Chimeric Antigen Receptor (CAR) T-cell therapy has revolutionized the treatment of B-cell acute leukemia (B-ALL), with several successful therapies targeting the CD19 protein on cancer cells. However, some leukemia cells can escape treatment by losing CD19, leading to relapses. To address this, our team has developed a next-generation CAR T-cell therapy that targets two leukemia markers at once: CD19 and CD22. Unlike conventional CAR T-cell therapies, our innovative approach uses genetically engineered T cells that not only carry a CAR against CD22 but also secrete a specialized antibody-like molecule (T-cell engager, TCE) that redirects other immune cells to attack CD19-positive cancer cells. This combination strategy, called CAR-STAb-T, enhances the immune response and prevents cancer cells from escaping therapy. In laboratory and animal models, our CAR-STAb-T cells showed stronger and longer-lasting leukemia control compared to traditional dual CAR T-cell strategies. Even when leukemia cells lost CD19, our engineered T cells continued to effectively eliminate cancer. These promising results suggest that CAR-STAb-T therapy could provide a more durable and effective treatment option for patients with B-ALL and warrant further clinical testing.
The aim of this project was to generate dual adoptive T-cell immunotherapy for B-ALL harnessing both CAR and TCE technology against CD199 and CD22 targets. Our promising results suggest that CAR-STAb-T therapy could provide a more durable and effective treatment option for patients with B-ALL and warrant further clinical testing.
CD19-targeted immunotherapies, including CAR-T cells and bispecific T cell engagers (TCEs), have significantly improved outcomes for relapsed/refractory (R/R) B-ALL. However, about 50% of patients relapse within a year, often due to antigen loss mechanisms, particularly CD19 downregulation. To address this, dual-targeting CAR-T strategies against CD19 and CD22 have been developed, including co-administration of separate CAR-T products, bicistronic vectors, and TanCARs. Despite their potential, these strategies face limitations such as imbalanced expansion of T cell subsets, increased regulatory complexities, and steric hindrance affecting CD22 binding.
To overcome these challenges, we proposed a novel dual-targeting CAR-STAb-T approach, combining CD22-targeted CAR-T cells with the secretion of a CD19xCD3 TCE. This method enhances anti-leukemic activity by recruiting bystander T cells, forming effective immune synapses, and overcoming antigen escape. In vitro and in vivo models demonstrate superior leukemia control by CAR-STAb-T cells compared to TanCAR-T cells and pooled CD19/CD22 CAR-T therapies. These findings highlight CAR-STAb-T cells as a promising alternative to conventional dual-targeted CAR-T therapies, offering enhanced efficacy and durability of responses for R/R B cell malignancies.
