Development of idiotype-specific vNAR-CAR-immune cells for the treatment of clonal malignancies

Treatment of B-cell leukemias and lymphomas in children and young adults using CAR-T cells has led to a dramatic improvement in progression-free survival and long-term prognosis. However, on-target/off-tumor toxicities of CAR-T cell therapy directed against universal hematologic antigens can result in severe long-term side effects.

To overcome this limitation, we redirect CAR-target specificity towards the unique lymphoma-specific B-cell receptor (BCR) idiotype, enabling exclusive elimination of malignant cells while maintaining healthy B cells.

Structure-guided CAR-design utilizing shark-derived vNAR domains recognizing a unique BCR idiotype and screening resulted in specific activation of vNAR-CAR (5) by SUP-B8 Burkitt lymphoma cells carrying the cognate BCR idiotype, with only minimum off-target effects. Currently, we further optimize the vNAR-CAR (5) using primary T and NK cells as CAR effectors in vitro and in vivo.

Taken together, our current proof-of-concept data demonstrate feasibility and functionality of vNAR-CAR immune cells with high specificity for the chosen BCR idiotype, suggesting this strategy as a general approach for selective targeting of clonal malignancies."

Publication History

Article published online:
17 May 2022