PLoS - Tumor Cell Marker PVRL4 (Nectin 4) Is an Epithelial Cell Receptor for Measles Virus
Measles virus is a primate-specific virus that causes acute respiratory disease and can also lead to short term immune suppression resulting in secondary infections by bacteria or parasites. Wild type measles virus attaches to and infects lymphocytes using the receptor CD150 (signaling lymphocyte activation molecule, SLAM). Measles virus is also known to infect epithelial cells of the upper respiratory system and lungs. However, the viral receptor on these cells was previously unknown. Adenocarcinomas are derived from glandular epithelial cells of organs including the lung, breast, or colon. We showed that wild type isolates of measles virus can infect human airway epithelial cells and many adenocarcinoma cell lines. A comparative analysis of membrane genes expressed in cells susceptible and non-susceptible for measles virus infections revealed candidate receptor proteins. Only PVRL4 (Nectin 4) converted cells that were resistant to measles viral infections, to cells that could support virus infections. PVRL4 is a tumor cell marker that is highly expressed on embryonic cells such as those of the placenta, but it is also expressed at lower levels in the trachea, oral mucosa, nasopharynx, and lungs. It is highly expressed on many lung, breast, colon, and ovarian tumors suggesting that they could be targeted with oncolytic measles virus.
2. Technology Review - A single injection of a virus that has been genetically engineered to kill cancer cells can reliably infect tumors and leave healthy tissue unharmed, according to an early stage trial of 23 patients with metastatic cancers. The findings help lay the groundwork for a new type of cancer medicine using cancer-killing viruses
Researchers injected different doses of the virus into patients with different types of metastatic cancers. After eight to 10 days, they biopsied tumor tissue from each patient and found that the virus was replicating itself in the tumors of seven of the eight patients who had received the highest dose, with no serious side effects. Several weeks after the injection, tumors in about half of the patients seemed to stop growing, and shrunk in one patient.
While the study is not the first to test a cancer-killing viral therapy, it is the first to thoroughly document the behavior of the virus in patients' biopsy tissue. The results confirm that viruses can be used to selectively target these cells.
Researchers still don't know how well the virus will combat cancer. Such early trials "are not supposed to determine efficacy, but obviously, everyone is looking," says Samuel Rabkin, a virologist at Massachusetts General Hospital in Boston. Rabkin was not involved in the study. Patients whose cancers seemed to stabilize weren't necessarily the ones in which the researchers found the virus replicating, he notes. "It is actually one of the large questions in the field—is the therapeutic effect directly related to the amount of virus replication in the tumor?"
Another concern is that if patients get more than one dose, the body might get better at fighting off the virus, which could disarm the therapy
Jennerex is already testing the therapy in larger trials. It recently completed a trial in liver cancer that significantly improved patients' survival rates, Kirn says.
The current trial's results don't just bode well for JX-594, he says, but for the field of cancer-killing viruses overall. "We can now engineer a variety of different therapeutic products into this viral backbone."
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