Cellectis, a biopharmaceutical company focused on developing immunotherapies based on gene edited CAR T-cells (UCART), announced the publication of a study in Scientific Reports, a Nature Publishing Group journal, describing a novel approach to a CAR design with an integrated environmental signal utilizing oxygen concentration to manipulate the CAR T-cell response.

In this report, Alexandre Juillerat, Ph.D. and his collaborators from the Cellectis innovation team designed a new CAR architecture that contains an integrated microenvironment sensor. Low oxygen concentration is recognized as a hallmark of the microenvironment of certain solid tumours. The implementation of the novel oxygen sensitive CAR architecture empowers CCellectis Studies Safety in New CAR Architecture Controlling CAR T-Cell Functions.

With the primary purpose of implementing additional levels of safety to the CAR T-cell technologies, in particular to minimize "on-target / off-tumour” effects, this study demonstrated the possibility to use peculiarities of the tumour microenvironment to create self-decision making CAR T-cells with impaired functions at high oxygen concentration. The results showed that this system also possessed the key feature to be prone to quickly return to its off state in the absence of the inducing signal (hypoxia), a characteristic that is of prime interest to protect healthy tissues distant from the tumour site. Beyond this first in vitro proof of concept, additional studies are expected to fully assess the therapeutic potential of this approach.

Dr. Alexandre Juillerat, Ph.D., graduated in Chemistry from the University of Lausanne, Switzerland. After receiving in 2006 his Ph.D. in protein engineering from the École Polytechnique Fédérale de Lausanne (EPFL, Switzerland), he moved to the laboratory of Structural Immunology at the Institut Pasteur in Paris, France, performing structure-function studies on a major adhesin of plasmodium falciparum. In 2010, he joined the R&D department of Cellectis in Paris, France, working on the development and implementation of sequence specific designer nucleases including the transcription activator-like effector nucleases TALEN. He then joined the Cellectis facility based in New York, NY, USA, leading projects associated with the development of the T-cell chimeric antigen receptor (CAR) technology.

Alexandre Juillerat, Alan Marechal, Jean Marie Filhol, Yannick Valogne, Julien Valton, Aymeric Duclert, Philippe Duchateau and Laurent PoirotAR T-cells with the possibility to auto-regulate (switch on or tune-up) their functions in low oxygen (hypoxic) environments.

With the primary purpose of implementing additional levels of safety to the CAR T-cell technologies, in particular to minimize "on-target / off-tumor” effects, this study demonstrated the possibility to use peculiarities of the tumour microenvironment to create self-decision making CAR T-cells with impaired functions at high oxygen concentration. The results showed that this system also possessed the key feature to be prone to quickly return to its off state in the absence of the inducing signal (hypoxia), a characteristic that is of prime interest to protect healthy tissues distant from the tumour site. Beyond this first in vitro proof of concept, additional studies are expected to fully assess the therapeutic potential of this approach.