Direct IL-6 sequestration with siltuximab rescues CAR T-cell proliferation from inflammatory suppression: A longitudinal multi-omic analysis supporting a paradigm shift in CRS management

Abstract Background: Interleukin-6 (IL-6) drives Cytokine Release Syndrome (CRS), a major toxicity of CAR T-cell therapy. The standard-of-care, tocilizumab, paradoxically elevates circulating IL-6, posing theoretical risks. Direct IL-6 sequestration with siltuximab offers a mechanistic advantage, but its impact on the critical interplay between hyperinflammation and CAR T-cell fitness remains unclear. We hypothesized that in severe CRS, the inflammatory milieu transitions from a consequence of T-cell activation to a driver of T-cell dysfunction, and that rapid IL-6 neutralization by siltuximab could preserve CAR T-cell function. Methods: We conducted a retrospective analysis of 77 patients with hematologic malignancies post-CAR T-cell infusion at our institution (Mar 2024-Jul 2025). Patients were stratified by CRS management: a siltuximab-treated cohort for grade ≥1 CRS (n=23) and a control cohort managed with other supportive measures (n=54). Using high-frequency longitudinal data (temperature, serum IL-6, peripheral CAR T-cells) and advanced statistical modeling (linear mixed-effects models, Spearman's correlation), we dissected the dynamic relationships between pyrexia, cytokine kinetics, and CAR T-cell expansion, while accounting for confounding by indication. Results: The siltuximab cohort presented with more fulminant CRS (median peak fever onset: 2.0 vs. 7.0 days, p<0.001), confirming a significant indication bias. The most critical finding emerged from this severely ill cohort: a strong, negative correlation between peak IL-6 levels and peak CAR T-cell expansion (Spearman's rho = -0.668, p=0.013), a relationship entirely absent in the control group (rho = -0.104, p=0.463). This “uncoupling” of inflammation from T-cell proliferation signifies a functional threshold where hyperinflammation becomes suppressive. Clinically, siltuximab demonstrated rapid and profound efficacy, reducing mean temperature from 39.4°C to 38.1°C within 24 hours (p<0.0001) and, consistent with its mechanism, directly neutralized IL-6 (median peak: 4327 pg/mL) without the paradoxical surge observed with IL-6R blockade. Conclusion: Our data provide the first clinical evidence for a critical inflammatory threshold beyond which the cytokine storm actively suppresses CAR T-cell proliferation. By rapidly and directly neutralizing IL-6, siltuximab not only provides superior control of fulminant CRS but may also be crucial for preserving CAR T-cell functional fitness. This study suggests that the choice of anti-IL-6 agent is not merely a toxicity management decision but a key determinant of cellular therapy efficacy. These findings strongly advocate for siltuximab as a premier, optimized strategy in CRS management and call for a paradigm shift in how we approach inflammation control in the CAR T-cell era.