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Enhanced safety and efficacy of protease-regulated CAR-T cell receptors.
Labanieh, Louai; Majzner, Robbie G; Klysz, Dorota; Sotillo, Elena; Fisher, Chris J; Vilches-Moure, José G; Pacheco, Kaithlen Zen B; Malipatlolla, Meena; Xu, Peng; Hui, Jessica H; Murty, Tara; Theruvath, Johanna; Mehta, Nishant; Yamada-Hunter, Sean A; Weber, Evan W; Heitzeneder, Sabine; Parker, Kevin R; Satpathy, Ansuman T; Chang, Howard Y; Lin, Michael Z; Cochran, Jennifer R; Mackall, Crystal L.
Afiliación
  • Labanieh L; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Majzner RG; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305
  • Klysz D; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Sotillo E; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Fisher CJ; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Vilches-Moure JG; Department of Comparative Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA.
  • Pacheco KZB; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Malipatlolla M; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Xu P; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Hui JH; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Murty T; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA 94305, USA; Biophysics Program, Stanford University School of Medicine, Stanford, CA 94
  • Theruvath J; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Mehta N; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
  • Yamada-Hunter SA; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Weber EW; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Heitzeneder S; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Parker KR; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Satpathy AT; Department of Pathology, Stanford University, Stanford, CA 94305, USA.
  • Chang HY; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
  • Lin MZ; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Department of Neurobiology, Stanford University, Stanford, CA 94305, USA; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Cochran JR; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.
  • Mackall CL; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305
Cell ; 185(10): 1745-1763.e22, 2022 05 12.
Article en En | MEDLINE | ID: mdl-35483375
ABSTRACT
Regulatable CAR platforms could circumvent toxicities associated with CAR-T therapy, but existing systems have shortcomings including leakiness and attenuated activity. Here, we present SNIP CARs, a protease-based platform for regulating CAR activity using an FDA-approved small molecule. Design iterations yielded CAR-T cells that manifest full functional capacity with drug and no leaky activity in the absence of drug. In numerous models, SNIP CAR-T cells were more potent than constitutive CAR-T cells and showed diminished T cell exhaustion and greater stemness. In a ROR1-based CAR lethality model, drug cessation following toxicity onset reversed toxicity, thereby credentialing the platform as a safety switch. In the same model, reduced drug dosing opened a therapeutic window that resulted in tumor eradication in the absence of toxicity. SNIP CARs enable remote tuning of CAR activity, which provides solutions to safety and efficacy barriers that are currently limiting progress in using CAR-T cells to treat solid tumors.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Receptores Quiméricos de Antígenos / Neoplasias Límite: Humans Idioma: En Revista: Cell Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Receptores Quiméricos de Antígenos / Neoplasias Límite: Humans Idioma: En Revista: Cell Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos