Complement Inhibition Prevents Oncolytic Vaccinia Virus Neutralization in Immune Humans and Cynomolgus Macaques

Evgin, Laura; Acuña, Sergio A.; Souza, Christiano Tanese de; Marguerie, Monique; Lemay, Chantal G.; Ilkow, Carolina S.; Findlay, C. Scott; Falls, Theresa; Parato, Kelley A.; Hanwell, David; Goldstein, Alyssa; Lopez, Roberto; Lafrance, Sandra; Breitbach, Caroline J.; Kirn, David H.; Atkins, Harold L.; Auer, Rebecca C.; Thurman, Joshua M.; Stahl, Gregory L.; Lambris, John D.; Bell, John C.; McCart, J. Andrea

doi:10.1038/mt.2015.49

Cited by 69 publications

(63 citation statements)

References 48 publications

(53 reference statements)

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“…We have previously shown that the Ad11 capsid has specific advantages in retaining viability in the presence of blood or serum at clinically relevant concentrations, opening up the potential for systemic delivery 3 . In contrast, alternative therapeutic virus classes, including vaccinia virus, HSV-1, reovirus, and measles have all been shown to be neutralized in human blood through either antibody-dependent or -independent neutralization, 27 in agreement with our own unpublished findings. Gaining a better understanding of systemic delivery was thus a key objective in the preclinical evaluation of enadenotucirev.…”

Section: Discussionsupporting

confidence: 86%

Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus

Illingworth

Bauzon

et al. 2017

Molecular Therapy - Oncolytics

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Enadenotucirev is an oncolytic group B adenovirus identified by a process of bio-selection for the ability to selectively propagate in and rapidly kill carcinoma cells. It is resistant to inactivation by human blood components, potentially enabling intravenous dosing in patients with metastatic cancer. However, there are no known permissive animal models described for group B adenoviruses that could facilitate a conventional approach to preclinical safety studies. In this manuscript, we describe our tailored preclinical strategy designed to evaluate the key biological properties of enadenotucirev. As enadenotucirev does not replicate in animal cells, a panel of primary human cells was used to evaluate enadenotucirev replication selectivity in vitro, demonstrating that virus genome levels were >100-fold lower in normal cells relative to tumor cells. Acute intravenous tolerability in mice was used to assess virus particle-mediated toxicology and effects on innate immunity. These studies showed that particle toxicity could be ameliorated by dose fractionation, using an initial dose of virus to condition the host such that cytokine responses to subsequent doses were significantly attenuated. This, in turn, supported the initiation of a phase I intravenous clinical trial with a starting dose of 1 × 1010 virus particles given on days 1, 3, and 5.

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Section: Discussionsupporting

confidence: 86%

Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus

Illingworth

Bauzon

et al. 2017

Molecular Therapy - Oncolytics

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“…Innate immunity and complement may impede delivery of oncolytic viruses, especially with the intravenous approach (27). However, transportation by cells may also protect virus during intravenous delivery, despite the presence of neutralizing antibodies prior to infusion (28).…”

Section: Discussionmentioning

confidence: 99%

Phase I Trial of Intravenous Oncolytic Vaccinia Virus (GL-ONC1) with Cisplatin and Radiotherapy in Patients with Locoregionally Advanced Head and Neck Carcinoma

Mell

Brumund

Daniels³

et al. 2017

Clinical Cancer Research

108

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Purpose: Preclinical models have shown that the effectiveness of GL-ONC1, a modified oncolytic vaccinia virus, is enhanced by radiation and chemotherapy. The purpose of this study was to determine the safety of GL-ONC1 when delivered intravenously with chemoradiotherapy to patients with primary, nonmetastatic head and neck cancer.Experimental Design: Patients with locoregionally advanced unresected, nonmetastatic carcinoma of the head/neck, excluding stage III-IVA p16-positive oropharyngeal cancers, were treated with escalating doses and cycles of intravenous GL-ONC1, along with radiotherapy and chemotherapy. The primary aims were to define the MTD and dose-limiting toxicities, and to recommend a dose for phase II trials.Results: Between May 2012 and December 2014, 19 patients were enrolled. The most frequent adverse reactions included grade 1-2 rigors, fever, fatigue, and rash. Grade 3 adverse reactions included hypotension, mucositis, nausea, and vomiting. In 2 patients, the rash was confirmed as viral in origin by fluorescence imaging and viral plaque assay. In 4 patients, viral presence in tumor was confirmed on midtreatment biopsy by quantitative PCR. In 1 patient, live virus was confirmed in a tongue tumor 7 days after receiving the first dose of virus. The MTD was not reached. With median follow-up of 30 months, 1-year (2-year) progression-free survival and overall survival were 74.4% (64.1%) and 84.6% (69.2%), respectively.Conclusions: Delivery of GL-ONC1 is safe and feasible in patients with locoregionally advanced head/neck cancer undergoing standard chemoradiotherapy. A phase II study is warranted to further investigate this novel treatment strategy.

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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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Complement Inhibition Prevents Oncolytic Vaccinia Virus Neutralization in Immune Humans and Cynomolgus Macaques

Cited by 69 publications

References 48 publications

Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus

Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus

Phase I Trial of Intravenous Oncolytic Vaccinia Virus (GL-ONC1) with Cisplatin and Radiotherapy in Patients with Locoregionally Advanced Head and Neck Carcinoma

Complement Inhibition: A Novel Form of Immunotherapy for Colon Cancer

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