Viruses designed to kill cancer cells are already used to treat one skin cancer and are commonly studied in other cancers.
A new study shows that oncolytic viruses known as viruses can be enhanced further to improve the body’s immune response to tumors. The researchers found that this new type of oncolytic virus can simultaneously kill the cancer cells and provide tumor immune cells with a hormone that they need to perform their own cell killing functions.
The dual-function virus was significantly more active in shrinking and removing tumors in mice with melanoma tumors than a regular oncolytic virus.
The findings of the study were published in Immunity on 17 September.
"The new thing here is that this virus has been engineered to relieve immunosuppression" in addition to killing tumor cells outright, explained Phillip Daschner, program director in NCI"™s Division of Cancer Biology, who was not involved with the study. "It"™s an idea that may be quickly translated to use in patients."
Shut Down by a Toxic Environment
Oncolytic viruses kill cancer cells, but studies also show they can increase the ability of the immune system to recognize and kill a tumor.
Specifically, the viruses enter tumor cells and multiply them, breaking up the cells. When this breakdown happens, cancer cell proteins that the immune system"“known as tumor antigens-recognizes are released into the bloodstream. This can lead to the incorporation of T cells into a tumor and can even lead to metastatic cancer elsewhere in the body.
But getting T cells to reach and enter a tumor is only part of the challenge, explained Greg Delgoffe, Ph.D., of the University of Pittsburgh Medical Center, who led the new study. "The tumor environment by its own nature is toxic," he said. "When T cells get in, they experience a harsh, low-oxygen, desert-like landscape." This environment can render immune cells unable to function.
Dr. Delgoffe’s lab tested an oncolytic virus (an engineered variant of the virus Vaccinia) to better understand how cancer-immune cell interactions alter following a viral tumor infection. They found that their virus was able to lead to a significant number of T cells entering tumors when injected into tumors in the mice.
The newly arrived T cells seemed healthy and vigorous, according to the researchers. Yet T cells ‘ ability to kill can fade and become soft spectators with reduced ability to damage cancer cells " a phenomenon also known as fatigue.
The T-cells found by Dr. Delgoffe and his team in the tumors were not depleted and suggest that they were new to the tumors. However, further testing showed that after entering the tumor, these newly arrived T cells developed rapid metabolic problems.
People often refer to immunotherapies as "accelerators," or agents that "take the brakes off" the immune system, Dr. Delgolffe said. "But accelerators and brakes don"™t matter if there isn"™t any gas in the tank."
"The virus on its own did a really good job of getting the immune cells activated," he said. So the research team wanted to enhance the virus, he continued, so that it would secrete something into the local environment to provide the gas for the T cells.
Supporting T Cells
The team quickly zeroed in on a hormone called leptin as a possible supportive molecule. Leptin is best known for helping the body regulate hunger"and therefore weight. But it"™s also needed by the body"™s immune cells.
Not only did the tumors the researchers analyzed have low concentrations of leptin, but the T cells in those tumors had high levels of the receptor for the hormone. "This was especially true for exhausted T cells," explained Dr. Delgolffe.
Cell culture experiments have shown that high levels of leptin improve T cells ‘ ability to kill tumor cells. The scientists have therefore tried to deliver high levels of leptin to the bloodstream of mice with melanoma tumors. But this way, leptin administered had no effect on tumor T cells.
To push leptin deep into the tumor microenvironment, the team of Dr. Delgoffe reengineered the oncolytic virus of the leptin gene. The virus will also generate leptin when it is replicated inside a cancer cell.
Once researchers injected the dual-function virus in mice directly into melanoma tumors, the tumors shrank significantly, and approximately a quarter of the mice reacted completely (i.e. their tumors completely disappeared). Such mice lived much longer than the mice with a leptin gene injected with a control virus.
In the mouse model of advanced pancreatic cancer the leptin-expressing virus also enhanced its survival.
Potential for Preventing Cancer Recurrence
Injection with the leptin-expressing virus also seemed to serve as a cancer vaccine in some mice with melanoma. When the team injected the same tumor cells into mice that had experienced a complete response to the leptin-engineered virus, the immune systems of most of these mice prevented tumor regrowth.
In the minority of mice that did have tumor regrowth, their tumors grew at slower rates. This suggests that the engineered virus had primed the immune system to remember and recognize the tumor cells (immune memory), Dr. Delgoffe said.
"It"™s very exciting that there"™s some evidence of immune memory against tumors," Daschner said. "If this could work the way a vaccine works, hopefully patients would develop immunity that could prevent tumor recurrence."
Dr. Delgoffe and his team are now investigating whether altering the leptin component of the virus could result in better responses. These tweaks include engineering leptin to make it better at finding and binding to T cells and to make it last longer in the tumor microenvironment. The researchers also plan to test the addition of other supportive molecules besides leptin to their virus.
Further studies will be needed before the dual-functioning virus is ready for testing in people, including understanding if the virus could work as well if injected into the bloodstream as when injected into a tumor, Daschner explained. Direct injection into a tumor would not always be possible in people, he said.
Viruses aren"™t the only microbe being studied as potential cancer treatments. NCI"™s Bugs as Drugs initiative, for example, is supporting research into treatments based on bacteria and bacteriophages (tiny viruses that infect bacteria). "It"™s a very exciting class of potential new therapies," he said.
The leptin-expressing virus, by comparison, has not improved the survival of tumors already known to have a T-cell-supporting microenvironment over and above what has been seen in the oncolytic virus that does not include the leptin gene.