Liposome Encapsulation of Oncolytic Virus M1 To Reduce Immunogenicity and Immune Clearance in Vivo

Abstract

Oncolytic viral therapy is an attractive novel strategy for cancer therapy. As a natural alphavirus, oncolytic virus M1 is able to infect and kill various zinc finger antiviral protein (ZAP)-deficient tumor cells selectively, while leaving normal cells undamaged. However, M1 can trigger the production of neutralizing antibodies that dramatically weaken its antitumor effect. In order to attenuate immunogenicity of the therapeutic M1 virus, we encapsulated it into liposomes (referred to as M-LPO) using the thin-film hydration method. The effect of anti-M1 neutralizing antibody on M-LPO was examined in LoVo and Hep 3B cell lines. In the absence of neutralizing antibodies, treating cells with naked M1, blank liposomes (LPO), M-LPO, or a simple mixture of M1 and liposomes (LPO+M1) inhibited cell growth. In the presence of neutralizing antibodies, only M-LPO inhibited cell growth. After intravenous administration, M-LPO reduced the production of the M1-neutralizing antibody and the corresponding immune response. Analysis of the M-LPO uptake by cells was examined by confocal microscopy using M1 labeled with FITC and liposomal shells labeled with RhB. The results suggest that M1 may be released from liposomes before or after M-LPO internalization. Taken together, our results suggest that encapsulating oncolytic virus M1 in liposomes may reduce intrinsic viral immunogenicity for improved anticancer therapy.

Materials promoting viral gene delivery

“…413 Most studies were conducted with complexes from cationic liposomes and VPs. Enhanced TE, shielding from immune response and broadened tropism of RV, 400,401,410,414 AAV, 415 Ad, 124,416,417 HSV, 418,419 as well as recently for oncolytic applications with reovirus 420 and alphavirus 421 were reported. Moreover, liposome vesicles from zwitterionic, cationic and PEG-lipid formulations can act as an artificial envelope for non-enveloped viruses and thereby enhance targeted delivery and prolong blood circulation lifetime (Fig.…”

Improving antitumor efficacy via combinatorial regimens of oncolytic virotherapy

“…Avoiding virus neutralization is achievable by chemical or physical modification with various biomaterials. An example of this strategy is the encapsulation and coating of virion with liposomes [ 156 , 157 ], nanovesicles [ 158 ], or polymers [ 159 ]. Some materials with stimuli-responsive properties may provide superior potential for systemic therapy, such as a pH-sensitive copolymer modified adenovirus for targeting the acidic tumor environment [ 160 ], and an enzyme-responsive liposome-coated adenovirus for reducing immunogenicity [ 161 ].…”

<p>Virus–Receptor Interactions and Virus Neutralization: Insights for Oncolytic Virus Development</p>

“…117,118 In a pre-clinical study, liposomes were used to encapsulate oncolytic alphavirus strain M1 (M-LPO) with anti-tumor efficacy in vitro and a reduced immunogenicity in mice when administered intravenously. 119 A similar approach was used to encapsulate a replicationcompetent, ONYX-015-based plasmid in liposomes. 120 Liposomes harboring the plasmids were resistant to antibodies neutralizing the parent strain, while the plasmids could only transfect tumor cells which are p53 deficient.…”