Characterization of the endotheliopathy, innate-immune activation and hemostatic imbalance underlying CAR-T cell toxicities: laboratory tools for an early and differential diagnosis

• DOI: 10.1136/jitc-2022-006365
• Publication Date: 2023-04-12T17:00:33Z
• Authors: Ana Belen Moreno-...; Sara Fernández; Helena Ventosa; Marta Palomo; Julia Martinez-Sa...; Alex Ramos; Valentín Ortiz-Ma...; Julio Delgado; Carlos Fernández ...; Alvaro Urbano-Isp...; Olaf Penack; J M Nicolás; Adrian Téllez; Gines Escolar; Enric Carreras; Francesc Fernánde...; Pedro Castro; Maribel Diaz-Ricart
• Keywords: Hemostasis; Immune Cell Therapies and Immune Cell Engineering; T-Lymphocytes; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; antineoplastic protocols; immunity; Interleukin-1 Receptor-Like 1 Protein; Hemostatics; 3. Good health; Diagnosis, Differential; Hematologic Neoplasms; Sepsis; von Willebrand Factor; Plasminogen Activator Inhibitor 1; cytotoxicity; Humans; hematologic neoplasms; immunologic; immunotherapy; cellular; RC254-282

BackgroundChimeric antigen receptor (CAR)-T cell-based immunotherapy constitutes a revolutionary advance for treatment of relapsed/refractory hematological malignancies. Nevertheless, cytokine release and immune effector cell-associated neurotoxicity syndromes are life-threatening toxicities in which the endothelium could be a pathophysiological substrate. Furthermore, differential diagnosis from sepsis, highly incident in these patients, is challenging. Suitable laboratory tools could be determinant for their appropriate management.MethodsSixty-two patients treated with CAR-T cell immunotherapy for hematological malignancies (n=46 with CD19-positive diseases, n=16 with multiple myeloma) were included. Plasma samples were obtained: before CAR-T cell infusion (baseline); after 24–48 hours; at suspicion of any toxicity onset and 24–48 hours after immunomodulatory treatment. Biomarkers of endothelial dysfunction (soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble TNF receptor 1 (sTNFRI), thrombomodulin (TM), soluble suppression of tumorigenesis-2 factor (ST2), angiopoietin-2 (Ang-2)), innate immunity activation (neutrophil extracellular traps (NETs), soluble C5b-9 (sC5b-9)) and hemostasis/fibrinolysis (von Willebrand Factor antigen (VWF:Ag), ADAMTS-13 (A13), α2-antiplasmin (α2-AP), plasminogen activator inhibitor-1 antigen (PAI-1 Ag)) were measured and compared with those in cohorts of patients with sepsis and healthy donors.ResultsPatients who developed CAR-T cell toxicities presented increased levels of sVCAM-1, sTNFRI and ST2 at the clinical onset versus postinfusion values. Twenty-four hours after infusion, ST2 levels were good predictors of any CAR-T cell toxicity, and combination of ST2, Ang-2 and NETs differentiated patients requiring intensive care unit admission from those with milder clinical presentations. Association of Ang-2, NETs, sC5b-9, VWF:Ag and PAI-1 Ag showed excellent discrimination between severe CAR-T cell toxicities and sepsis.ConclusionsThis study provides relevant contributions to the current knowledge of the CAR-T cell toxicities pathophysiology. Markers of endotheliopathy, innate immunity activation and hemostatic imbalance appear as potential laboratory tools for their prediction, severity and differential diagnosis.