On January 11, 2016 Cellectis (Paris:ALCLS) (NASDAQ:CLLS) (Alternext: ALCLS – Nasdaq: CLLS) reported the publication of a study in Scientific Reports, a Nature Publishing Group journal, describing the design and development of a new CAR architecture with an integrated switch-on system that permits control over CAR T-cell functions (Press release, Cellectis, JAN 11, 2016, View Source [SID:1234508770]). This integrated switch-on system offers the advantages of controllable CAR T-cells for safety while allowing for the possibility of multiple cytotoxicity cycles using a small molecule drug.

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The possibility to control spatially and temporally the CAR T activity is very desirable to mitigate potential unwanted risks, such as cytokine-release syndrome1 (CRS) and the "on-target, off-tumor" effect2. To date, few strategies are available and mostly rely on suicide mechanisms that ultimately lead to a complete eradication of the engineered T-cells, thus resulting in a premature end of the treatment. Consequently, implementing non-lethal, spatio-temporal control of gene edited CAR T-cells represents an important advancement in improving the CAR T-cell technology.

In this report, Alexandre Juillerat, Ph.D., and his collaborators engineered a system directly integrated within the CAR architecture. In particular, they showed that such system turns a CAR T-cell from an off-state to an on-state upon addition of a small molecule, inducing the cytolytic properties of the gene edited T-cell. Overall, this non-lethal system not only offers the advantage of a temporal control of activation to mitigate the risk of CAR-induced toxicities but also enables opportunities for spatial activation of the engineered CAR T-cells using local targeted drug delivery.

Alexandre Juillerat, Ph.D. Innovation Senior Scientist

Dr. Alexandre Juillerat, Ph.D., graduated in Chemistry of 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.

Design of chimeric antigen receptors with integrated controllable transient functions

Alexandre Juillerat, Alan Marechal, Jean-Marie Filhol, Julien Valton, Aymeric Duclert, Laurent Poirot and Philippe Duchateau
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