Context-specific synthetic T cell promoters from assembled transcriptional elements.

Autor:	Appelbaum J; Fred Hutch Cancer Center., Wei J; Seattle Children's Research Institute., Mukherjee R; Seattle Children's Research Institute., Ishida T; Seattle Children's Research Institute., Rosser J; Seattle Children's Research Institute., Saxby C; Seattle Children's Research Institute., Chase J; Seattle Children's Research Institute., Carlson M; Seattle Children's Research Institute., Sather C; Fred Hutchinson Cancer Research Center., Rahfeldt W; Seattle Children's Research Institute., Meechan M; Seattle Children's Research Institute., Baldwin M; Seattle Children's Research Institute., Flint L; Seattle Children's Research Institute., Spurrell C; Seattle Children's Research Institute., Gustafson J; Seattle Children's Research Institute., Johnson A; Seattle Children's Research Institute., Jensen M; Seattle Children's Research Institute.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2023 Oct 17. Date of Electronic Publication: 2023 Oct 17.
DOI:	10.21203/rs.3.rs-3339290/v1
Abstrakt:	Genetic engineering of human lymphocytes for therapeutic applications is constrained by a lack of transgene transcriptional control, resulting in a compromised therapeutic index. Incomplete understanding of transcriptional logic limits the rational design of contextually responsive genetic modules1. Here, we juxtaposed rationally curated transcriptional response element (TRE) oligonucleotides by random concatemerization to generate a library from which we selected context-specific inducible synthetic promoters (iSynPros). Through functional selection, we screened an iSynPro library for "IF-THEN" logic-gated transcriptional responses in human CD8 + T cells expressing a 4-1BB second generation chimeric antigen receptor (CAR). iSynPros exhibiting stringent off-states in quiescent T cells and CAR activation-dependent transcriptional responsiveness were cloned and subjected to TRE composition and pattern analysis, as well as performance in regulating candidate antitumor potency enhancement modules. These data reveal synthetic TRE grammar can mediate logic-gated transgene transcription in human T cells that, when applied to CAR T cell engineering, enhance potency and improve therapeutic indices. Competing Interests: Declaration of Competing Interests: M.C.J. Juno Therapeutics, BMS, Umoja Therapeutics, A.J.J., J.M.R., M.C.J. PD1:MYD88 patent application C.P.S., M.C.J. LASI-7/21 patent application J.W., M.C.J. iSynPro patent application
Databáze:	MEDLINE
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