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bioRxiv · 10.1101/2024.08.05.606578

Scarless circular mRNA-based CAR-T cell therapy elicits superior anti-tumor efficacy

Hu, Q.·Zhao, H.·Zhou, K.·Hua, X.·Zhang, X.
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Abstract

Messenger RNA (mRNA)-based transient expression of CAR shows optimal safety profiles and provides promising opportunities to address existing challenges of viral vector-based CAR-T therapies and to meet emerging medical needs in noncancerous indications. However, linear mRNAs are intrinsically unstable and thus just achieve compromised efficacy. Here, we engineered a permuted intron exon (PIE) platform to synthesize scarless circular mRNA (cmRNA) for potent CAR expression and long-lasting efficacy. cmRNA significantly increased amount and duration of anti-CD19 CAR expression on human T cells. cmRNA-based anti-CD19 CAR-T cells elicit superior anti-tumor efficacy over linear mRNA counterparts, demonstrated by parallel lines of evidence including in vitro specific cell-killing, cytokine release, transcriptomics patterns, and in vivo tumor elimination and survival benefit. We found that cmRNA-based anti-CD19 CAR-T efficiently eliminated target cells in vivo and provide long-lasting antitumor efficacy. These results suggested that cmRNA could be a potent platform for unleashing full potential of mRNA technologies in cell therapies.

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Hu, Q., Zhao, H., Zhou, K., Hua, X., Zhang, X.. 2024-08-05. Scarless circular mRNA-based CAR-T cell therapy elicits superior anti-tumor efficacy. https://doi.org/10.1101/2024.08.05.606578

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