In a recent article in Molecular Therapy, Sanofi presented preclinical data for an in vivo CAR-T platform that reengineers T cells directly within the body, bypassing the weeks-long ex vivo manufacturing required for ex vivo CAR-Ts. The platform uses mRNA to instruct the cell to produce the chimeric antigen receptor (CAR), resulting in transient CAR expression. The company has heavily invested in developing the technology. In August 2021, Sanofi acquired Translate Bio for $3.2bn, gaining full access to its large library of lipid nanoparticles (LNPs). These fat-based particles shield the mRNA in the bloodstream. A challenge in administering LNPs is that they naturally accumulate in the liver, where they are filtered. Realising this, Sanofi acquired Tidal Therapeutics in April 2021 for $470m. With this purchase, Sanofi can leverage Tidal’s VHH nanobody-based technology, which selectively binds to CD8 on cytotoxic T cells, enhancing tumour cell targeting and transfection efficiency. A non-viral targeted LNP represents an innovative approach for in vivo CAR-T programs.
In a preclinical mouse model, LN15 was optimised for T-cell transfection with an anti-CD8 VHH nanobody, which showed higher efficiency than other targeting ligands and encoded a CAR that recognises CD22 on B-cell malignancies. The construct led to tumour suppression, liver uptake of less than 5%, and CAR expression persisted for several days. This is a key difference from ex vivo autologous CAR-Ts, which use viral vectors to permanently integrate CAR DNA into the genome and can persist for months to years. The majority of in vivo CAR-Ts in development, such as autologous CARs, use viral vectors that integrate into the genome, producing a durable CAR. Sanofi’s agent uses mRNA that produces transient CAR-T cells, allowing repeated dosing, which eliminates insertional mutagenesis risk, but raises questions about remission durability.
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Clinical trials will need to demonstrate whether in vivo mRNA-based CAR-T remission durability is comparable to autologous or viral in vivo counterparts. Questions remain whether repeated dosing will maintain efficacy without anti-drug immune responses. From a safety perspective, using mRNA eliminates any risk of insertional mutagenesis; however, LNPs introduce other risks such as inflammation or cytokine release syndrome, which will be monitored in clinical studies. How does this modality compare to other off-the-shelf therapies, such as bispecific antibodies? If clinically validated and shown to be durable, there is a rationale for moving it to earlier lines of therapy to compete with bispecific antibodies. Regardless of competitive positioning, a non-viral, off-the-shelf in vivo platform has the potential to reduce cost, manufacturing time, and access barriers to CAR-T therapy. GlobalData analysts’ consensus forecasts a 25% compound annual growth rate (CAGR) for CAR-Ts, from $5bn globally in 2024 to $23.6bn in 2031.
