Co-opting micro-organisms as anticancer agents is not a new concept, with multiple agents investigated since the beginning of the 20th century for their potential to kill tumor cells with some degree of selectivity or to redirect immune responses against malignant cells. Other than the instillation of bacillus Calmette-Guérin for superficial bladder cancer, these approaches were eventually abandoned because of lack of controlled evidence for antitumor responses, significant toxicity, and a shift to pharmacologic therapies. But over the past 5 years, a number of anticancer attenuated or engineered viruses have begun to be developed, based on a better understanding of both the viruses and the target tumors. An engineered adenoviral mutant (ONYX-015) has shown some activity against head and neck tumors in phase 1 and 2 clinical trials.
Peng and colleagues (page 2002) describe a very exciting property of the measles virus, namely efficient and selective killing of human myeloma cells. They have chosen to use the Edmundston-B live attenuated vaccine strain, given safely to hundreds of millions of people. Exposure of myeloma cell lines and primary myeloma plasma cells to this virus resulted in efficient infection, replication, multinucleated syncytia formation, and cell death, in contrast to lack of effects on human peripheral blood lymphocytes. Intratumoral or intravenous injection of the virus resulted in marked shrinkage of already established human myeloma tumors growing in immunodeficient mice. There was no systemic toxicity, but mouse cells do not have the receptor for the measles virus. Prior human experience using the virus as a vaccine involved lower doses administered subcutaneously. One potential problem with administration of an attenuated measles virus, namely, pre-existing immunity from prior vaccination, may be less of an obstacle in myeloma patients, known to have significant defects in mounting specific antibody responses.
The mechanisms for the selective killing of myeloma cells by this virus are unknown but could include increased uptake into tumor cells due to higher receptor levels, enhanced intracellular viral replication, or impaired antiviral responses of tumor cells. Further experimentation is in progress to answer these questions. The virus is also attractive because it can potentially be redirected to alternative tumor types by modification of a surface H-glycoprotein or enhanced in antitumor properties by addition of other genes to the measles genome. Meanwhile, clinical testing of this virus in myeloma patients would seem justified in the near future after completion of more extensive toxicity testing.
