The Journal of infection · 2026
Host immune biomarkers associated with infection risk after CAR T-cell therapy.
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Reynolds Gemma K, Williams Lewis, Giner Goknur, Garnham Alex, Jansen Therease, Dowling Mark R, Minson Adrian, Chee Lynette, Dickinson Michael, Anderson Mary Ann, Thursky Karin, Oliaro Jane, Harrison Simon J, Slavin Monica A, Doerflinger Marcel, Teh Benjamin W
Аннотация
BACKGROUND: Infection is the leading cause of non-relapse mortality after CAR-T therapy, yet individual risk prediction remains challenging. This exploratory study evaluated immune correlates of infection and other treatment-emergent adverse events in patients with diffuse large B-cell lymphoma (DLBCL) receiving CAR-T.
METHODS: Twenty patients with relapsed or refractory DLBCL received axicabtagene ciloleucel (n = 7) or tisagenlecleucel (n = 13), with prospective blood collection at apheresis, (baseline), post-lymphodepletion, and day 30 (D30). Cytokine responses were assessed in stimulated peripheral blood mononuclear cells; transcriptomic profiling was performed using bulk RNA-seq. Infections were classified as early (apheresis-D30) or late (D30-D90). Associations between immune features and infection were explored using multivariable regression.
RESULTS: Eighteen infections (13 early, 5 late) occurred in 11 patients (55%). Early infections were associated with higher baseline neutrophil activation cytokines (OR=4.35, p=0.047), lower TREM-1 levels following stimulation (OR=1.37 per 500pg/mL decrease, p=0.004), and upregulation of heme metabolism genes. Late infections correlated with increased MCP-1 secretion (OR=1.82 per 500pg/mL, p=0.013) and suppression of TNF-α-related pathways at D30. By D30, cytokine responses associated with Th1 (295 vs. 9365pg/mL, p < 0.001), T-cell (263 vs. 531pg/mL) and B-cell pathways (220 vs. 584pg/mL) were significantly suppressed compared to baseline (p < 0.001) accompanied by transcriptomic downregulation of immune activation signatures. Distinct immune patterns were also observed in toxicity. CRS (grade ≥ 2) was linked to suppressed Th1 cytokines at D30 (IL-12: 3 vs. 403pg/mL, p < 0.001) and RNASE1 overexpression, while ICANS (grade ≥ 1) was associated with increased Th1 cytokines (2368 vs. 1361pg/mL, p=0.007), independent of corticosteroid use.
CONCLUSIONS: Longitudinal immune profiling identified distinct immunological signatures linked to infection risk and CAR-T-related toxicities. These findings suggest a role for immune monitoring in improving risk stratification and guiding supportive care after CAR-T therapy.
METHODS: Twenty patients with relapsed or refractory DLBCL received axicabtagene ciloleucel (n = 7) or tisagenlecleucel (n = 13), with prospective blood collection at apheresis, (baseline), post-lymphodepletion, and day 30 (D30). Cytokine responses were assessed in stimulated peripheral blood mononuclear cells; transcriptomic profiling was performed using bulk RNA-seq. Infections were classified as early (apheresis-D30) or late (D30-D90). Associations between immune features and infection were explored using multivariable regression.
RESULTS: Eighteen infections (13 early, 5 late) occurred in 11 patients (55%). Early infections were associated with higher baseline neutrophil activation cytokines (OR=4.35, p=0.047), lower TREM-1 levels following stimulation (OR=1.37 per 500pg/mL decrease, p=0.004), and upregulation of heme metabolism genes. Late infections correlated with increased MCP-1 secretion (OR=1.82 per 500pg/mL, p=0.013) and suppression of TNF-α-related pathways at D30. By D30, cytokine responses associated with Th1 (295 vs. 9365pg/mL, p < 0.001), T-cell (263 vs. 531pg/mL) and B-cell pathways (220 vs. 584pg/mL) were significantly suppressed compared to baseline (p < 0.001) accompanied by transcriptomic downregulation of immune activation signatures. Distinct immune patterns were also observed in toxicity. CRS (grade ≥ 2) was linked to suppressed Th1 cytokines at D30 (IL-12: 3 vs. 403pg/mL, p < 0.001) and RNASE1 overexpression, while ICANS (grade ≥ 1) was associated with increased Th1 cytokines (2368 vs. 1361pg/mL, p=0.007), independent of corticosteroid use.
CONCLUSIONS: Longitudinal immune profiling identified distinct immunological signatures linked to infection risk and CAR-T-related toxicities. These findings suggest a role for immune monitoring in improving risk stratification and guiding supportive care after CAR-T therapy.