Integrin alpha8beta1 is Identified as a Potential CAR-T Target for BCMA-Resistant Relapsed Multiple Myeloma.

BACKGROUND

B cell maturation antigen (BCMA)-targeted chimeric antigen receptor T cell (CAR-T) therapy has improved outcomes for relapsed/refractory multiple myeloma (R/R MM), but most patients eventually relapse, largely due to antigen escape, clonal heterogeneity, and immune-evasive tumor subclones. Novel targets are urgently needed to complement BCMA CAR-T and reduce relapse.

METHODS

We analyzed several single-cell transcriptomic datasets from patients who relapsed after BCMA CAR-T to identify relapse-associated surface antigens. We characterized ITGA8 expression in normal tissues and hematopoietic cells, evaluated its biological function in myeloma cells, and generated α8β1-targeted CAR-T cells. Preclinical efficacy was assessed in vitro and in xenograft models in combination with BCMA CAR-T.

RESULTS

ITGA8 was significantly enriched in MM cells at early relapse following BCMA CAR-T therapy, marking a quiescent, immune-evasive subpopulation. ITGA8 was absent from normal hematopoietic stem and immune cells but showed restricted expression in vascular smooth muscle cells. α8β1 CAR-T specifically lysed ITGA8-positive myeloma cells and complemented with BCMA CAR-T to control tumor in models mimicking antigen loss.

CONCLUSION

This preclinical proof-of-concept study identifies integrin α8β1 as a potential CAR-T target worthy of further development for BCMA-resistant relapsed MM. While short-term tumor control was improved, this does not equate to validated clinical relapse prevention. Safety related to off-tumor expression in non-hematopoietic tissues remains to be fully evaluated.