ABSTRACT
Ligand-induced receptor dimerization or oligomerization is a widespread mechanism for ensuring communication specificity, safeguarding receptor activation, and facilitating amplification of signal transduction across the cellular membrane. However, cell-surface antigen-induced multimerization (dubbed AIM herein) has not yet been consciously leveraged in chimeric antigen receptor (CAR) engineering for enriching T cell-based therapies. We co-developed ciltacabtagene autoleucel (cilta-cel), whose CAR incorporates two B-cell maturation antigen (BCMA)-targeted nanobodies in tandem, for treating multiple myeloma. Here we elucidated a structural and functional model in which BCMA-induced cilta-cel CAR multimerization amplifies myeloma-targeted T cell-mediated cytotoxicity. Crystallographic analysis of BCMA-nanobody complexes revealed atomic details of antigen-antibody hetero-multimerization whilst analytical ultracentrifugation and small-angle X-ray scattering characterized interdependent BCMA apposition and CAR juxtaposition in solution. BCMA-induced nanobody CAR multimerization enhanced cytotoxicity, alongside elevated immune synapse formation and cytotoxicity-mediating cytokine release, towards myeloma-derived cells. Our results provide a framework for contemplating the AIM approach in designing next-generation CARs.
Subject(s)
Multiple Myeloma , Receptors, Chimeric Antigen , Humans , Receptors, Chimeric Antigen/genetics , Multiple Myeloma/genetics , Multiple Myeloma/therapy , Immunotherapy, Adoptive/methods , B-Cell Maturation Antigen , T-LymphocytesABSTRACT
OBJECTIVE: To explore the method repairing the infra-orbital defect after basal cell carcinoma resection. METHOD: A facial rotation flap was applied to repair the infra-orbital defects from tumor resection in 28 cases. RESULT: All defects were repaired by this one-stage method, which avoided skin graft, shortened the operation time and minimized the operation trauma. The incision sears are inconspicuous. The facial contours are more satisfactory. CONCLUSION: This technique is simple and effective in repairing the infra-orbital defects, worthy of extensive application.
