The use of oncolytic viruses to stimulate a patient’s immune system as well as directly kill tumour cells is a novel approach to eradicating cancer, but antibodies that permanently inactivate the virus are often generated that counter treatment efficacy. An Ottawa-based lab has come up with a way of countering this problem by using a complement inhibitor that prevents the virus’ neutralization, thereby ensuring viral vectors reach their target.
Multiple doses of oncolytic viruses are likely needed to maximize the therapeutic effect, however the delivery of the latter doses is limited by the presence of anti-viral antibodies both in the blood as well as in the tumor microenvironment.
The present study published in Molecular Therapy – Oncolytics (November 2016) shows that the antibodies that are generated against the lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP), while non-neutralizing on their own, can mediate virus neutralization in a complement-dependent manner. An oncolytic virus that was pseudotyped with this glycoprotein was neutralized by immune serum with intact complement, whereas neutralization was prevented when a complement inhibitor was present.
This discovery has had immediate benefit to patients: by using a transient complement inhibitor oncolytic viruses pseudotyped with the LCMV glycoprotein can be effectively delivered to a tumour without being neutralized by antibodies for a period of time, thus increasing its efficacy. For example, virus stability in the blood of immunized animals increased by approximately 100-fold when a complement was inhibited, leading to a corresponding increase in viral titer in the tumour.
The present study also shed light on using animal models in oncolytic virus research. The antibody response to LCMV has been studied primarily in mouse models, and it was thought that the antibodies that were generated against the virus were essentially biologically inert. However, mouse complement does not fully recapitulate the effects of human complement. The team more accurately modelled the effect of complement by using rats instead of mice, and it became clear that the anti-LCMV GP antibodies induced profound complement-mediated neutralization. This finding underscores that mouse models have important limitations that must be recognized when designing translational therapeutic approaches.
Study: Complement inhibition enables tumour delivery of LCMV glycoprotein pseudotyped viruses in the presence of antiviral antibodies
Authors: Laura Evgin, Carolina S Ilkow, Marie-Claude Bourgeois-Daigneault, Christiano Tanese de Souza, Lawton Stubbert, Michael S Huh,Victoria A Jennings, Monique Marguerie, Sergio A Acuna, Brian A Keller, Charles Lefebvre, Theresa Falls, Fabrice Le Boeuf, Rebecca A Auer, John D Lambris, J Andrea McCart, David F Stojdl and John C Bell.
Funding: J.C.B. is supported by the Terry Fox Research Institute, the Ontario Institute for Cancer Research, and the Ottawa Regional Cancer Foundation.
TFRI Links, Spring 2017