Update on the measles virus, a novel therapy for glioblastoma
In the 1970s, it was reported that natural infection with the measles virus (MV) led to spontaneous regression of hematologic cancers in African children. This and other, similar reports led to investigations of the oncolytic, or cancer-fighting, properties of MV and other viruses and their potential in cancer treatment.
Although approved in Asian countries, virotherapy drugs have not yet been approved in the United States. Mayo Clinic is the first institution to use MV as a cancer therapy, including treatment of glioblastoma multiforme (GBM), the most lethal brain tumor.
Under Mayo's previous Specialized Program of Research Excellence (SPORE) grant, medical oncologist Evanthia Galanis, M.D., with the departments of Oncology and Orthopedic Oncology at Mayo Clinic in Rochester, Minn., and colleagues brought MV from animal models to human testing in just three years. The phase 1 clinical trial used a modified MV strain in patients and found it safe and well tolerated.
Under a new SPORE grant, Dr. Galanis and neurosurgeon Ian F. Parney, M.D., Ph.D., with the Department of Neurosurgery at Mayo Clinic in Rochester, Minn., the project's co-directors, plan to develop a new phase 1 trial, focusing on re-engineered versions of MV to optimize its therapeutic impact and the ability to track the propagation of the virus.
Although wild-type MV can pose a serious health risk, millions of doses of vaccine strains of the virus, derived from the Edmonston vaccine lineage, have been administered worldwide with proven safety. Oncolytic viruses show selective preference for tumors because they can readily enter the tumor by exploiting either the molecular pathways associated with the malignant transformation or the specific receptors that are overexpressed by tumor cells.
Building on identified mechanisms of MV entry and propagation in particular, Dr. Galanis and her co-investigators discovered that a vaccine strain of MV causes glioma cells to fuse, forming multinuclear cell aggregates that trigger apoptosis. Each cell infected by the virus causes another 50 to 100 cells to fuse and die. This cell death recruitment, called the bystander effect, suggests that MV could be a particularly potent therapeutic agent.
The four subtypes of GBM tumors are based on variations in gene signatures, which result in protein differences across the subtypes. Some of these expressed proteins migrate to the surface of cells. Re-engineering the molecular characteristics of MV, a process called re-targeting, enables the virus to more efficiently recognize tumor subtype receptor proteins and to enter cells through them.
In addition, the Mayo research team has been able to modify the virus through genetic engineering so that it carries therapeutic transgenes and thus is even more effective.
Addressing the challenges of MV therapy
Animal model testing
Rodents are not susceptible to MV because they do not express MV receptors. For that reason, mice have been genetically engineered to produce MV receptors that mimic those in humans. Collaborating with Jann N. Sarkaria, M.D., with the Department of Radiation Oncology at Mayo Clinic in Rochester, Minn., and the head of the Animal Core facility of Mayo's brain cancer SPORE program, Dr. Galanis' team tested the virus in 10 different xenograft models.
There was significant anti-tumor efficacy in each of these tumor models and no toxicity. Before testing MV therapy in human clinical trials, however, additional toxicology studies were conducted, and the virus was found safe in measles-susceptible rhesus macaques, a primate species considered to be the gold standard of animal models for measles neurotoxicity.
Of note, brain tissue adjacent to tumors also expresses MV receptors, but at such low levels that the virus cannot propagate enough to harm normal brain cells.
Tracking virus propagation
Monitoring the propagation of MV is critical to determining its efficacy as a cancer treatment. A researcher cannot conduct multiple biopsies in treated patients for obvious safety considerations. Under the SPORE grant, Dr. Galanis and colleagues are testing two approaches for tracking viral replication — one through peripheral blood sampling and the other through radiographic imaging.
- The first approach involves engineering strains of MV to carry the soluble marker human carcinoembryonic antigen (CEA), which led to the construction of the viral strain MV-CEA. This antigen is not expressed by glioma cells but can be measured in the blood. Such a blood test would demonstrate propagation but would not be location specific.
- The second approach is to introduce into the virus a gene called sodium iodine symporter (NIS), which traps radioactive iodine and thus could be imaged by CT SPECT. The additional advantage of this approach, notes Dr. Galanis, is that "targeted imaging of MV activity would allow us to both determine viral localization and target radiation, in the form of therapeutic iodine radioisotopes, to the tumor. What we have found in animal models is that viral replication actually increases in irradiated cells. The combination of virus and radiation creates a strong synergistic effect."
Human anti-measles immunity
Another challenge to using MV therapeutically is the fact that most patients have been immunized against MV. This immunization is less of a challenge when MV is injected directly into the tumor during a neurosurgical procedure, as it is in GBM, than its systemic administration for other forms of cancer. Targeted tumor injection of MV also overcomes the effects of the blood-brain barrier.
Independent of the route of viral administration, blocking the innate immune response within the tumor itself can promote viral spread in the tumor. This modification of the innate immune response can be accomplished by using the immunosuppressant cyclophosphamide.
Its effectiveness as an additive to MV for GBM has been demonstrated in mice bearing human tumor xenografts. Furthermore, administration of the MV-NIS strain of the virus in combination with cyclophosphamide has been found to reduce the primary immune response and prolong viral gene expression in squirrel monkeys.
Another strategy that Dr. Galanis and colleagues are investigating is the use of mesenchymal stem cells, which may not only aid in circumventing anti-measles immunity but also may facilitate the systemic delivery of the viral treatment. This strategy can be important in cancers such as ovarian cancer, for which Dr. Galanis is developing a human safety trial.
Phase 1 GBM clinical trial extension
Drs. Galanis and Parney and their colleagues look forward to Mayo's SPORE-funded development of the follow-up phase 1 clinical trial using new strains of engineered MV, such as MV-NIS. Dr. Galanis notes that the rapid translation from laboratory to human testing in the previous trial was greatly expedited by the SPORE grant, which facilitates teamwork. The grant helped in the acquisition of human tumor tissue samples, for example, and supported in vivo testing in animal models, as opposed to testing established cell lines in vitro. Thus, preclinical efficacy studies were conducted in tumor models that more closely mimic human tumor morphological and histopathologic features.
Mayo's vector production laboratory has developed improved production methods so that increased doses of the virus can be delivered in small volumes — an important consideration when injecting the brain.
The efficient collaboration between researchers in Mayo's molecular medicine laboratories and its Toxicology and Biodistribution laboratory also helped validate the safety of MV therapy in primates, a key consideration when introducing a novel therapeutic approach such as MV. The tight links between laboratories and the level of integration with patient care at Mayo hold promise for an equally efficient transition into the follow-up phase 1 clinical trial.
Of note, the high expression of MV receptors in human GBM tumors is a mechanism that tumor cells use to escape immune surveillance. It now appears that re-engineered MV could be the Trojan horse that takes these receptors up on their invitation and delivers a much-needed and powerful weapon in the fight against GBM.