Measles virus selectively blind to signaling lymphocyte activation molecule as a novel oncolytic virus for breast cancer treatment

Abstract

Oncolytic viruses hold much promise as novel therapeutic agents that can be combined with conventional therapeutic modalities. Measles virus (MV) is known to enter cells using the signaling lymphocyte activation molecule (SLAM), which is expressed on cells of the immune system. Although human breast cancer cell lines do not express SLAM, we found that a wild-type MV (HL strain) efficiently infected various breast cancer cell lines, causing cell death. Based on this finding, we used reverse genetics to generate a recombinant MV selectively unable to use SLAM (rMV-SLAMblind). The rMV-SLAMblind lacked infectivity for SLAM-positive lymphoid cells, while retaining oncolytic activity against breast cancer cells. We showed that, unlike the MV vaccine strains, rMV-SLAMblind used PVRL4 (polio virus receptor-related 4) as a receptor to infect breast cancer cells and not the ubiquitously expressed CD46. Consistent with this, rMV-SLAMblind infected CD46-positive primary normal human cells at a much-reduced level, whereas a vaccine strain of the Edmonston lineage (rMV-Edmonston) efficiently infected and killed them. The rMV-SLAMblind showed antitumor activity against human breast cancer xenografts in immunodeficient mice. The oncolytic activity of rMV-SLAMblind was significantly greater than that of rMV-Edmonston. To assess the in vivo safety, three monkeys seronegative for MV were inoculated with rMV-SLAMblind, and no clinical symptoms were documented. On the basis of these results, rMV-SLAMblind could be a promising candidate as a novel oncolytic virus for breast cancer treatment.

Connections matter − how viruses use cell–cell adhesion components

“…Although the direct effect of CAR and JAM expression levels on the replication of coxsackievirus and reovirus in tumor cells has not been clearly defined, expression levels of CAR and nectins do, indeed, correlate with the oncolytic efficiency of adenovirus, HSV and the measles virus (Jiang et al, 2009;Sugiyama et al, 2013;Yu et al, 2007). Cell-associated viruses, such as HSV and the measles virus, can destroy tumors owing to efficient receptor-dependent lateral spread in cancerous tissues.…”

The Tumor-Associated Marker, PVRL4 (Nectin-4), Is the Epithelial Receptor for Morbilliviruses

“…A recombinant MeV that was unable to use SLAM (SLAM blind) targeted PVRL4 on human breast cancer xenografts in immunodeficient mice and showed oncolytic activity [113]. In addition to targeting tumor markers, other strategies increase oncolytic activity by arming oncolytic viruses with therapeutic genes [114,115,116] or using vesicular stomatitis virus (VSV)/MeV hybrid viruses as an oncolytic platform [117].…”

Antitumor Virotherapy by Attenuated Measles Virus (MV)

“…It has also been described as a tumor marker which is frequently overexpressed in many adenocarcinomas, such as ovarian, lung, colon and breast tumors [36,37,38]. It has been demonstrated recently that nectin-4 is necessary for the tumor selectivity of infection by MV in some breast cancers [39]. …”

“…Many studies have described oncolytic properties of MV, in vitro and in vivo , on immunodeficient mice bearing human tumor xenografts. Hence, oncolytic efficacy of MV has been demonstrated against T-cell lymphoma [41,42], myelomas [43], pancreatic cancer [44], glioblastomas, gliomas [45,46], ovarian carcinomas [30], prostate cancer [47], breast cancer [39,47,48], melanoma [49], renal cell carcinoma [50], mesothelioma [7,51], medulloblastoma [52,53] and lung/colorectal adenocarcinoma [54]. Recently, Zhang et al demonstrated a therapeutic efficacy of MV against human hepatoblastoma, both in vivo and in vitro [55].…”