Injecting small amounts of two immune-stimulating agents directly into solid tumors in mice eliminated all traces of cancer, including distant, untreated metastases, according to a new study.
The approach works for many different types of cancers, including those that arise spontaneously, the study finds.
The researchers believe the local application of very small amounts of the agents could serve as a rapid and relatively inexpensive cancer therapy that is unlikely to cause the adverse side effects often seen with body-wide immune stimulation.
“When we use these two agents together, we see the elimination of tumors all over the body,” says Ronald Levy, professor of oncology at Stanford University and lead author of the study, which appears in Science Translational Medicine.
“This approach bypasses the need to identify tumor-specific immune targets and doesn’t require wholesale activation of the immune system or customization of a patient’s immune cells.”
“…we saw amazing, body-wide effects, including the elimination of tumors all over the animal.”
One of the agents is already approved for use in humans; and the other has been tested for human use in several unrelated clinical trials. A clinical trial was launched in January to test the effect of the treatment in patients with lymphoma.
Levy works in the field of cancer immunotherapy, in which researchers try to harness the immune system to combat cancer. Work in his lab led to the development of rituximab, one of the first monoclonal antibodies approved for use as an anticancer treatment in humans.
Some immunotherapy approaches rely on stimulating the immune system throughout the body. Others target naturally occurring checkpoints that limit the anti-cancer activity of immune cells. Still others, like the CAR T-cell therapy recently approved to treat some types of leukemia and lymphomas, require a patient’s immune cells to be removed from the body and genetically engineered to attack the tumor cells.
Many of these approaches have been successful, but they each have downsides—such as difficult-to-handle side effects and high-cost and lengthy preparation or treatment times.
“All of these immunotherapy advances are changing medical practice,” Levy says. “Our approach uses a one-time application of very small amounts of two agents to stimulate the immune cells only within the tumor itself. In the mice, we saw amazing, body-wide effects, including the elimination of tumors all over the animal.”
T cells lead the charge
Cancers often exist in a strange kind of limbo with regard to the immune system. Immune cells like T cells recognize the abnormal proteins often present on cancer cells and infiltrate to attack the tumor. However, as the tumor grows, it often devises ways to suppress the activity of the T cells.
The new method works to reactivate the cancer-specific T cells by injecting microgram amounts of two agents directly into the tumor site. (A microgram is one-millionth of a gram).
The first, a short stretch of DNA called a CpG oligonucleotide, works with other nearby immune cells to amplify the expression of an activating receptor called OX40 on the surface of the T cells. The second, an antibody that binds to OX40, activates the T cells to lead the charge against the cancer cells.
Because the two agents are injected directly into the tumor, only T cells that have infiltrated it are activated. In effect, these T cells are “prescreened” by the body to recognize only cancer-specific proteins.
Some of these tumor-specific, activated T cells then leave the original tumor to find and destroy other identical tumors throughout the body.
The approach worked startlingly well in laboratory mice with transplanted mouse lymphoma tumors in two sites on their bodies. Injecting one tumor site with the two agents caused the regression not just of the treated tumor, but also of the second, untreated tumor.
In this way, 87 of 90 mice were cured of the cancer. Although the cancer recurred in three of the mice, the tumors again regressed after a second treatment. The researchers saw similar results in mice with breast, colon, and melanoma tumors.
Mice genetically engineered to spontaneously develop breast cancers in all 10 of their mammary pads also responded to the treatment. Treating the first tumor that arose often prevented the occurrence of future tumors and significantly increased the animals’ life span.
Finally, lead author Idit Sagiv-Barfi, instructor of medicine, explored the specificity of the T cells by transplanting two types of tumors into the mice. She transplanted the same lymphoma cancer cells in two locations, and she transplanted a colon cancer cell line in a third location. Treatment of one of the lymphoma sites caused the regression of both lymphoma tumors but did not affect the growth of the colon cancer cells.
“This is a very targeted approach,” Levy says. “Only the tumor that shares the protein targets displayed by the treated site is affected. We’re attacking specific targets without having to identify exactly what proteins the T cells are recognizing.”
The current clinical trial is expected to recruit about 15 patients with low-grade lymphoma.
If successful, Levy believes the treatment could be useful for many tumor types. He envisions a future in which clinicians inject the two agents into solid tumors in humans prior to surgical removal of the cancer as a way to prevent recurrence due to unidentified metastases or lingering cancer cells, or even to head off the development of future tumors that arise due to genetic mutations like BRCA1 and 2.
“I don’t think there’s a limit to the type of tumor we could potentially treat, as long as it has been infiltrated by the immune system,” Levy says.
The National Institutes of Health, the Leukemia and Lymphoma Society, the Boaz and Varda Dotan Foundation, the Phil N. Allen Foundation, and Stanford’s department of medicine supported the work.
Source: Stanford University