Oncolytic Virus Combination Therapies-with Complement Inhibition
Complement Inhibition & OVs for Tumor Treatment
As a potential tumor therapeutic agent, Oncolytic Virus (OVs) possess various antitumor activities. These include direct tumor lysis that causes tumor destruction, delivery of therapeutic transgenes, triggers rupture of blood vessels, and severe induction of anti-tumor immunity. To date, the successful clinical development of OVs has mainly focused on local treatment by injection directly into the tumor bed. Although this method provides local tumor destruction and the potential to generate systemic antitumor immunity, it does not take into account the ability of viral infection and the destruction of metastatic tumors. This has led to the slower development of OVs as intravenous drugs.
Complement is a key component of the innate immune system's first line of defense, acting to target foreign pathogens for opsonization, neutralization, phagocytosis and clearance from the circulatory system. Antibody-mediated complement activation has an important effect on the anti-tumor activity of OV. As early as the 1950s, it has been shown that complement can enhance the neutralizing ability of antibodies induced by the smallpox vaccine. The residual immunity after vaccination was evaluated by immunoblotting and ELISAs. The results showed the durability of these antibodies against the virus. However, in the absence of complement, these antibodies have weak or no neutralizing activity in vitro. Therefore, inactivation of complement is likely to increase the survival rate of OV in the blood of hosts with existing virus immunity.
- Example
In immunized rats, complement depletion stabilizes the vaccinia virus in the blood and improves delivery to the tumor. When the virus is injected directly into the tumors of immunized animals, depletion of complement also enhances tumor infection. The feasibility and safety of using the complement inhibitor CP40 in combination with vaccinia virus were tested in animal models. CP40 pretreatment can cause an average 10-fold increase in blood infection titers early after infusion, and prolong the time that infectious viruses can be detected in the blood of animals with immune function. These results indicate that complement inhibitors can reduce OV depletion in vivo, which may be very important for future cancer treatment strategies.
Fig.1 Inhibition of specific components of the complement pathway and viral expression. (Magge, 2013)
Combination of Complement Inhibitors and OVs
The complement molecule C3 is located on the central axis of three more complement activation pathways, and therefore is an attractive therapeutic target. In animal models of viral immunization, complement inhibition can improve the delivery of intravenous vaccinia virus to tumors. Compstatin is a 13-amino acid peptide selected from the phage display library and can be combined with human and non-human primates C3 and C3b. Since its discovery, several analogs with improved pharmacodynamics and pharmacokinetic properties have been developed, among which the analog CP40 has become the main clinical drug candidate, which can inhibit antibody-mediated virus neutralization. In addition, in immunized crab-eating macaques, CP40 prolongs the half-life of vaccinia virus infection in the circulation after intravenous injection. These findings provide a powerful complementary intervention strategy for single-dose OV vaccines and multi-dose treatments with increasing antibody titers.
Reference
- Magge, D.; et al. Inhibitors of C5 complement enhance vaccinia virus oncolysis. Cancer gene therapy. 2013, 20.6: 342-350.