A remote-controlled CAR-T for safer immunotherapy

(Press-News.org) FEBRUARY 19, 2026, NEW YORK – Among the most promising tools of cancer therapy, engineered immune cells known as chimeric antigen-receptor (CAR) T cells have already transformed the treatment of blood cancers. Yet, despite their promise, CAR-T cells do have their limitations. For one thing, they’ve so far largely failed against solid tumors, which is to say, most types of cancer. For another, they can inadvertently kill healthy cells along with cancerous ones—or, separately, provoke a systemic immune overreaction—causing serious and sometimes even lethal side effects.

To address these challenges, researchers led by Ludwig Lausanne’s Melita Irving and Greta Maria Paola Giordano Attianese and their colleagues Leo Scheller and Bruno Correia of the École Polytechnique Fédérale de Lausanne (EPFL) have engineered a CAR-T cell that can swiftly, and with minimal fuss, be switched off, on demand. The researchers report in the current issue of Nature Chemical Biology the design and preclinical evaluation of these new CAR-T cells, demonstrating both their efficacy and controllability in mouse models of cancer.

“Our work introduces a simple and clinically realistic way to reversibly dial down CAR-T cell activation using as a remote control a cancer drug, venetoclax, that is already in clinical use as a cancer therapy,” said Irving. “The remote control doesn’t trigger the self-destruction of the CAR-T cells, which is how many others have approached this challenge, but simply prompts them to disengage and fall off from their cancerous targets. This capability could help clinicians better modulate the delivery of CAR-T therapy and perhaps enable its application to more patients and types of cancer.”

Classical CARs sport a protein receptor that sticks out of the engineered T cell like a wand. This cancer cell-detecting end of the CAR is typically derived from the antigen-binding fragment of an antibody molecule, which can be designed to grab virtually any target with exquisite specificity.

When it detects its molecular quarry—a cancer antigen—this engineered receptor triggers the transmission of signals from its tail end inside the cell to engage the T cell’s cytotoxic machinery. The internal signaling components are stitched together from the biochemically active part, or “domain”, of a protein called CD3-ζ, which is required to activate the T cell upon antigen binding, and another from a “co-stimulatory” protein (like CD28) that boosts the function and persistence of the T cells after activation.

Irving, Giordano Attianese and their colleagues previously devised a method to control CAR-T activity by separating the cell’s internal signaling chain from the receptor and using venetoclax to bring them together to activate the CAR-T cell. In that system, another drug induced the degradation of the internal signaling component to switch off the CAR-T cell.

Their new remote-controlled CAR-T cell sports a “drug-regulated off-switch PPI CAR” (DROP-CAR) that places the switch on the outside of the cell. The signaling component of the CAR inside the cell is linked to a strip of protein on the outside of the cell. That strip carries at its tip a computationally designed human domain known as dmLD3 that binds a protein named BCL-2 with very high affinity. The cancer-sensing antibody of the CAR, for its part, carries at its tail end the bit of BCL-2 recognized by dmLD3.

Held together by this spontaneous protein-protein interaction (hence the “PPI” in its name), the CAR remains intact and functional until venetoclax disrupts that interaction. At that point, the dmLD3 and BCL-2 domains disengage and the CAR falls apart, switching off CAR-T cell’s lights. When venetoclax is withdrawn, the CAR reassembles and the CAR-T cells get back to killing cancer cells.

“Unlike previous controllable CAR designs, our system uses only human protein components and a clinically approved, non-immunosuppressive drug to directly disrupt tumor cell binding by the CAR-T cells,” said Giordano Attianese. “Because the switch acts at the level of cell–cell contact rather than inside the cell—by, for example, blocking signaling, degrading CAR components or inducing cell death—it offers an enhanced safety profile and permits control of the CAR-T cells without requiring their sacrifice, thus preserving them for continued treatment.”

This ability to control CAR-T cell activity could also help mitigate a phenomenon known as T cell “exhaustion” that accounts for the failure of many T cell-based immunotherapies. Caused by the continuous and nonproductive stimulation of T cells in the immunosuppressive microenvironment of tumors, exhaustion pushes T cells into a functionally sluggish state in which they’re incapable of killing their target cells. Previous studies have shown that giving CAR-T cells periods of rest between bouts of active tumor targeting can reverse the genomic alterations that drive exhaustion and boost their functional efficacy. DROP-CAR-T cells are well suited to this strategy.

Since the drug required to control DROP-CARs is already approved for cancer therapy, Irving, Giordano Attianese and their colleagues suggest their CAR-T system is uniquely poised for clinical evaluation.

Swiss National Science Foundation, the Fondazione Teofilo Rossi di Montelera e di Premuda, the Prostate Cancer Foundation, the Swiss Institute for Experimental Cancer Research, the National Centers of Competence in Research, the European Research Council, the Swiss Cancer League, the ETH Domain and the Anniversary Foundation of Swiss Life for Public Health and Medical Research.

 

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About Ludwig Cancer Research

Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for more than 50 years. Ludwig combines basic science with the translation and clinical evaluation of its discoveries to accelerate the development of new cancer diagnostics, therapies and prevention strategies. Since 1971, Ludwig has invested nearly $3 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit www.ludwigcancerresearch.org.

For additional information please contact communications@ludwigcancerresearch.org

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