Improving the safety of CAR-T cell therapy by controlling CRS-related coagulopathy

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Abstract
The CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy has been widely proved effective on relapsed and refractory (r/r) B cell acute lymphoblastic leukemia (B-ALL). Meanwhile, CAR-T therapy-related toxicities, including cytokine release syndrome (CRS) and neurological toxicities, are drawing researchers’ attention. In addition, our research team notices that coagulopathy and even disseminated intravascular coagulation (DIC) are common problems during CAR-T therapy. In our phase 1/2 clinical trial (NCT02965092), 53 r/r B-ALL patients underwent leukapheresis on day − 11 and received lymphodepleting chemotherapy on day − 7 to day − 5. Finally, they received split infusions of anti-CD19 CAR-T cells on day 0 to day 2. Plasma concentrations of tissue factor (TF) and platelet endothelial cell adhesion molecular-1 (PECAM-1) were also measured to identify the mechanism of coagulation disorders. The overall 1-month remission rate of the 53 patients was 88.7%. During the treatment course, 19 patients experienced grade 3–4 CRS, 8 patients developed grade 2–3 neurological toxicities. Beyond that, 30 patients (30/53, 56.6%) suffered from coagulation disorders, and half of them should be diagnosed as DIC. Benefiting from replacement and anticoagulant therapy, 14 patients successfully got out of the conditions of DIC. Remarkably, the severity of coagulopathy was positively correlated with CRS grade. What is more, plasma TF and PECAM-1 levels indicated that vascular endothelial factors played key roles in the process of CRS-related coagulopathy. To conclude, coagulation disorders frequently happen during CAR-T therapy. TF and PECAM-1 are of great importance in the etiology and pathogenesis of coagulation problems. Early and proper interventions targeted at CRS-related coagulopathy contribute a lot to the control of side effects in CAR-T therapy.
Funding Information
  • Major Technological Innovation Special Project of Hubei Province of China (2018ACA141)
  • National Natural Science Foundation of China (81770132, 81873434)

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