Capstan Therapeutics, a start-up founded by a group of influential scientists from the University of Pennsylvania, has launched with $165 million to develop transient engineered chimeric antigen receptor (CAR)-T cells in vivo. The startup aims to develop modified mRNA contained in T cell-targeting lipid nanoparticles to generate disease-specific CAR-Ts in vivo. Its founders include CAR-T pioneers Carl June and Bruce Levine, as well as Drew Weissman, whose seminal work with Katalin Karikó on RNA nucleoside modification paved the way for mRNA-based vaccine development. Capstan aims to develop CAR-Ts without the unwieldy production routines and the toxic lymphodepletion protocols associated with current methods. As well as cancer, the company aims to tackle autoimmune disease, fibrosis and blood disorders by directing a programmed T cell response against defined pathological cell populations. Earlier this year, the founding scientists reported that its approach reduced fibrosis in a mouse model of cardiac injury. They engineered T cells to express a CAR directed against fibroblast activation protein, which is expressed in fibrosis. The mRNA payload was delivered in lipid nanoparticles decorated with antibodies that bind CD5, a receptor expressed by T cells and a subset of B cells but not required for cell function. The approach is transient as the mRNA is rapidly degraded, which eliminates safety concerns about engineered T cells persisting indefinitely; it also opens up the possibility of repeat dosing. The manufacturing is more akin to that of mRNA-based vaccines than current CAR-T therapies, which are notoriously difficult to scale. “It’s unlikely that we will need our own manufacturing,” says CEO Laura Shawver.
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CAR-Ts made entirely within the body. Nat Biotechnol 40, 1421 (2022). https://doi.org/10.1038/s41587-022-01512-x