MeV-Stealth: A CD46-specific oncolytic measles virus resistant to neutralization by measles-immune human serum

Abstract

The frequent overexpression of CD46 in malignant tumors has provided a basis to use vaccine-lineage measles virus (MeV) as an oncolytic virotherapy platform. However, widespread measles seropositivity limits the systemic deployment of oncolytic MeV for the treatment of metastatic neoplasia. Here, we report the development of MeV-Stealth, a modified vaccine MeV strain that exhibits oncolytic properties and escapes antimeasles antibodies in vivo. We engineered this virus using homologous envelope glycoproteins from the closely-related but serologically non-cross reactive canine distemper virus (CDV). By fusing a high-affinity CD46 specific single-chain antibody fragment (scFv) to the CDV-Hemagglutinin (H), ablating its tropism for human nectin-4 and modifying the CDV-Fusion (F) signal peptide we achieved efficient retargeting to CD46. A receptor binding affinity of ~20 nM was required to trigger CD46-dependent intercellular fusion at levels comparable to the original MeV H/F complex and to achieve similar antitumor efficacy in myeloma and ovarian tumor-bearing mice models. In mice passively immunized with measles-immune serum, treatment of ovarian tumors with MeV-Stealth significantly increased overall survival compared with treatment with vaccine-lineage MeV. Our results show that MeV-Stealth effectively targets and lyses CD46-expressing cancer cells in mouse models of ovarian cancer and myeloma, and evades inhibition by human measles-immune serum. MeV-Stealth could therefore represent a strong alternative to current oncolytic MeV strains for treatment of measles-immune cancer patients.

Repurposing Live Attenuated Trivalent MMR Vaccine as Cost-effective Cancer Immunotherapy

“…Previous works have pointed out that pre-existing immunity to OVs is detrimental to their oncolytic activity. 51,124,125 Moreover, several authors have shown that neutralizing antibodies to measles can hamper its systemic delivery and antitumor effect. 122,126 Accordingly, strategies to overcome this limitation have been proposed with various degrees of success.…”

Viruses as tools in gene therapy, vaccine development, and cancer treatment

“…Measles virus is an enveloped, non-segmented single-stranded negative-sense RNA virus [ 8 ]. A vaccine based on a modified measles virus strain, MeV-Stealth, has been used to treat ovarian cancer in mice by causing lysis of cancer cells expressing CD46 [ 101 ]. Measles vaccines encoding interleukin 12 and interleukin 15 agonists were tested in tumor models in vitro .…”

Current landscape and perspective of oncolytic viruses and their combination therapies

“…MV is a single-stranded nonsegmental negative-strand RNA virus, which can recognize and infect a variety of cancer cells expressing CD46 and nectin-4 [42] . MV has been demonstrated to have good oncolytic activity.…”