When Arie Belldegrun and David Chang bagged all of Pfizer’s off-the-shelf CAR-T therapies, they highlighted a collaboration program with Cellectis that potentially puts Allogene Therapeutics on a path to commercialization. Two months later, the French biotech is following up with a safer, next-generation chimeric antigen receptor construct now positioned for the clinic.
In a paper published in Scientific Reports today, Cellectis reports an all-in-one CAR architecture that combines cancer-killing potency, a “suicide switch” for safety, as well as purification and detection capacities. Dubbed CubiCAR, the molecule was shown to be “efficiently and robustly” depleted in the presence of Rituxan (rituximab) both in vitro and in vivo.
The idea of a suicide switch is, of course, not new. CAR-T is a living drug that could theoretically stay inside patients for years, and given the well-known safety concerns with CAR-T — such as cytokine release syndrome and neurotoxicity — an emergency switch has been touted as a lifesaver.
Cellectis’ big achievement here, innovation team leader Julien Valton tells me, is the integration of both the safety mechanism and other desirable qualities in one molecule. That distinguishes CubiCAR from most of the other suicide switches in the clinic right now, which he says expresses the CAR and the switch in separate molecules — leading to potential imbalance between the two.
“Sometimes, we have instances where the CAR is expressed, and we couldn’t see the suicide switch,” he says.
Pfizer had been involved in the project since Cellectis came up with it three years ago, providing Valton’s team with a BCMA-targeting CAR for multiple myeloma. That product now belongs to Allogene, which is working with Cellectis to find clinical applications for the construct. Meanwhile, Cellectis is also putting the CubiCAR scaffold to use in their own CARs hitting the CD123, CD22 and other antigens.
The partners now joins the likes of Bellicum and Autolus in pursuit of better, safer cell therapies, first for blood cancer and eventually — ideally — for solid tumors.
While CubiCAR’s suicide switch is activated by an antibody, other companies have opted for the small molecule-mediated approach. One of them is Poseida Therapeutics, whose CEO Eric Ostertag told C&EN that antibody-mediated switches can “take days to really work.”
There’s no real way to measure it until the drug is tested in humans, but Valton tells me that “using Cellectis’ experimental conditions in vitro, it takes about 15 minutes to deplete the vast majority of Safeguard CAR T-cells with clinically relevant dose of [rituximab]. This kinetic is on par with the data obtained with ICaspase9 and RQR8 suicide switches documented in the literature.”
Plus, Valton says, CubiCAR is also easily detected and purified — meaning the active elements can be efficiently extracted — by the antibody QBEND10.
“Not only is the CubiCAR architecture an integrated, compact safeguard allowing for the fast and efficient depletion of CAR T-cells, it is also compatible with multiple scFvs that are designed against different targets, which gives it the unique potential to make CAR T-cell immunotherapies safer,” says Cellectis CSO Philippe Duchateau in a statement.
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