Dual-Targeting CAR-T Therapy GC502: Preclinical Insights into B Cell Malignancies Treatment

The abstract discusses a new development in CAR-T therapy. The autologous CD19 CAR-T therapy has shown promising results but is hindered by factors such as cost and manufacturing time. A universal CAR-T (UCAR-T) known as GC027, targeting CD7 for treating T-ALL, has shown effectiveness and safety in a Chinese trial. The study suggests that targeting CD7 can create a therapeutic window by reducing host versus graft (HvG) rejection.

A new therapy, GC502, has been developed that targets both CD19 and CD7 for B-cell malignancies. It is manufactured from healthy donor leukopaks and includes a 4-1BB-based second-generation dual-targeting CAR with anti-CD19 and anti-CD7 scFvs. Disruption of TRAC and CD7 loci is done to prevent graft versus host disease and fratricide. The CAR construct was optimized with a T-cell enhancer for better efficacy.

The results showed high knockout efficiencies and significant differences in cytotoxicity and expansion among different CAR orientations. The leading CAR candidates were selected based on their cytotoxicity and response durability. The addition of an enhancer improved tumor killing and CAR-T cell expansion. Under sub-optimal dosages, the anti-leukemia response was enhanced in both B-ALL and T-ALL mouse models.

GC502 was compared to single CAR products and showed comparable toxicities and efficacies in a T-ALL mouse model. The CD19 functionality of GC502 was also evaluated and compared to another CD19 CAR product. In a B-ALL mouse model, GC502 maintained a "leukemia-free" status longer than the CD19 CAR treated group.

In conclusion, GC502 has been optimized for dual CAR functionality and durability, showing strong anti-tumor efficacy and potential to suppress HvG. The dual CAR design of GC502 presents as a novel "off-the-shelf" CAR-T technology.