title: A Multidrug-resistant Engineered CAR T Cell for Allogeneic Combination Immunotherapy.
abstract: The adoptive transfer of chimeric antigen receptor (CAR) T cell represents a highly promising strategy to fight against multiple cancers. The clinical outcome of such therapies is intimately linked to the ability of effector cells to engraft, proliferate, and specifically kill tumor cells within patients. When allogeneic CAR T-cell infusion is considered, host versus graft and graft versus host reactions must be avoided to prevent rejection of adoptively transferred cells, host tissue damages and to elicit significant antitumoral outcome. This work proposes to address these three requirements through the development of multidrug-resistant T cell receptor αβ-deficient CAR T cells. We demonstrate that these engineered T cells displayed efficient antitumor activity and proliferated in the presence of purine and pyrimidine nucleoside analogues, currently used in clinic as preconditioning lymphodepleting regimens. The absence of TCRαβ at their cell surface along with their purine nucleotide analogues-resistance properties could prevent their alloreactivity and enable them to resist to lymphodepleting regimens that may be required to avoid their ablation via HvG reaction. By providing a basic framework to develop a universal T cell compatible with allogeneic adoptive transfer, this work is laying the foundation stone of the large-scale utilization of CAR T-cell immunotherapies.
authors.affiliation: Cellectis. Inc, New York City, New York, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Valton
authors.affiliation: Cellectis. Inc, New York City, New York, USA.
authors.forename: Valérie
authors.initials: V
authors.lastname: Guyot
authors.affiliation: Cellectis SA, Paris, France.
authors.forename: Alan
authors.initials: A
authors.lastname: Marechal
authors.affiliation: Cellectis SA, Paris, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Filhol
authors.affiliation: Cellectis. Inc, New York City, New York, USA.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Juillerat
authors.affiliation: Cellectis SA, Paris, France.
authors.forename: Aymeric
authors.initials: A
authors.lastname: Duclert
authors.affiliation: Cellectis SA, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Duchateau
authors.affiliation: Cellectis SA, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Poirot
mesh_terms: D018941:Antigens, CD19 / Q000235:genetics; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic; D003842:Deoxycytidine Kinase / Q000172:deficiency / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics*; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects / Q000379:methods; D020128:Inhibitory Concentration 50; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D014184:Transplantation, Homologous
chemical_list: D018941:Antigens, CD19; D000970:Antineoplastic Agents; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011993:Recombinant Fusion Proteins; D003842:Deoxycytidine Kinase