 E7 protein (PCPV-E7), stimulated strong antigen-specific Tcell responses in TC1 tumor-bearing mice. Complete regression of tumors was obtained in a CD8 + T-cell-dependent manner after intratumoral injection of PCPV-E7, followed by intravenous injection of the cancer vaccine MVA-E7. PCPV also proved active when injected repeatedly intratumorally in MC38 tumor-bearing mice, generating tumor-specific T-cell responses without encoding a specific MC38 antigen. From a translational perspective, we demonstrated that PCPV-E7 effectively stimulated IFN-c production by T cells from tumor-draining lymph nodes of HPV + -infected cancer patients. Conclusion. We propose PCPV as a viral vector suitable for vaccination in the field of personalised cancer vaccines, in particular for heterologous prime-boost regimens.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionsupporting

confidence: 63%

Pseudocowpox virus, a novel vector to enhance the therapeutic efficacy of antitumor vaccination

et al. 2022

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“…Tumor immunotherapy, such as PD-1/PD-L1, CTLA-4 antibody therapy and CAR-T/CAR-NK immune cell therapy, is based on the activation of immune cells, especially T cells, which can kill cancer cells [ 21 , 22 ]. For solid tumors, the number of formerly-owned and lately-migrated immune cells in the TME is very small, which is the difficulty of immunotherapy for solid tumors [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Chimeric Oncolytic Adenovirus Armed Chemokine Rantes for Treatment of Breast Cancer

et al. 2022

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The immunosuppressive state in the tumor microenvironment (TME) of breast cancer makes it difficult to treat with immunotherapy. Oncolytic viruses not only lyse tumor cells but also reshape the TME. Therefore, they can play a multi-mechanism synergistic effect with immunotherapy. In this study, an oncolytic adenovirus Ad5F11bSP-Rantes was constructed and used as a vector to express the chemokine Rantes. The objective of this study was to test the dual mechanisms of the oncolytic effect mediated by virus replication and the enhanced anticancer immune response mediated by Rantes chemotaxis of immune cells. It was found that Ad5F11bSP-Rantes has strong infectivity and effective killing activity against breast cancer cells. In the established triple negative breast cancer (TNBC) xenograft model in NCG mice whose immune system was humanized with human peripheral blood mononuclear cells (PBMCs), Ad5F11bSP-Rantes achieved 88.33% tumor inhibition rate. Rantes expression was high in mouse blood, a large number of CD3+ lymphocytes infiltrated in tumor tissues and E-cadherin was up-regulated in cancer cells, suggesting that Ad5F11bSP-Rantes altered the TME and induced a reversal of cancer cell epithelial–mesenchymal transition (EMT). In conclusion, oncolytic adenovirus can exert the oncolytic effect and the chemotactic effect of immune cells and realize the synergy of multiple anticancer effects. This strategy creates a candidate treatment for the optimization of breast cancer, especially TNBC, combination therapy.

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“…Immunogenic viruses are one of the strategies to alter TIME for enhancing antitumor immunity 10,11,12,13 . However, whether viral replication and oncolysis are required for viral-induced antitumor immunity is still being debated 14,15,16,17 .…”

Section: Introductionmentioning

confidence: 99%

“…Intratumoral injection of heat-inactivated MVA generates potent antitumor immunity via cGAS and is dependent on CD8 + T cells and Batf3-dependent CD103 + dendritic cells 17 . We also compared the antitumor immunity of live oncolytic vaccinia virus with a heat-inactivated version and found that inactivated oncolytic vaccinia generates more potent antitumor effects 16 . These results led us to conclude that vaccinia viral replication and oncolysis is not essential for the induction of antitumor immunity.…”

Section: Introductionmentioning

confidence: 99%

IL-12-expressing highly immunogenic recombinant modified vaccinia virus Ankara reprograms tumor-infiltrating myeloid cells to overcome immune resistance

Liu

Mazo

Yang

et al. 2022

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Novel strategies to reprogram tumor-infiltrating myeloid cells for cancer immunotherapy are urgently needed, given that the primary and acquired resistance to immune checkpoint blockade (ICB) therapy has hindered the overall success of immunotherapy. Modified vaccinia virus Ankara (MVA) is a highly attenuated, non-replicative vaccinia virus and an approved vaccine against smallpox and monkeypox. Here we report rational engineering of recombinant MVA, MQ833, by removing three immune suppressive genes, E5R, E3L, and WR199, from the MVA genome and inserting three transgenes encoding Flt3L, OX40L, and IL-12. Intratumoral (IT) delivery of MQ833 generates potent antitumor responses dependent on CD8+ T cells, neutrophils, and M1-like macrophages, the nucleic acid-sensing pathways mediated by MDA5/STING, and interferon feedback loop. IT MQ833 promotes the recruitment and activation of neutrophils and inflammatory monocytes into the injected tumors, depletion of M2-like macrophages, and expansion of M1-like macrophages, generating potent antitumor immunity against tumors resistant to ICB.

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Elucidating mechanisms of antitumor immunity mediated by live oncolytic vaccinia and heat-inactivated vaccinia

Cited by 14 publications

References 54 publications

Pseudocowpox virus, a novel vector to enhance the therapeutic efficacy of antitumor vaccination

Pseudocowpox virus, a novel vector to enhance the therapeutic efficacy of antitumor vaccination

Chimeric Oncolytic Adenovirus Armed Chemokine Rantes for Treatment of Breast Cancer

IL-12-expressing highly immunogenic recombinant modified vaccinia virus Ankara reprograms tumor-infiltrating myeloid cells to overcome immune resistance

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