Immuno-oncology treatments like PD-1 inhibitors and CAR-T cells have generated excitement among cancer doctors and patients in recent years because of their high cure rates, but they’re far from perfect. CAR-T cells, for example, require removing immune cells from patients and engineering them in a time-consuming and expensive process. So a research team at Stanford is investigating a much simpler way to stimulate the immune system to recognize and attack cancer cells—and charting promising results in mouse trials.
The approach involves injecting tiny amounts of two immune-boosting molecules directly into tumors. One, called CpG oligonucleotide, is a short stretch of DNA that ramps up the expression of OX40, a protein that resides on the surface of the immune system’s T cells. The other is an antibody that binds to OX40 and directs the T cells to eliminate cancer cells. The treatment worked well in mice with lymphoma, breast, colon and melanoma tumors, the team reported in the journal Science Translational Medicine.
Stanford has begun a clinical trial that’s expected to include about 15 patients with lymphoma, according to a statement from the university.
Even though the treatment targets T cells that reside in tumors, the researchers were able to show that some of the tumor-specific immune cells actually left the original cancerous site and traveled around the body, seeking out and destroying similar tumors.
"Our approach uses a one-time application of very small amounts of two agents to stimulate the immune cells only within the tumor itself,” said senior author Ronald Levy, a professor of oncology at Stanford, in the statement. Levy is well-known in the oncology world for pioneering research that led to the development of Genentech’s cancer blockbuster Rituxan. “In the mice, we saw amazing, bodywide effects, including the elimination of tumors all over the animal."
In one of the mouse trials, 87 out of 90 mice that had lymphoma tumors in two sites and received the treatment in just one of those tumors were cured, according to the statement. The three mice that relapsed were given the treatment a second time and their cancers disappeared. The researchers observed similar successes in the other tumor types.
The scientists wanted to prove that the treatment was teaching the T cells to recognize proteins specific to the tumors that they were injecting, so they implanted one type of lymphoma cell in two locations in the mice, and put colon cancer cells in a separate spot. After they treated one lymphoma tumor, both lymphomas were beaten back but the colon cancer kept growing.
"This is a very targeted approach," Levy said. "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 Stanford approach is one of several aimed at broadening the population of cancer patients who might benefit from immuno-oncology approaches. In December, a team at the at the University of California at San Francisco announced they have started a phase 1 trial of a therapeutic vaccine that works by targeting a misshapen protein on the surface of a rare type of childhood brain tumor. Scientists at the University of Chicago and the Icahn School of Medicine at Mount Sinai are developing new technologies aimed at improving checkpoint-inhibiting drugs like PD-1 blockers.
Stanford’s Levy has high hopes for his team’s two-drug combo approach. He believes that if the research pans out in human patients, the vaccine could someday be injected into tumors prior to surgical removal, to prevent relapses caused by unidentified metastases. "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," he said.