In an effort to mitigate adverse effects associated with CAR T therapies, researchers at Cellectis S.A. (NASDAQ:CLLS; Euronext:ALCLS) and its collaborator Allogene Therapeutics Inc. (South San Francisco, Calif.) developed an integrated safeguard for CAR T cells to inactivate the cells. The researchers described the construct, dubbed CubiCAR, in a paper published Tuesday in Scientific Reports.
While other companies have developed safety, or suicide, switches for CAR T therapies, products in the clinic express the mechanism on the cell surface separate from the CAR, lead author Julien Valton told BioCentury. In contrast, Cellectis' construct is incorporated within the CAR itself.
This integration, Valton said, could prevent the cell populations from becoming unbalanced, which occurs when more CAR is expressed than suicide switch. Valton is innovation team leader of cellular engineering and adoptive CAR T cell immunotherapy at Cellectis.
According to the paper, other drawbacks of safety switches include their large size and potential immunogenicity.
The researchers incorporated CD20 mimotopes and a CD34 epitope into the CAR construct of CAR T cells against tumor necrosis factor (TNF) receptor superfamily member 17 (BCMA; TNFRSF17; CD269). The CD20 mimotopes allow the cells to be cleared by the anti-CD20 mAb Rituxan rituximab, and the CD34 epitope enables cell detection and purification by an anti-CD34 mAb during the manufacturing process to create a more homegenous product.
In a mouse model of BCMA-positive multiple myeloma, both CubiCAR cells and CAR T cells reduced MM cells in the blood, bone marrow and spleen. An injection of Rituxan in mice treated with CubiCAR T cells decreased CubiCAR T cells and increased proliferation of MM cells, while unmodified CAR T cells were unaffected by Rituxan.
Valton said Cellectis has already implemented the CubiCAR safety structure into its products, and plans to evaluate the cells' safety and antitumor activity in a humanized mouse model.
Last year, the company published a paper in the same journal describing a different safety CAR construct designed to decrease on-target, off-tumor activity by restricting CAR T cell activity to hypoxic environments such as the tumor microenvironment with an oxygen-sensitive domain (see BioCentury Extra, Jan. 23, 2017).
Allogene spun out of Pfizer Inc. (NYSE:PFE) in April and assumed rights to the pharma's allogeneic CAR T products developed through a partnership with Cellectis (see BioCentury Extra, April 3).