Although cancer-killing viruses have shown promise against brain tumors in many preclinical trials, they have tended to wash out when used in humans. Naked virus, injected directly into cavities left by resected, debulked tumors, simply doesn’t stay long enough to replicate and kill residual cancer cells. Before it can replicate and spread, the oncolytic virus is flushed away by cerebrospinal fluid.
Still, one virus, oncolytic herpes simplex virus (oHSV), appeared to have so much potential against malignant glioblastoma multiforme, the most common brain tumor in human adults, that researchers looked for a way to increase its staying power. The researchers, led by Khalid Shah, Ph.D., of the Harvard Stem Cell Institute, resorted to making good use of a hydrogel.
Dr. Shah and his team started with mesenchymal stem cells (MSCs), which are attractive drug delivery vehicles because they trigger a minimal immune response and can be utilized to carry oncolytic viruses. After loading human MSCs with oHSV, the researchers injected the cells into glioblastoma tumors developed in mice. Then the researchers used multiple imaging markers to track the virus it passed from the stem cells to the first layer of brain tumor cells and subsequently into all of the tumor cells.
So far, so good, at least in the mouse model. But how could such infiltration be achieved in the clinic? Well, here’s where the hydrogel comes in.
“We know that 70–75% of glioblastoma patients undergo surgery for tumor debulking, and we have previously shown that MSCs encapsulated in biocompatible gels can be used as therapeutic agents in a mouse model that mimics this debulking,” said Dr. Shah. “So, we loaded MSCs with oncolytic herpes virus and encapsulated these cells in biocompatible gels and applied the gels directly onto the adjacent tissue after debulking. We then compared the efficacy of virus-loaded, encapsulated MSCs versus direct injection of the virus into the cavity of the debulked tumors."
Using imaging proteins to watch in real time how the virus combated the cancer, Dr. Shah's team noticed that the gel kept the stem cells alive longer, which allowed the virus to replicate and kill any residual cancer cells that were not cut out during the debulking surgery. This translated into a higher survival rate for mice that received the gel-encapsulated stem cells.
“They survived because the virus doesn’t get washed out by the cerebrospinal fluid that fills the cavity,” Dr. Shah explained. “Previous studies that have injected the virus directly into the resection cavity did not follow the fate of the virus in the cavity. However, our imaging and side-by-side comparison studies showed that the naked virus rarely infects the residual tumor cells. This could give us insight into why the results from clinical trials with oncolytic viruses alone were modest.”
These results are presented in an article entitled “Stem Cells Loaded with Multimechanistic Oncolytic Herpes Simplex Virus Variants for Brain Tumor Therapy.” It is scheduled to appear in the June issue of the Journal of the National Cancer Institute.
The word “multimechanistic” in the article’s title refers to another innovation the researchers introduced—they used more than one kind of oHSV. The additional oHSV, a proapoptotic variant, was engineered to express a tumor-killing agent called TRAIL.
“Using novel diagnostic and armed oHSV mutants and real-time multimodality imaging, the efficacy of MSC-oHSV and oHSV-TRAIL encapsulated in biocompatible synthetic extracellular matrix was tested in different mouse GBM models, which more accurately reflect the current clinical settings of malignant, resistant, and resected tumors,” the authors wrote. “MSC loaded with oHSV-TRAIL effectively induced apoptosis-mediated killing and prolonged median survival in mice bearing oHSV- and TRAIL-resistant GBM in vitro.”
“Our approach can overcome problems associated with current clinical procedures,” Dr. Shah asserted. “The work will have direct implications for designing clinical trials using oncolytic viruses, not only for brain tumors, but for other solid tumors.”
Further preclinical work will be needed to use the herpes-loaded stem cells for breast, lung, and skin cancer tumors that metastasize to the brain. Dr. Shah predicts the approach will enter clinical trials within the next two to three years.