Advancements in CAR-T Therapy: A BCMA-Targeted Centyrin-Derived Approach for Multiple Myeloma

Introducing P-BCMA-101, a novel CAR-T cell therapy that utilizes Centyrin molecules, non-immunoglobulin scaffolds, for targeting the B cell maturation antigen (BCMA) in multiple myeloma (MM). This approach addresses the challenges associated with traditional CAR-T cell therapies, which can be difficult and costly to manufacture and may cause significant side effects with variable response durability.

P-BCMA-101 is distinguished by its manufacturing process, which employs a non-viral piggyBacTM (PB) transposon system using in vitro transcribed mRNA and plasmid DNA, eliminating the need for lentivirus or g-retrovirus. This system is safer, less mutagenic, and non-oncogenic, allowing for efficient delivery of large transgenes with stable and prolonged expression.

The therapy also includes a DHFR gene mutein, which, in combination with methotrexate (MTX), facilitates the enrichment of CARTyrin-expressing cells and reduces variability in patient product material. P-BCMA-101 features a safety switch for in vivo depletion if adverse events occur. The CARTyrin component is based on a human protein sequence, offering similar binding affinity to antibody-derived fragments but with enhanced size, thermostability, and reduced immunogenicity.

The manufacturing process from primary human T cells is efficient, avoiding cytokines, and yields a sufficient number of CARTyrin-expressing cells for treatment. Over 95% of the cell product expresses the CARTyrin within 18 days of electroporation. Notably, more than 60% of these cells exhibit a stem-cell memory phenotype.

In vitro, P-BCMA-101 cells have shown robust activity against BCMA-expressing tumor targets, and in vivo, a single administration of P-BCMA-101 in a human MM model led to rapid tumor elimination and improved survival within 7 days.

P-BCMA-101 represents a significant advancement in CAR-T cell therapies, with an advantageous stem-cell memory phenotype and potent anti-tumor efficacy against BCMA+ myeloma cells. The team plans to initiate a phase I clinical trial of P-BCMA-101 for patients with relapsed and/or refractory MM.