The monitoring value of twelve inflammatory cytokines in chimeric antigen receptor T cell immunotherapy / 中华检验医学杂志

ABSTRACT

Objective:To investigate the significance of 12 inflammatory cytokines in early detection and treatment guidance of hematologic malignant patients with Cytokine release syndrome (CRS) after Chimeric antigen receptor (CAR)-T cell immunotherapy.Methods:A total of 12 patients, including 6 males and 6 females, aged 53.0 (49.8, 62.5) years old, were treated with CAR-T cell immunotherapy in the First Affiliated Hospital of Nanjing Medical University from 2017 to 2020. Cytometric bead array was used to detect the serum levels of IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12P70, IL-17A, IFN-α, IFN-γ, and TNF-α at different time points after cell infusion in all patients receiving CAR-T cell immunotherapy. C-reactive protein (CRP), D-dimer (D-D), serum ferritin (SF), and lactate dehydrogenase (LDH) were measured at the corresponding period. CRS was classified into four grades according to the diagnostic criteria, from 0 to 3. The differences of the above mentioned parameters between the four groups were compared. The Speedman correlation coefficient was used to analyze the correlation between inflammatory cytokine expression levels and CRS grades. Plot the subject′s receiver operating characterist (ROC) curve to determine the sensitivity and specificity of inflammatory cytokines to predict CRS.Results:CRS grading was performed on day 1, 4, 7, and 11 after CAR-T cell infusion in 12 patients. There are 48 cases in total, including 25 cases of CRS grade 0, 6 cases of CRS grade 1, 9 cases of CRS grade 2, and 8 cases of CRS grade 3. The correlation analysis of 48 cases showed that the expression levels of IL-4, IL-6, IL-10, TNF-α, IFN-γ, IL-1β, and IL-8 were positively correlated with CRS grade ( P<0.05). The correlation coefficients were 0.384, 0.730, 0.632, 0.341, 0.681, 0.319, and 0.622, respectively. 7 inflammatory cytokines (IL-6, IL-10, IFN-γ, IL-8, IL-2, TNF-α, and IFN-α) were elevated in 12 patients, and the average time to start the rise was 3.4, 5.3, 6.1, 2.9, 4.3, 6.0 and 5.8 days, respectively. The time for CRP, D-D, SF, and LDH to begin to rise were 6.6, 7.6, 8.3 and 7.6 days, which were higher than that of the 7 inflammatory cytokines. After effective treatment, except for IL-6, the remaining 6 inflammatory cytokines (IL-10, IFN-γ, IL-8, IL-2, TNF-α and IFN-α) had their recovery times as 7.8, 3.9, 5.1, 8.0, 6.0, and 2.5 day,respectively, which were lower than that of CRP, D-D, SF, and LDH(9.7, 9.2, 13.7, and 13.8 days, respectively). The ROC showed that IL-6, IL-10, IFN-γ, and IL-8 can serve as biomarkers for diagnosis of CRS with high sensitivity and specificity. Conclusion:The monitoring of 12 inflammatory cytokines play an important role in CRS grading after CAR-T cell immunotherapy, which contributes to the early diagnosis of CRS and the prediction of clinical outcome.