ArticleFrontiers in immunology2025
Multiplex engineering using microRNA-mediated gene silencing in CAR T cells.
Article in Frontiers in immunology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- A synthetic NKG2A engager enables long-term persistence of HLA-deficient allogeneic engineered Tregs.EMBO molecular medicine · 2026Article
- miRBind2 enables sequence-only prediction of miRNA binding and transcript repression.Bioinformatics (Oxford, England) · 2026Article
- Roles and potential applications of non-coding RNAs in cancer treatment with immune checkpoint inhibitors and immunomodulatory therapies.Cancer drug resistance (Alhambra, Calif.) · 2026Review
- Multiplex engineering and multifunction T cells for precise and effective immunotherapies.Frontiers in immunology · 2025Review
Corrections and comments
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Authors and funding
20 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Background: Multiplex gene-edited chimeric antigen receptor (CAR) T-cell therapies face significant challenges, including potential oncogenic risks associated with double-strand DNA breaks. Targeted microRNAs (miRNAs) may provide a safer, functional, and tunable alternative for gene silencing without the need for DNA editing. Methods: As a proof of concept for multiplex gene silencing, we employed an optimized miRNA backbone and gene architecture to silence T-cell receptor (TCR) and major histocompatibility complex class I (MHC-I) in mesothelin-directed CAR (M5CAR) T cells. The efficacy of this approach was compared to CD3ζ and β2-microglobulin (β2M) CRISPR/Cas9 knockout (KO) cells. miRNA-expressing cassettes were incorporated into M5CAR lentiviral vectors, enabling combined gene silencing and CAR expression. Antitumor activity was evaluated using Results: Silenced (S) M5CAR T cells retained antitumor functionality comparable to, and in some cases exceeding, that of KO cells. Conclusions: Titratable multiplex gene silencing via targeted miRNAs offers an alternative to gene editing for CAR T cells, with potential advantages in potency, persistence, metastasis prevention, and immune evasion for allogeneic products. This strategy may overcome tumor-induced immunosuppression while avoiding the risks associated with DNA double-strand breaks.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.