Scientists at UC San Francisco (UCSF) have engineered T cells to produce a potent cancer-fighting cytokine, but only when they encounter tumor cells. Immunotherapy eliminated melanoma and pancreatic cancer in mice without major side effects, and offers a promising new strategy to fight these and other hard-to-treat cancers.
The cells deliver IL-2, a powerful inflammatory molecule naturally produced by the immune system. IL-2 supercharges T lymphocytes, immune cells capable of killing cancer cells and protecting against infections. While oncologists have known for decades that IL-2 has potent anticancer activity, its use has been limited by the toxic response it produces when administered systemically.
In the study, published December 15, 2022 in the journal Sciencethe researchers managed to maintain the cytokine in cancer by programming tumor-infiltrating T cells to produce their own IL-2 when they recognize a cancer cell.
We have taken advantage of these cells’ ability to be local delivery agents and only bring out their T-cell enhancers when they recognize they are in the right place. I think this is a model of how we can use cell therapies to deliver many kinds of potent but toxic therapeutic agents in a much more targeted way. »
Wendell Lim, PhD, Byers Distinguished Professor of Cellular and Molecular Biology, director of the UCSF Cell Design Institute and lead author of the study.
Cross the barriers
Cell therapies have been very effective against many blood cancers, where the cells are easily accessible because they are free-floating. Solid tumors, however, build multiple defensive walls that prevent therapeutic T cells from getting through. to enter it. And even if the cells manage to enter the tumor, they often run out before they are able to eliminate the cancer cells.
Since the 1980s, oncologists have known that high doses of IL-2 allow T cells to overcome these obstacles, and the cytokine has been used as a cancer therapy in difficult cancer cases. But simply giving patients a systemic infusion of IL-2 can lead to high fever, leaky blood vessels and organ failure.
Lim and lead author Greg Allen, MD, PhD, assistant professor of medicine and member of the Cell Design Institute, sought to harness the effects of IL-2 by designing cells that enhance the anti-cancer immune response only where it is needed: in the tumor.
They chose to tackle notoriously difficult-to-treat tumours, such as those of the pancreas, ovary and lung, which form nearly inviolable barriers against T cells.
To make T cells that can sense their presence in the tumor, the researchers used a synthetic Notch receptor (or synNotch), a flexible type of molecular sensor, which Lim’s lab had developed several years earlier. These receptors cross the cell membrane, with ends that protrude inside and outside the cell. The outer part recognizes and binds to tumor cells, which triggers the inner part to produce IL-2.
The team tested synNotch cells on a number of deadly tumors, including melanoma and pancreatic cancer, and found that the cells worked exactly as expected.
“We have succeeded in designing these therapeutic cells so that they can cross the defensive barriers of the tumour. Once in the tumor, they were able to take hold and start killing cancer cells effectively,” Allen said. “We took over these tumors and in some cases we cured them. »
A positive feedback circuit
This approach owes its success to the engineering of a circuit within the cell that amplifies the immune response in a controlled manner. This prompts the cell to produce IL-2 only under the specific conditions it is programmed to recognize.
“That induction circuit is really a positive feedback loop, an important part in making these design T cells that are able to act so efficiently,” Allen said.
The circuit begins when the synNotch receiver tells the T cell to produce IL-2. This IL-2 backfires on the cell, causing it to divide, in turn creating other cells that produce even more IL-2. The entire process is confined to the tumor, thereby protecting the rest of the body.
Allen, who is both a researcher and an oncologist, hopes to start testing this therapeutic approach in clinical trials on patients with pancreatic cancer in 2024.
“The most advanced immunotherapies just don’t work in a lot of these difficult solid tumors,” he said. “We believe this type of design can overcome one of the main hurdles and do so in a way that is safe and without side effects. »
Source :
University of California–San Francisco
Journal reference:
Allen, G.M., et al. (2022) Synthetic cytokine circuits that direct T cells to tumors excluded from the immune system. Science. doi.org/10.1126/science.aba1624.