Nanobody-Engineered CLL-1 CAR-T Cells: Optimizing Tumor-Specific Cytotoxicity and Minimizing Off-Tumor Toxicity - PubMed
10 hours ago
- #AML
- #CAR-T therapy
- #nanobody
- AML is an aggressive hematologic malignancy with poor prognosis due to rapid expansion of undifferentiated myeloid progenitors.
- CAR-T cell therapy in AML is limited by on-target, off-tumor toxicities from shared antigen expression on healthy cells.
- A nanobody-based CAR-T cell platform targeting CLL-1 was developed to minimize toxicity and enhance specificity.
- CLL-1 is a myeloid-restricted surface antigen enriched on AML blasts and leukemic stem cells but minimally expressed on healthy hematopoietic stem cells.
- CLL-1 and CD33 nanobody CAR constructs were engineered and compared for functional activity.
- Functional validation included real-time cytotoxicity monitoring, serial tumor re-challenge assays, and NSG xenograft models.
- CLL-1 CAR-T cells showed rapid and durable cytotoxicity while sparing normal hematopoietic progenitors.
- CLL-1 CAR-T cells retained a favorable memory phenotype with stable proliferation and viability.
- Cytokine release assays confirmed effective and antigen-specific immune activation.
- CLL-1-targeted nanobody CAR-T cells offer a promising therapeutic avenue with reduced off-target toxicity and enhanced translational potential.