Intratumoral delivery of inactivated modified vaccinia virus Ankara (iMVA) induces systemic antitumor immunity via STING and Batf3-dependent dendritic cells

Dai, Peihong; Wang, Weiyi; Yang, Ning; Serna-Tamayo, Cristian; Ricca, Jacob; Zamarin, Dmitriy; Shuman, Stewart; Merghoub, Taha; Wolchok, Jedd D.; Deng, Liang

doi:10.1126/sciimmunol.aal1713

Cited by 108 publications

(141 citation statements)

References 46 publications

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“…However, the idea that tumor cell lysis by the pathogen is essential has been recently challenged by evidence demonstrating that an inactivated oncolytic virus is capable of initiating antitumor immunity via the STING pathway and may support better immunity than its active oncolytic virus counterpart (44). Additionally, our data indicate that TLR activation via interaction with viral-derived PAMPs is increased in the context of inactivated virus, which may initiate an innate immune response and thereby remodel the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 78%

Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer

Newman

Chesson

Herzog

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

151

142

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Reprogramming the tumor microenvironment to increase immune-mediated responses is currently of intense interest. Patients with immune-infiltrated “hot” tumors demonstrate higher treatment response rates and improved survival. However, only the minority of tumors are hot, and a limited proportion of patients benefit from immunotherapies. Innovative approaches that make tumors hot can have immediate impact particularly if they repurpose drugs with additional cancer-unrelated benefits. The seasonal influenza vaccine is recommended for all persons over 6 mo without prohibitive contraindications, including most cancer patients. Here, we report that unadjuvanted seasonal influenza vaccination via intratumoral, but not intramuscular, injection converts “cold” tumors to hot, generates systemic CD8+ T cell-mediated antitumor immunity, and sensitizes resistant tumors to checkpoint blockade. Importantly, intratumoral vaccination also provides protection against subsequent active influenza virus lung infection. Surprisingly, a squalene-based adjuvanted vaccine maintains intratumoral regulatory B cells and fails to improve antitumor responses, even while protecting against active influenza virus lung infection. Adjuvant removal, B cell depletion, or IL-10 blockade recovers its antitumor effectiveness. Our findings propose that antipathogen vaccines may be utilized for both infection prevention and repurposing as a cancer immunotherapy.

show abstract

Section: Discussionmentioning

confidence: 78%

Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer

Newman

Chesson

Herzog

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

151

142

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“…Using heat-inactivation, Dai et al showed that a non-replicating modified vaccinia virus Ankara (MVA) was more effective than replicating MVA as an OV invivo. 66 Inactivated MVA (iMVA) was able to shrink not only melanoma tumors following direct intratumoral injection, but it was also able to control the growth of non-injected distant tumors, indicating a potent antitumor immunity induction. The effectiveness and adaptive antitumor immune response activation of iMVA were also observed in a murine colon cancer model.…”

Section: Ovt As Immunotherapymentioning

confidence: 99%

Oncolytic viruses: how “lytic” must they be for therapeutic efficacy?

2019

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Oncolytic viruses (OVs) preferentially target and kill cancer cells without affecting healthy cells through a multi-modal mechanism of action. While historically the direct killing activity of OVs was considered the primary mode of action, initiation or augmentation of a host antitumor immune response is now considered an essential aspect of oncolytic virotherapy. To improve oncolytic virotherapy, many studies focus on increasing virus replication and spread. In this article, we open for discussion the traditional dogma that correlates replication with the efficacy of OVs, pointing out several examples that oppose this principle.

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“…immune therapies currently in preclinical development have shown efficacy by altering the microenvironment in ways other than directly killing tumor cells. These include therapies using Toxoplasma gondii, Salmonella, Semliki Forest virus, and inactivated modified vaccinia virus Ankara, all of which have been tested preclinically in a B16 melanoma model and all of which function by altering the cytokine milieu, increasing leukocyte infiltration of tumors, and/or increasing antigen recognition or function of CD8 ϩ T cells (27)(28)(29)(30)(31)(32)(33).…”

mentioning

confidence: 99%

“…Given the disparate effects of CMV in various settings, we wished to define the mechanism by which MCMV delayed tumor growth using the B16-F0 melanoma model. This was a particularly attractive model because B16 melanomas are notoriously aggressive, are resistant to immune therapies, and have been used extensively for exploring interventions that overcome this resistance, such as administering pathogens that kill tumor cells or modulate the immune environment (27)(28)(29)(30)(31)(32)(33). Moreover, B16-F0 tumors are immunologically "cold," containing few infiltrating immune cells in the absence of interventions.…”

mentioning

confidence: 99%

Murine Cytomegalovirus Infection of Melanoma Lesions Delays Tumor Growth by Recruiting and Repolarizing Monocytic Phagocytes in the Tumor

Wilski

Casale

Purwin

et al. 2019

J Virol

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Cytomegalovirus (CMV) is a ubiquitous betaherpesvirus that infects many different cell types. Human CMV (HCMV) has been found in several solid tumors, and it has been hypothesized that it may promote cellular transformation or exacerbate tumor growth. Paradoxically, in some experimental situations, murine CMV (MCMV) infection delays tumor growth. We previously showed that wild-type MCMV delayed the growth of poorly immunogenic B16 melanomas via an undefined mechanism. Here, we show that MCMV delayed the growth of these immunologically “cold” tumors by recruiting and modulating tumor-associated macrophages. Depletion of monocytic phagocytes with clodronate completely prevented MCMV from delaying tumor growth. Mechanistically, our data suggest that MCMV recruits new macrophages to the tumor via the virus-encoded chemokine MCK2, and viruses lacking this chemokine were unable to delay tumor growth. Moreover, MCMV infection of macrophages drove them toward a proinflammatory (M1)-like state. Importantly, adaptive immune responses were also necessary for MCMV to delay tumor growth as the effect was substantially blunted in Rag-deficient animals. However, viral spread was not needed and a spread-defective MCMV strain was equally effective. In most mice, the antitumor effect of MCMV was transient. Although the recruited macrophages persisted, tumor regrowth correlated with a loss of viral activity in the tumor. However, an additional round of MCMV infection further delayed tumor growth, suggesting that tumor growth delay was dependent on active viral infection. Together, our results suggest that MCMV infection delayed the growth of an immunologically cold tumor by recruiting and modulating macrophages in order to promote anti-tumor immune responses. IMPORTANCE Cytomegalovirus (CMV) is an exciting new platform for vaccines and cancer therapy. Although CMV may delay tumor growth in some settings, there is also evidence that CMV may promote cancer development and progression. Thus, defining the impact of CMV on tumors is critical. Using a mouse model of melanoma, we previously found that murine CMV (MCMV) delayed tumor growth and activated tumor-specific immunity although the mechanism was unclear. We now show that MCMV delayed tumor growth through a mechanism that required monocytic phagocytes and a viral chemokine that recruited macrophages to the tumor. Furthermore, MCMV infection altered the functional state of macrophages. Although the effects of MCMV on tumor growth were transient, we found that repeated MCMV injections sustained the antitumor effect, suggesting that active viral infection was needed. Thus, MCMV altered tumor growth by actively recruiting macrophages to the tumor, where they were modulated to promote antitumor immunity.

show abstract

Intratumoral delivery of inactivated modified vaccinia virus Ankara (iMVA) induces systemic antitumor immunity via STING and Batf3-dependent dendritic cells

Cited by 108 publications

References 46 publications

Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer

Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer

Oncolytic viruses: how “lytic” must they be for therapeutic efficacy?

Murine Cytomegalovirus Infection of Melanoma Lesions Delays Tumor Growth by Recruiting and Repolarizing Monocytic Phagocytes in the Tumor

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