All-in-one CAR-T packages therapy and safety in one molecule

Cellectis lab
The ability to track and destroy CAR-T cells on demand is especially important for a medicine that is essentially uncontrollable once reinfused back into the patient. (Cellectis)

CAR-T cancer treatments have made enormous strides in recent years but still present safety concerns. The treatments are "autologous," meaning they're made from patients' own immune cells. But they are engineered to spark an immune response against cancer—a response that could be too strong and therefore dangerous to patients.

French biotech Cellectis has devised a form of CAR-T that combines the therapeutic effects with a safeguard. That could pave the way to "allogenic" CAR-Ts that can be made from donor cells and sold off-the-shelf.

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Dubbed CubiCAR, Cellectis' all-in-one construct has an embedded multifunctional tag for the purification, tracking and elimination of CAR-T cells, the company said. A study published in Scientific Reports showed that the CAR-T cells were effectively destroyed by the antibody rituximab in vivo. This could offer oncologists the opportunity to shut down the cells if they spark dangerous immune reactions.

Adding a safeguard, or “safety switch,” to CAR-T is not a new idea. Bellicum is working on T cell therapies with a switch that can be triggered to destroy the engineered cells if they cause side effects. And Gilead—which bought Kite and its CAR-T treatment Yescarta last summer—picked up a company developing “throttle technologies,” or small molecules that act as an on-off switch for CAR-T.

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But other switches are displayed on T cell surfaces separately from CARs, which can lead to a mismatch between the two, Cellectis scientists said in their paper. This, in turn, can result in populations of CAR-T cells that lack the safeguard. CubiCAR was designed to eliminate that risk.

The all-in-one approach has a fan in Allogene, which burst on the scene in April with $300 million in series A money and the rights, by way of Pfizer, to 17 of Cellectis’ allogenic CAR-T assets. Because allogeneic CAR-T cells are made from donor cells, the technology could cut down on the manufacturing time, costs and complexity of the treatments.

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“The transformational impact of autologous CAR T therapy for the treatment of hematologic cancers has been firmly established,” said Barbra Sasu, Ph.D., chief scientific officer of Allogene, in a statement. “We plan to evaluate this CubiCAR approach and other novel CAR T engineering developed in partnership with our colleagues at Cellectis across our extensive CAR T pipeline.”

Researchers at Boston University are also developing an all-in-one approach. They call it SUPRA CAR, a split, universal, and programmable CAR system designed to address issues of safety, specificity and patient relapse. Using adapter molecules, they were able to control the strength of T-cell activation, or switch it off entirely, in vitro. The team is working with synthetic biology company Senti Biosciences to translate their findings into the clinic.

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