Based on a recent study, Harvard Stem Cell Institute (HSCI) scientists at Massachusetts General Hospital may have discovered a possible solution for how to effectively kill tumor cells using cancer-killing viruses. The researchers note that ensnaring virus-loaded stem cells in a gel and then applying them to tumors greatly improved survival in mice with glioblastoma multiforme, the most common brain tumor in human adults and also the hardest to efficiently treat.
The study, which was led by Khalid Shah, MS, PhD, an HSCI Principal Faculty member, has been published in the Journal of the National Cancer Institute.
Additionally, Shah heads the Molecular Neurotherapy and Imaging Laboratory at Massachusetts General Hospital.
Cancer-killing or oncolytic viruses have been applied in numerous phase 1 and 2 clinical trials for brain tumors but has produced limited success. In preclinical studies, oncolytic herpes simplex viruses appeared considerably promising, as they naturally contaminate dividing brain cells. Yet, the therapy hasn't made an effective transition when applied on human patients. The issues prior researchers couldn't find a solution to was how to keep the herpes viruses at the tumor site long enough to work.
Shah and his team decided to test out mesenchymal stem cells (MSCs), a type of stem cell that gives rise to bone marrow tissue, which has always been an attractive drug delivery vehicle due to the fact that they trigger a minimal immune response and can be employed to transport oncolytic viruses.
Shah and his team placed the herpes virus into human MSCs and injected the cells into glioblastoma tumors developed in mice. Using several imaging markers, it was possible to observe the virus as it crossed from the stem cells to the first layer of brain tumor cells and subsequently into all of the tumor cells.
"So, how do you translate this into the clinic?" asked Shah, who also serves as an Associate Professor at Harvard Medical School.
"We know that 70-75 percent 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. 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," he said.
Using imaging proteins to observe in real time how the virus countered the cancer, Shah's team noticed that the gel kept the stem cells alive longer, which enabled the virus to multiply and kill any remaining cancer cells that were not cut out during the debulking surgery. This carried over 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. 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," commented Shah.
The study also tackled another weakness of cancer-killing viruses, which is that not all brain tumors are vulnerable to the therapy. The researchers' answer was to develop oncolytic herpes viruses to express an additional tumor-killing agent, called TRAIL. Once more, using mouse models of glioblastoma, this time created from brain tumor cells that were opposed to the herpes virus, the therapy resulted in an increased animal survival.
"Our approach can overcome problems associated with current clinical procedures. The work will have direct implications for designing clinical trials using oncolytic viruses, not only for brain tumors, but for other solid tumors," said Shah.
More preclinical work will be required in order to apply the herpes-filled stem cells for breast, lung, and skin tumors that metastasize to the brain. Shah believes the method will be welcomed into clinical trials within the next two to three years.