地塞米松对体外及RRMM患者体内CAR-T细胞扩增无影响

Chimeric antigen receptor (CAR)-T cell therapy is an effective treatment for relapsed/refractory multiple myeloma (RRMM). The Phase 1 trial of anitocabtagene autoleucel (anito-cel), an autologous D-Domain BCMA-directed CAR-T cell therapy, demonstrated a 100% overall response rate and a median progression free survival rate of 30.2 months, with a median follow-up of 34 months (Bishop et al., 2024). No delayed neurotoxicities were observed (Kaur et al., 2025), such as parkinsonism or cranial nerve palsies reported in up to 10% of real-world ciltacabtagene autoleucel (cilta-cel)-treated patients and associated with elevated absolute lymphocyte count (ALC) indicative of CAR-T cell hyper-expansion as a major risk factor (Lim et al., 2025). Pre-emptive intervention using dexamethasone (Dex) based on ALC has been proposed to limit uncontrolled expansion and prevent delayed neurotoxicity (Turner et al., 2025). However, in patients with large B-cell lymphoma treated with axicabtagene ciloleucel in ZUMA-1, prophylactic steroids did not hinder CAR-T cell expansion (Cohort 6; Oluwole et al., 2021). Thus, further investigation of the impact of Dex on CAR-T cell expansion and function is warranted. In the Phase 1 study of anito-cel (n=38), 66% of patients received Dex to treat cytokine release syndrome (CRS) events. Patients requiring Dex intervention showed higher soluble BCMA levels at screen, indicative of greater tumor burden. No patients received prophylactic Dex. Consequent Dex use did not suppress CAR-T cell expansion below levels observed in non-Dex-treated patients (ALCmax: 1.39 [0.82-3.07] vs 1.01 [0.49-1.28] k/ul). Differences in CAR-T cell activation-associated cytokines were observed between Dex and non-Dex-treated patients. The increase of CAR-T cell expansion in patients with higher tumor burden, who required intervention with steroids, is consistent in vitro when CAR-T cells were stimulated with a high BCMA density cell line (H929) compared to a low BCMA density cell line (Raji). For these in vitro studies, surrogate versions for anito-cel (D-Domain), cilta-cel (VHH) and idecabtagene vicleucel (scFV) were generated and the impact of Dex on CAR-T cell phenotype and functionality was assessed. Treatment with Dex did not impact CAR-T cell expansion, cytolytic activity, CAR expression, CD4:CD8 ratio or differentiation/activation state. While Dex did not impact CAR-T cell expansion (D-Domain 4.8 vs 4.4; VHH 5.4 vs 4.3; scFV 5.3 vs 4.9 fold expansion), Dex treatment decreased IL-2 production, in vitro , making it an effective CRS treatment. While increased ALC and rapid CAR-T cell expansion within the first 28 days has been identified as a biomarker for delayed neurotoxicities, these data suggest that high dose steroids may not be an efficacious intervention for ALC restraint. Instead, Dex treatment is likely to curb proinflammatory cytokines and thus is an appropriate intervention for CRS management.