Circular mRNA CAR-T: Does the Data Support a Shift from Linear Designs?

The study posits that a novel 'scarless' circular mRNA (cmRNA) design drives more durable protein expression than standard linear formats. While the data indicates superior performance in rodent models and cell cultures, the transition to clinical application represents a significant variable not yet addressed. This research investigates Circular mRNA CAR-T therapies, aiming to mitigate the instability inherent in current linear mRNA approaches.

Methodology: The PIE Platform

The investigators utilised a high-efficiency permuted intron-exon (PIE) system. This method synthesises circular constructs without 'scars' or extraneous junction sequences. Theoretically, removing these foreign sequence markers streamlines manufacturing. It may also reduce the likelihood of the host immune system flagging the therapy prematurely, although this specific immunological benefit requires verification in human subjects. The primary objective was to overcome the transient nature of linear mRNA, which typically supports only short-lived protein expression.

Evaluating Circular mRNA CAR-T Efficacy

Performance metrics were assessed using primary human T cells. The results appear distinct. Compared to linear controls, the cmRNA variants significantly extended the duration of antigen receptor expression for both anti-CD19 and anti-GPRC5D targets. Linear mRNA faded rapidly. Conversely, the circular format maintained magnitude over time. Functionally, the study reports that these modified T cells exhibited sustained activation patterns. Transcriptomic analysis revealed an absence of exhaustion signatures—a frequent failure point in existing treatments. In vivo models demonstrated tumour elimination and improved survival rates. However, mice are imperfect proxies for human oncology. While the transcriptomics suggest a robust profile, the leap to patient application involves biological complexity that a controlled lab environment cannot fully simulate. The findings position cmRNA as a potential tool for controllable expression, yet valid concerns regarding long-term safety in human hosts persist.