CAR-T manufacturing reduces heterogeneity between CIDP and multiple myeloma patient-derived T cells.

Rationale:​​ CAR-T cell therapy has demonstrated remarkable promise for managing specific autoimmune disorders. However, it remains unclear, whether long-term immunosuppressive therapy in autoimmune patients adversely affects the phenotype and function of patient-derived CAR-T products. This study aimed to compare the characteristics of T cells and manufactured CAR-T cells from patients with multiple myeloma (MM) and chronic inflammatory demyelinating polyneuropathy (CIDP). ​​Methods:​​ T cells isolated from MM and CIDP patients, as well as healthy volunteers (for baseline comparisons only), were analyzed. CAR-T cells were generated using an identical manufacturing process. A comprehensive analysis was conducted, including flow cytometry for phenotypic and functional assessment, transcriptomic profiling via RNA sequencing, and in vitro functional assays such as cytokine secretion and cytotoxicity tests. ​​Results:​​ T cells from CIDP patients showed phenotypes and functional profiles more comparable to those from healthy volunteers. In contrast, MM-derived T cells showed increased CD8⁺ T cell frequency, elevated exhaustion markers, reduced naïve and less-differentiated subsets, and enhanced effector molecule production upon non-specific stimulation. CAR-T manufacturing reduced these inherent differences, yielding similar differentiation states, transcriptomic profiles, and convergent cytotoxic capacities. However, distinct immunomodulatory features persisted, as CIDP-derived CAR-T cells displayed reduced activation markers and lower IFN-γ secretion upon antigen stimulation compared to MM-derived CAR-T cells. ​​Conclusions:​​ Our study reveals that CAR-T manufacturing process can reduce pre-existing T-cell heterogeneity across different patient populations. These findings support the feasibility of autologous CAR-T therapies in immunosuppressed autoimmune patients, demonstrating that critical cytolytic functions are preserved despite residual alterations in cytokine profiles.