New molecule offers a more targeted and potent immunotherapy

A newly developed molecule brings together two powerful immunotherapy strategies in one treatment. Researchers at the University of Basel and University Hospital Basel, Switzerland, have demonstrated that this fusion protein can both block the "do not attack" signal used by cancer cells and selectively activate tumor-fighting immune cells. This dual action could pave the way for more effective cancer therapies with fewer side effects.

Back in the early 1980s, Linda Taylor, just 33 years old, was diagnosed with advanced skin cancer and faced a grim prognosis. Luckily, she met Dr. Stephen Rosenberg from the National Cancer Institute in Bethesda, Maryland, who treated her with an experimental approach harnessing the body's own immune system to fight the disease. In 1984, Taylor became the first patient ever to be cured through immunotherapy – a groundbreaking case that forever changed the landscape of cancer treatment.

That pioneering therapy relied on interleukin-2 (IL-2), a signaling molecule that activates many types of immune cells to attack tumors. IL-2 later became the first immunotherapy approved by the U.S. Food and Drug Administration (FDA). However, while effective, IL-2 therapy often causes severe side effects and can also stimulate regulatory T cells, which dampen the immune response instead of boosting it.

Fewer side effects, increased efficiency

To overcome these limitations, scientists have recently developed improved IL-2 variants designed to specifically target tumor-killing immune cells. The new fusion protein – developed by the pharmaceutical company Roche – takes this a step further by combining an IL-2 variant (IL-2v) with an antibody that binds to PD-1, a receptor found in high numbers on immune cells within tumors.

In Science Translational Medicine, a research team led by Professor Alfred Zippelius from the Department of Biomedicine reports promising results with that fusion protein using cancer and immune cells from lung cancer patients. The researchers showed that the molecule selectively activated immune cells isolated from patient tumors that directly target and destroy cancer cells, without triggering the suppressive regulatory T cells. Importantly, it also reawakened "exhausted" immune cells that had been rendered inactive by chronic stimulation in the tumor environment.

Blockage removal and activation

The fusion of the two components, PD-1 antibodies and IL-2v, has two advantages: The antibody guides IL-2v directly to the tumor site, where it activates the immune cells most capable of destroying cancer cells. At the same time, the antibody blocks the PD-1 pathway, which tumors use to suppress immune attack, effectively releasing the immune system's brakes and allowing it to respond more aggressively.

The tumor normally restricts the immune system, but the fusion molecule overcomes this inhibition and additionally activates the immune cells."

Dr. Clara Serger, University of Basel

The team's findings provide crucial insights into how this innovative therapy works and may help guide further refinements. The fusion protein is currently being evaluated in an ongoing phase I clinical trial led by Roche.