Inhibitors of C5 complement enhance vaccinia virus oncolysis

Magge, Deepa; Guo, Zong Sheng; O’Malley, Michael J.; Francis, Lily; Ravindranathan, Roshni; Bartlett, David L.

doi:10.1038/cgt.2013.26

Cited by 27 publications

(19 citation statements)

References 41 publications

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“…For instance, intravenous or intra-arterial administration of OVs such as recombinant HSV1 leads to its rapid recognition and elimination by the circulating complement and antibodies of the humoral defense system (18, 19). This also has been shown for VV (20), NDV (21), MV (22), and Ad (23, 24). Intratumoral administration also can lead to complement- and antibody-mediated destruction of the OV.…”

Section: Innate Immunitysupporting

confidence: 70%

Oncolytic Viruses and Their Application to Cancer Immunotherapy

Rabkin

2014

Cancer Immunology Research

342

286

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Oncolytic viruses (OVs) selectively replicate in and kill cancer cells, and spread within the tumor, while not harming normal tissue. In addition to this direct oncolytic activity, OVs are also very effective at inducing immune responses to themselves and to the infected tumor cells. OVs encompass a broad diversity of DNA and RNA viruses that are naturally cancer-selective or can be genetically-engineered. OVs provide a diverse platform for immunotherapy; they act as in situ vaccines, and can be armed with immune modulatory transgenes or combined with other immunotherapies. However, the interactions of OVs with the immune system may affect therapeutic outcomes in opposing fashions: negatively by limiting virus replication and/or spread, or positively by inducing antitumor immune responses. Many aspects of the OV-tumor/host interaction are important in delineating the effectiveness of therapy; they include: (i) innate immune responses and the degree of inflammation induced, (ii) types of virus-induced cell death, (iii) inherent tumor physiology, such as infiltrating and resident immune cells, vascularity/hypoxia, lymphatics, and stromal architecture, and (iv) tumor cell phenotype, including alterations in IFN signaling, oncogenic pathways, cell surface immune markers (MHC, co-stimulatory, NK receptors), and the expression of immunosuppressive factors. Recent clinical trials with a variety of OVs, especially those expressing GM-CSF, have demonstrated efficacy and induction of antitumor immune responses in the absence of significant toxicity. Manipulating the balance between anti-virus and antitumor responses, often involving overlapping immune pathways, will be critical to the clinical success of OVs.

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Section: Innate Immunitysupporting

confidence: 70%

Oncolytic Viruses and Their Application to Cancer Immunotherapy

Rabkin

2014

Cancer Immunology Research

342

286

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“…27 A recently published study demonstrated that in immune hosts, antibody-mediated vaccinia virus neutralization is dependent on the complement system, and in both small and large immunized animals, the combination of complement inhibition with vaccinia virus treatment results in increased delivery to tumor and virus stability in the blood. 28 Ultimately, further evaluation of complement inhibition in combination with other immunotherapies such as viral oncolytic therapy will determine the ideal role for complement inhibition in the clinical setting.…”

Section: Discussionmentioning

confidence: 99%

Complement Inhibition: A Novel Form of Immunotherapy for Colon Cancer

et al. 2015

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Background Complement is a central part of both the innate and adaptive immune response and its activation has traditionally been considered part of the immunosurveillance response against cancer. Its pro-inflammatory role and its contribution to the development of many illnesses associated with inflammatory states implicate complement in carcinogenesis. Methods We evaluated the role of three protein inhibitors of complement—cobra venom factor, humanized cobra venom factor, and recombinant staphylococcus aureus superantigen-like protein 7—in the setting of a transplantable murine colon cancer model. Outcomes were evaluated by monitoring tumor growth, and flow cytometry, ELISPOT, and quantitative real-time PCR were used to determine the impact of complement inhibition on the host immune response. Results Complement inhibitors were effective at depleting complement component C3 in tumor bearing mice and this was temporally correlated with a decreased rate of tumor growth during the establishment of tumors. Treatment with cobra venom factor resulted in increased CD8+ T cells as a percentage of tumor-infiltrating cells as well as a reduced immunosuppressive environment evidenced by decreased myeloid derived suppressor cells in splenocytes of treated mice. Complement inhibition resulted in increased expression of the chemoattractive cytokines CCL5, CXCL10, and CXCL11. Discussion Complement depletion represents a promising mode of immunotherapy in cancer by its ability to impair tumor growth by increasing the host’s effective immune response to tumor and diminishing the immunosuppressive effect created by the tumor microenvironment and ultimately could be utilized as a component of combination immunotherapy.

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“…However, though the inflammatory response was affected, the development of the adaptive immune response was not, as upon reinfection these differences were no longer apparent (32). Instead C5 appears to be rapidly activated independently of C3 exerting an influence over the development of the innate immune response by participating in local recruitment of neutrophils and may function independently of host Abs to induce clearance of VACV (33). Therapeutic treatment with a specially engineered C5a agonist, EP67, completely protects from lethal influenza infection (34); therefore, the rapid activation of the C5 component induced by MVA infection may go some way toward explaining the short-term protection provided by MVA.…”

Section: Discussionmentioning

confidence: 99%

Complement Component C5 Recruits Neutrophils in the Absence of C3 during Respiratory Infection with Modified Vaccinia Virus Ankara

Price

Bánki

Scheideler

et al. 2015

The Journal of Immunology

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Efficient leukocyte migration is important for an effective host response to viral infection and the development of adaptive immunity. The poxvirus strain modified vaccinia virus Ankara (MVA), a safe and efficient viral vector, rapidly induces chemokine expression and respiratory recruitment of leukocytes, which is unique among vaccinia viruses. In addition to chemokines, the complement system contributes to the attraction and activation of different types of leukocytes. Using a murine model of intranasal infection, we show in this study that MVA-induced neutrophil recruitment depends on complement component C5. Remarkably, we find that C5 mediates neutrophil recruitment to the lung, even in the absence of the central complement component C3. Our findings argue for complement C5 activation during MVA infection of the lung via a C3-independent pathway, which enables rapid recruitment of neutrophils.

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Inhibitors of C5 complement enhance vaccinia virus oncolysis

Cited by 27 publications

References 41 publications

Oncolytic Viruses and Their Application to Cancer Immunotherapy

Oncolytic Viruses and Their Application to Cancer Immunotherapy

Complement Inhibition: A Novel Form of Immunotherapy for Colon Cancer

Complement Component C5 Recruits Neutrophils in the Absence of C3 during Respiratory Infection with Modified Vaccinia Virus Ankara

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