The Complement Response Against an Oncolytic Virus Is Species-Specific in Its Activation Pathways

Abstract

A variety of oncolytic viruses (OVs) are being tested in clinical trials for different human cancers. Although the innate immune response is critical as the first line of defense in thwarting viral infection of mammalian cells, little is known of this response in the context of OV therapy of tumors. Investigations of activities against a herpes simplex OV demonstrated that HSV-seronegative sera from rats, mice, and humans efficiently neutralize this OV in vitro. Although this neutralization is due to complement, activation of this innate host defense differs in its pathways among species routinely used in preclinical tumor trials. In rats, both natural immunoglobulins and mannan-binding lectin (MBL) activate complement against the OV, while in mice only MBL is relevant to this activation. However, in humans only natural immunoglobulins play a role in complement activity. Quantitative analyses confirm that in vivo complement depletion facilitates the initial infection of tumors by systemic OVs. Therefore, complement activation against oncolytic HSV vectors proceeds through different pathways in different species. These findings are relevant to preclinical rodent studies of OV therapy and their application to human clinical trials.

Intracarotid delivery of oncolytic HSV vector G47Δ to metastatic breast cancer in the brain

“…36 For example, complement depletion with cobra venom factor results in significantly increased numbers of oncolytic HSV-infected brain tumor cells after intracarotid delivery with RMP7 BBBD. 44 Cyclophosphamide, which depresses innate IgM levels and complement activation in rats, as well as other immune functions, also enhanced viral transduction of intracerebral tumors after intracarotid delivery with BBBD and extended the survival of U87dEGFR glioma-bearing nude rats. 45 We have not examined the impact of complement activation in our model, which might have resulted in even greater efficacy, although the complement pathway in mice is somewhat different from rats.…”

“…45 We have not examined the impact of complement activation in our model, which might have resulted in even greater efficacy, although the complement pathway in mice is somewhat different from rats. 44,46,47 After gaining access to the brain parenchyma, the ability of G47D to replicate specifically in tumor cells and spread throughout the tumor is apparent from continued labeling of the tumor for at least 19 days after injection. We have previously detected extensive X-gal staining of G207-infected human subcutaneous tumors at 15 and 24 days after treatment, 5,48 while others have detected infectious HSV up to 31 days postinfection.…”

Clearance of Adenovirus by Kupffer Cells Is Mediated by Scavenger Receptors, Natural Antibodies, and Complement

“…Polyreactive natural IgM antibodies play an important role in the control of viral infections in vivo, where they are a vital innate defense during the early stages of an infection, before the adaptive immune system has mounted an antigen-specific response (8,37,38,69). In addition, natural antibodies are a major obstacle to in vivo gene therapy with retroviruses, bacteriophage, herpes simplex virus type 1, and baculovirus (21,42,51,52,61).…”

An ex vivo loop system models the toxicity and efficacy of PEGylated and unmodified adenovirus serotype 5 in whole human blood

“…17 Furthermore, it is known that complement activation differs between species. 39 Therefore, the immune response against, and the clearance of, uncoated and PEGylated Ad5 in human blood could be quite different to the immune response in mice, even if the mice have been immunized to have preformed anti-Ad5 antibodies or if immunodeficient mice are injected with human erythrocytes.…”