Inflammatory signatures for quick diagnosis of life-threatening infection during the CAR T-cell therapy

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.

Infection during the first year in patients treated with CD19 CAR T cells for diffuse large B cell lymphoma

“…Other risk factors for infection after CAR T cell therapy shown by previous studies included higher number of prior treatments, higher doses of CAR T cells, older age, previous history of infection, and CD22-specific CAR T cells 5 , 8 . Finally, a recent study described the association between double peak IL-6 pattern (second surge of serum IL-6 after initial normalization) and life-threatening infection 26 . Along with the current interest of anti-IL6 therapy in severe acute respiratory syndrome coronavirus 2 patients with respiratory failure 27 – 34 , it is at least worth noting that we did not observe an association between the use of tocilizumab and infections in this cohort.…”

Severe Candida glabrata pancolitis and fatal Aspergillus fumigatus pulmonary infection in the setting of bone marrow aplasia after CD19-directed CAR T-cell therapy – a case report

“…In multivariate analyses, the use of systemic corticosteroids for the management of CRS or ICANS has emerged as a major risk factor of infection [ 18 ]. Certain inflammatory signatures – such as the “double peaks of IL-6” pattern observed in our patient – have been shown to confer an especially high risk of life-threatening infection [ 19 ].…”

Dual specific CD19/CD22‑targeted chimeric antigen receptor T‑cell therapy for refractory diffuse large B‑cell lymphoma: A case report

“…Currently, although there are drugs that can control CRS, complications remain a barrier to standard treatment. It has been demonstrated that the degree of CRS severity is associated with disease burden at the time of infusion, as a higher tumor burden results in more serious CRS (45), suggesting that in the case of low tumor burden, such as early disease, the risk and severity of CRS in patients undergoing CAR T-cell therapy may be markedly reduced. Therefore, in the present study, radiotherapy was used prior to CAR T-cell therapy, successfully decreasing the tumor burden of the patient.…”