T cells have been engineered to produce IL-2 and kill tumor cells specifically when encountered. This new immunotherapy eliminated melanoma and pancreatic cancer in mice without major side effects, and may offer a promising new strategy for fighting hard-to-treat solid tumors.
“I think this is a model for how we can use cell therapies to deliver many types of potent but toxic therapeutic agents in a much more targeted manner,” said Wendell Lim, PhD, director of the UCSF Cell Design Institute and senior author of this research.
In the study, published this week in Science, the researchers kept the cytokine contained within the cancer by programming the T cells to make IL-2, but only when they recognized tumor antigens on a cancer cell.
It’s been known for decades that IL-2, an immune molecule, has potent anti-cancer activity. However, the cytokine produces a toxic response when given systemically.
Meanwhile, T cells contain lytic granules containing enzymes called perforins that kill target cells by essentially punching holes in them. Modified T cells have been used successfully to treat B cell malignancies. But solid tumors have an immunosuppressive microenvironment that blocks T cell infiltration, activation, and proliferation. This is considered one of the major barriers to solid tumor immunotherapy.
As a result, while immunotherapies have changed the landscape of cancer treatment, relatively few patients (13% by one estimate) respond to such treatment.
The UCSF researchers used a synthetic Notch (or synNotch) receptor that Lim’s lab developed several years earlier. The receptor spans the cell membrane, with ends that protrude both inside and outside the cell. The outside portion recognizes and binds to tumor cells, triggering the inside portion to produce IL-2.
“We’ve taken advantage of the ability of these cells to be local delivery agents and to crank out their T cell amplifiers only when they recognize they’re in the right place,” said Lim.
These researchers aimed to focus the cytokine’s effects only in a tumor. The team tested the synNotch cells on a number of tumors, including melanoma and pancreatic cancer. The approach was effective in each case.
“We were able to design these therapeutic cells to slip past the tumor’s defensive barriers. Once in the tumor, they could establish a foothold, and begin effectively killing cancerous cells,” said Greg Allen, MD, PhD, lead author of the study, adjunct assistant professor of medicine, and a fellow at the Cell Design Institute. “We got on top of these tumors and in some cases cured them.”
“This induction circuit is really a positive-feedback loop, an important element behind making these designer T cells that are able to operate so effectively,” Allen added.
The circuit begins when the synNotch receptor tells the T cell to make IL-2. That IL-2 feeds back on the cell, causing it to divide, in turn creating more cells that make even more IL-2. The entire process is confined within the tumor, protecting the rest of the body from harm.
Allen hopes to begin testing the therapeutic approach in clinical trials with pancreatic cancer patients in 2024.
“The most advanced immunotherapies are just not working in a lot of these difficult solid tumors,” he said. “We think this type of design can overcome one of the major barriers and do it in a way that’s safe and free of side effects.”
