T cell dysfunction associated with repeated CAR-T cell manufacturing failure following prolonged bispecific antibody...

We describe a patient with two consecutive manufacturing failures after prolonged bispecific antibody treatment in which longitudinal immune phenotyping and functional assays were performed to investigate potential mechanisms.

CAR-T cell therapy and bispecific antibodies (BsAb) have significantly improved outcomes in relapsed/refractory multiple myeloma (r/rMM), yet the optimal treatment sequence remains unclear, particularly regarding the impact of prior BsAb exposure on downstream CAR-T manufacturability.

A 72-year-old man with r/rMM had two CAR-T cell manufacturing failure events following multiple therapies including an FcRL5 × CD3 bispecific antibody. Both collections yielded an insufficient CAR-T cell dose. Longitudinal immune phenotyping revealed markers of T cell dysfunction, including loss of CCR7, CD27, and CD28, alongside severely impaired TCR-driven proliferation with preserved interleukin-2 responsiveness.

These findings link profound T cell dysfunction with repeated CAR-T cell manufacturing failures and suggest that pre-leukapheresis immune phenotyping may identify patients at risk for manufacturing failure.