Triple therapy sparks a powerful immune attack on leukemia

The findings were recently reported in Science Advances.

How Necroptosis Strengthens Immune Responses

Immunotherapy represents a major shift in cancer treatment, as it relies on the body's natural defenses to identify and eliminate tumor cells. Immune cells act like vigilant sentries, moving through tissues and detecting remaining cancer cells that could lead to relapse. Among the new approaches being explored is a form of programmed cell death called necroptosis. Unlike apoptosis, which quietly removes cells, necroptosis produces signals that draw immune cells to the area. These signals help prompt the immune system to attack and clear any surviving tumor cells.

Scientists in the Dynamics of Immune Responses Unit (a joint Inserm/Institut Pasteur unit) investigated whether necroptosis could help treat blood cancers. Their initial work showed that malignant B cells do not readily undergo necroptosis because they lack the MLKL protein, which is essential for this process.

Triple Therapy Overcomes a Key Barrier

To address this limitation, the team used a combination of three drugs already approved for clinical use. This combination successfully triggered necroptosis in malignant B cells and produced a powerful immune response that completely eliminated leukemia in a preclinical model. "The triple therapy we used forces cancer cells to die in a way that activates the immune system," says Philippe Bousso, Inserm Research Director and Head of the Institut Pasteur's Dynamics of Immune Responses Unit.

Real-Time Imaging Reveals Immune Activation

The researchers relied on an advanced intravital imaging method to watch immune cells interact with cancer cells in real time. This allowed them to directly observe how different forms of cell death influenced immune behavior.

"This novel immunotherapy strategy, successfully tested in preclinical models, turns tumor cells into triggers for the immune system, pointing to a potential therapeutic avenue for certain cancers, such as lymphomas or leukemias affecting B cells," explains Philippe Bousso.

"By changing the way cancer cells die, we can harness the support of our immune system to fight against the tumor," he adds.

The research received support from the institutions noted above, along with the European Research Council (ERC) and the ARC Foundation for Cancer Research.