A Versatile Safeguard for Chimeric Antigen Receptor T-Cell Immunotherapies
Julien Valton1*, Valerie Guyot1, Bijan Boldajipour3, Alexandre Juillerat1, Aymeric Duclert2, Barbra Sasu3, Philippe Duchateau2 and Laurent Poirot2
1Cellectis, Inc., 430E, 29th Street, New York, NY 10016, USA ; 2Cellectis S.A., 8 rue de la Croix Jarry, 75013 Paris; 3Pfizer/Rinat, 230 E Grand Ave, South San Francisco, CA 94080, USA
In less than a decade, adoptive CAR T-cell therapies have revolutionized the field of cancer treatment with unprecedented frequencies of complete remissions in different indications. Despite this success, safety concerns have been raised regarding mild to life threatening adverse effects related to CAR T-cells activity. To address these issues, different molecular safeguards were developed. However, while all of them enable efficient on-demand depletion of engineered T-cells, each of them display specific drawbacks ranging from potential immunogenicity, significant payloads, to reliance on unapproved small molecules as activating agent. In addition, all safeguards are translated independently from the CAR, an architecture that could potentially lead to unbalanced CAR/safeguard ratio. To overcome these limitations, we sought to integrate a safeguard in the CAR to generate an all-in-one architecture. Here we report the development and preclinical evaluation of a compact and versatile architecture that in addition to enabling universal detection and purification of the resulting CAR T-cells, enables their fast and efficient eradication by the FDA-approved Rituximab (RTX) in vivo. We further demonstrate that this architecture is compatible with multiple tumor indications, thus bearing the potential to improve the overall safety of CAR T-cell immunotherapies for a broader range of patients.
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