CAR T cells are a powerful anticancer modality, but first-generation CAR T-cell treatments are hard to control. After administration, the cells can overstimulate the immune system, causing potentially fatal adverse events such as cytokine release syndrome. While physicians have developed ways to mitigate the side effects and reduce the rate of severe outcomes, they still lack the means to turn the cell therapies off completely.

Multiple R&D teams in academia and industry are working to provide that level of control. The goal is to make CAR T-cell therapies more like conventional treatments, in that physicians can dial the intensity of the intervention up and down incrementally after seeing how patients respond.

Researchers at Boston University posted details of their contribution to the effort in a September 8 article in the journal Cancer Cell. The paper describes the development of edited T cells, called Versatile ProtEase Regulatable CAR T cells (VIPER CARs).

Like other CAR T cells, VIPER CARs feature a receptor that crosses the cell membrane, with part housed inside the cell and part outside. The portion of the receptor that is outside of the cell binds with cancer antigens, activating the T cell and driving the destruction of cancer cells.

VIPER CARs feature an additional protein chain. When a protease inhibitor interacts with the protein chain, it triggers reactions that, depending on the design of the CAR, either switch the therapy on or off. Multiple protease inhibitors, such as Incivek and Mavyret, are approved in indications including hepatitis C.

"That is the most exciting part of this study, that the antivirals are already FDA approved," Huishan Li, PhD, lead author of the paper and a postdoctoral fellow at the Boston University College of Engineering, said in a statement.

The researchers validated their VIPER CARs in a xenograft tumor and a cytokine release syndrome mouse model. Pitted against other CARs that can be deactivated by drug molecules, the researchers found that the VIPER CARs delivered best-in-class performance.

Building on their success, the researchers combined various CAR technologies to engineer several VIPER CAR circuits. The therapies could target two different receptors, reducing the risk of cancers nullifying their effectiveness through antigen escape.

"We see this as the next generation of this type of therapy," said Wilson Wong, PhD, a Boston University College of Engineering associate professor of biomedical engineering. "We not only have a safety control in place, but we also can have multiple versions at the same time."

Having shown that the VIPER CARs work in cell cultures and in mice, the researchers are now undertaking further development with a view to ultimately testing the technology in humans in clinical trials.

CRISPR reveals way to enhance the function, persistence of CAR T-cell therapies
The use of CRISPR knockout screens have uncovered a new regulator of immunity that could enhance the function and persistence of anticancer T-cell therapies,...

Single-cell sequencing finds subset of CAR T cells that drive anticancer effects
A small subset of the CAR T cells prepared for therapy produce most of the anticancer activity, suggesting it may be possible to improve the treatment,...

Cancer researchers publish study on avidity enhancement of CAR T cells
A team of cancer researchers led by Dr. Marcela Maus have published a preclinical study detailing the use of the Lumicks z-Movi Cell Avidity Analyzer...