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    Oral Communication

    Vascular Biology

    Mechanisms Regulating Vessel Wall Function and Integrity

    OC 10.5 - Endotheliopathy, innate-immune activation and hemostatic imbalance underlying CAR -T cell toxicities: tools for early and differential diagnosis

    Saturday, June 24, 2023
    14:00 – 14:15 ET
    Room: 515
    Session Available As: On-Demand

      Co-Author(s)

    • Ana Belén Moreno-Castaño, MD

      Medical Doctor
      Hemostasis and Erythropathology Laboratory, Hematopathology, Department of Pathology, Centre de Diagnòstic Biomèdic (CDB), Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
      Barcelona, Catalonia, Spain

      • Co-Author(s)

    • SF

      Sara Fernandez

      MD
      Medical Intensive Care Unit, Hospital Clinic, Barcelona, Spain.
      Barcelona, Catalonia, Spain

    • MP

      Marta Palomo

      PhD
      Hematology External Quality Assessment Laboratory, Biomedical Diagnostic Center, Hospital Clinic of Barcelona, Barcelona, Spain.
      Barcelona, Catalonia, Spain

      • Presenting Author(s)

    • Julia Martinez-Sanchez, PhD

      PhD student
      Hemostasis and Erythropathology Laboratory, Hematopathology, Department of Pathology, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain.
      Barcelona, Catalonia, Spain

      • Co-Author(s)

    • AR

      Alex Ramos

      Predoctoral Student
      Josep Carreras Leukaemia Research Institute (Campus Clinic). Barcelona
      Barcelona, Catalonia, Spain

    • PM

      Patricia Molina

      Laboratory Technician
      Hemostasis and Erythropathology Laboratory, Hematopathology, Pathology Department, Centre Diagnòstic Biomèdic (CDB), Hospital Clínic, Barcelona, Spain
      Barcelona, Catalonia, Spain

    • MP

      Marc Pino

      Laboratory Technician
      Hemostasis and Erythropatology Laboratory, Pathology Department, CDB
      Barcelona, Catalonia, Spain

    • VO

      Valentín Ortiz-Maldonado

      MD
      Hematology Department, Institut Clínic de Malalties Hemato-Oncològiques (ICMHO), Hospital Clínic, Barcelona
      Barcelona, Catalonia, Spain

    • JD

      Julio Delgado

      MD, PhD
      Hematology Department, Institut Clínic de Malalties Hemato-Oncològiques (ICMHO), Hospital Clínic, Barcelona
      Barcelona, Catalonia, Spain

    • CF

      Carlos Fernández de Larrea

      Hematologist
      Hematology Department, Institut Clínic de Malalties Hemato-Oncològiques (ICMHO), Hospital Clínic, Barcelona
      Barcelona, Catalonia, Spain

    • U

      Álvaro Urbano

      MD, PhD
      Hematology Department, Institut Clínic de Malalties Hemato-Oncològiques (ICMHO), Hospital Clínic, Barcelona
      Barcelona, Catalonia, Spain

    • GE

      Gines Escolar

      MD PhD Senior Consultant
      Hemostasis and Erythropathology Laboratory, Hematopathology, Department of Pathology, Centre de Diagnòstic Biomèdic (CDB), Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
      Barcelona, Catalonia, Spain

    • EC

      Enric Carreras

      Medical Doctor
      Josep Carreras Leukaemia Research Institute, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain.
      Barcelona, Catalonia, Spain

    • FF

      Francesc Fernández-Avilés

      MD, PhD
      Hematology Department, Institut Clínic de Malalties Hemato-Oncològiques (ICMHO), Hospital Clínic, Barcelona
      Barcelona, Catalonia, Spain

    • PC

      Pedro Castro

      MD, PhD
      Medical Intensive Care Unit, Hospital Clinic, Barcelona, Spain.
      Barcelona, Catalonia, Spain

    • MD

      Maribel Diaz-Ricart

      PhD Senior Consultant
      Hemostasis and Erythropathology Laboratory, Hematopathology, Department of Pathology, Centre de Diagnòstic Biomèdic (CDB), Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
      Barcelona, Catalonia, Spain

    Background: Chimeric antigen receptor (CAR)-T cell-based immunotherapy constitutes a revolutionary advance for relapsed/refractory hematologic malignancies treatment. Nevertheless, cytokine release (CRS) and immune effector cell-associated neurotoxicity (ICANS) 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.

    Aims: To analyze the interplay between biomarkers of endothelial dysfunction, innate immunity activation and hemostatic alterations and the appearance of CAR-T cell toxicities. Also, to compare biomarker levels with those in septic patients.

    Methods: Sixty-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 collected: (A) before the CAR-T cell infusion; (B) 24-48h after; (C) at the suspicion of the onset of any toxicity (fever, hypotension, hypoxia and/or neurotoxicity); and (D) 24-48h after immunomodulatory treatment. Biomarkers of endothelial dysfunction (sVCAM-1, sTNFRI, TM, ST2, Ang-2), innate immunity activation (NETs, sC5b-9) and hemostasis/fibrinolysis (VWF:Ag, ADAMTS-13, alpha-2-antiplasmin, PAI-1:Ag) were measured and compared with those cohorts of septic patients (n= 21) and healthy donors (n=49).

    Results: Patients who developed CAR-T cell toxicities (n=19) presented increased levels of sVCAM-1, sTNFR-1 and ST2 at their clinical onset with respect to post-infusion values. Twenty-four hours after infusion, ST2 levels were good predictors of any CAR-T cell toxicity (Figure 1), and combination of ST2, Ang-2 and NETs differentiated patients who required ICU admission (n=17) 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 (Figure 2).

    Conclusion(s): This study makes an important contribution 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.

    Learning Objectives:

    • This study provides relevant contributions unveiling the pathophysiology of CAR-T cell toxicities, where endotheliopathy, innate-immunity activation and hemostatic imbalance are major cornerstones and potential targets for their treatment.
    • The biomarkers analyzed may have a potential role in the laboratory confirmation of these complications and in the prediction of their clinical severity.
    • These molecules investigated provide a distinctive profile that may be helpful for the differential diagnosis between CAR-T cell toxicities and sepsis.