Abstract
BackgroundChimeric antigen receptor-modified (CAR) T-cell immunotherapy is a novel promising therapy for treatment of B-cell malignancy. Cytokine release syndrome (CRS) and infection are the most common adverse events during CAR T-cell therapy. Similar clinical presentation of concurrent CRS and infection makes it difficult to differentially diagnose and timely treat the condition.MethodsWe analyzed the features of infection events during the first 30 days after CAR T-cell infusion (CTI) in 109 patients from three clinical trials (ChiCTR-OPN-16008526, ChiCTR-OPC-16009113, ChiCTR-OPN-16009847). Based on the dynamic changes of interleukin (IL)-6 and ferritin, we proposed the “double peaks of IL-6” pattern as a feature of life-threatening infection during the first 30 days after CTI. Meanwhile, we screened candidate biomarkers from 70-biomarker panel to establish a prediction model for life-threatening infection.ResultsIn this study, 19 patients (17.4%) experienced a total of 19 infection events during the first 30 days after CAR T-cell infusion. Eleven patients (10.1%) had grade 4–5 infection, which were all bacterial infection and predominantly sepsis (N = 9). “Double peaks of IL-6” appeared in 9 out of 11 patients with life-threatening infection. The prediction model of three-cytokines (IL-8, IL-1β and interferon-γ) could predict life-threatening infection with high sensitivity (training: 100.0%; validation: 100.0%) and specificity (training: 97.6%; validation: 82.8%). On base of the aforementioned methods, we proposed a workflow for quick identification of life-threatening infection during CAR T-cell therapy.ConclusionsIn this study, we worked out two diagnostic methods for life-threatening infection during CAR T-cell therapy by analyzing inflammatory signatures, which contributed to reducing risks of infection-induced death.
Highlights
Chimeric antigen receptor-modified (CAR) T-cell immunotherapy represents a novel promising treatment and has achieved impressive anti-tumor responses in patients with refractory or relapsed (r/r) B-cell malignancies [1,2,3,4,5,6]
The median time of Cytokine release syndrome (CRS) beginning in three studies was all on day 2 after CTI and the median time of CRS ending was separately day 9, day 8, day 7 in CAR19/22, CAR-BCMA and CAR19/22+ hematopoietic stem cell transplantation (HSCT) (Additional file 1: Figure S5B)
Despite different designs and types of CAR-T cells used in three therapy groups, the CAR copies reached to a peak within 2 weeks after CTI, which was consistent with the occurrence time of CRS
Summary
Chimeric antigen receptor-modified (CAR) T-cell immunotherapy represents a novel promising treatment and has achieved impressive anti-tumor responses in patients with refractory or relapsed (r/r) B-cell malignancies [1,2,3,4,5,6]. Since infection mimics CRS in terms of elevated inflammatory factors and fever, the diagnosis of infection becomes difficult in the presence of CRS [9]. It is necessary to distinguish between infection and CRS in order to give proper treatment during CAR T-cell therapy. Chimeric antigen receptor-modified (CAR) T-cell immunotherapy is a novel promising therapy for treatment of B-cell malignancy. Cytokine release syndrome (CRS) and infection are the most common adverse events during CAR T-cell therapy. Similar clinical presentation of concurrent CRS and infection makes it difficult to differentially diagnose and timely treat the condition
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