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Evolution of the clinical-stage hyperactive TcBuster transposase as a platform for robust non-viral production of adoptive cellular therapies.
Skeate, Joseph G; Pomeroy, Emily J; Slipek, Nicholas J; Jones, Bryan J; Wick, Bryce J; Chang, Jae-Woong; Lahr, Walker S; Stelljes, Erin M; Patrinostro, Xiaobai; Barnes, Blake; Zarecki, Trevor; Krueger, Joshua B; Bridge, Jacob E; Robbins, Gabrielle M; McCormick, Madeline D; Leerar, John R; Wenzel, Kari T; Hornberger, Kathlyn M; Walker, Kirsti; Smedley, Dalton; Largaespada, David A; Otto, Neil; Webber, Beau R; Moriarity, Branden S.
Afiliação
  • Skeate JG; Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
  • Pomeroy EJ; Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
  • Slipek NJ; Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
  • Jones BJ; Bio-Techne, Minneapolis, MN 55413, USA.
  • Wick BJ; Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
  • Chang JW; Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
  • Lahr WS; Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
  • Stelljes EM; Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
  • Patrinostro X; Bio-Techne, Minneapolis, MN 55413, USA.
  • Barnes B; Bio-Techne, Minneapolis, MN 55413, USA.
  • Zarecki T; Bio-Techne, Minneapolis, MN 55413, USA.
  • Krueger JB; Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
  • Bridge JE; Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
  • Robbins GM; Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
  • McCormick MD; Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
  • Leerar JR; Bio-Techne, Minneapolis, MN 55413, USA.
  • Wenzel KT; Bio-Techne, Minneapolis, MN 55413, USA.
  • Hornberger KM; Bio-Techne, Minneapolis, MN 55413, USA.
  • Walker K; Bio-Techne, Minneapolis, MN 55413, USA.
  • Smedley D; Bio-Techne, Minneapolis, MN 55413, USA.
  • Largaespada DA; Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
  • Otto N; Bio-Techne, Minneapolis, MN 55413, USA.
  • Webber BR; Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: webb0178@umn.edu.
  • Moriarity BS; Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: mori0164@umn.edu.
Mol Ther ; 32(6): 1817-1834, 2024 Jun 05.
Article em En | MEDLINE | ID: mdl-38627969
ABSTRACT
Cellular therapies for the treatment of human diseases, such as chimeric antigen receptor (CAR) T and natural killer (NK) cells have shown remarkable clinical efficacy in treating hematological malignancies; however, current methods mainly utilize viral vectors that are limited by their cargo size capacities, high cost, and long timelines for production of clinical reagent. Delivery of genetic cargo via DNA transposon engineering is a more timely and cost-effective approach, yet has been held back by less efficient integration rates. Here, we report the development of a novel hyperactive TcBuster (TcB-M) transposase engineered through structure-guided and in vitro evolution approaches that achieves high-efficiency integration of large, multicistronic CAR-expression cassettes in primary human cells. Our proof-of-principle TcB-M engineering of CAR-NK and CAR-T cells shows low integrated vector copy number, a safe insertion site profile, robust in vitro function, and improves survival in a Burkitt lymphoma xenograft model in vivo. Overall, TcB-M is a versatile, safe, efficient and open-source option for the rapid manufacture and preclinical testing of primary human immune cell therapies through delivery of multicistronic large cargo via transposition.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Imunoterapia Adotiva / Linfoma de Burkitt / Transposases / Receptores de Antígenos Quiméricos / Vetores Genéticos Limite: Animals / Humans Idioma: En Revista: Mol Ther Assunto da revista: BIOLOGIA MOLECULAR / TERAPEUTICA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Imunoterapia Adotiva / Linfoma de Burkitt / Transposases / Receptores de Antígenos Quiméricos / Vetores Genéticos Limite: Animals / Humans Idioma: En Revista: Mol Ther Assunto da revista: BIOLOGIA MOLECULAR / TERAPEUTICA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos