Key Points:
- Unlike hematologic targets, TMR Chimeric Antigen Receptors (CARs) lack stimulatory signals for proliferation outside the tumor, limiting CAR-T exposure
- A surrogate CAR-Specific Stimulating Protein (CSSP) approach, encoded by synthetic mRNA and expressed in antigen-presenting cells, was developed to boost CAR-T proliferation in vitro and in vivo
- CSSPs selectively stimulated CAR-T cells through the CD3ζ chain, enabling proliferation similar to or greater than non-specific CD3 stimulation
- TMR-HER2 CAR-T cells, which do not proliferate with HER2 antigen alone, were activated and expanded when co-cultured with CSSP-expressing monocytes
- This novel mRNA-based approach provides a potential adjunctive therapy to enhance CAR-T persistence and expansion beyond the tumor microenvironment
