Using an immunocompetent mouse model of aggressive B cell lymphoma, Boulch et al. showed that IV injection of anti-CD19 CD4+, but not CD8+, CAR T cells alone induced cytokine release syndrome (CRS)-like effects on body temperature, weight, and serum cytokine and chemokine levels. In patients with diffuse large B-cell lymphoma treated with anti-CD19 CAR T cells, those who experienced CRS had a higher proportion of CD4+ CAR T cells in the blood. Using an IFNγ knockout murine model and a model with variable tumor burden, it was shown that CD4+ CAR T cell-induced CRS was dependent on a high tumor burden, but not IFNγ production.
Contributed by Maartje Wouters
ABSTRACT: Anti-CD19 chimeric antigen receptor (CAR) T cell therapy represents a breakthrough for the treatment of B cell malignancies. Yet, it can lead to severe adverse events, including cytokine release syndrome (CRS), which may require urgent clinical management. Whether interpatient variability in CAR T cell subsets contributes to CRS is unclear. Here, we show that CD4+ CAR T cells are the main drivers of CRS. Using an immunocompetent model of anti-CD19 CAR T cell therapy, we report that CD4+, but not CD8+, CAR T cells elicit physiological CRS-like manifestations associated with the release of inflammatory cytokines. In CAR T cell-treated patients, CRS occurrence and severity are significantly associated with high absolute values of CD4+ CAR T cells in the blood. CRS in mice occurs independently of CAR T cell-derived interferon γ (IFN-γ) but requires elevated tumor burden. Thus, adjusting the CD4:CD8 CAR T cell ratio to patient tumor load may help mitigate CAR T cell-associated toxicities.
Author Info: (1) Institut Pasteur, Université Paris Cité, INSERM U1223, Dynamics of Immune Responses Unit, équipe Labellisée Ligue Contre le Cancer, 75015 Paris, France. (2) Institut Pasteur, U
Author Info: (1) Institut Pasteur, Université Paris Cité, INSERM U1223, Dynamics of Immune Responses Unit, équipe Labellisée Ligue Contre le Cancer, 75015 Paris, France. (2) Institut Pasteur, Université Paris Cité, INSERM U1223, Dynamics of Immune Responses Unit, équipe Labellisée Ligue Contre le Cancer, 75015 Paris, France. (3) Université Paris Cité, Hôpital Saint-Louis, AP-HP Nord, Laboratoire d'Immunologie, Paris, France; INSERM UMR976, Institut de Recherche St-Louis, Paris, France. (4) Institut Pasteur, Université Paris Cité, INSERM U1223, Dynamics of Immune Responses Unit, équipe Labellisée Ligue Contre le Cancer, 75015 Paris, France. (5) Université Paris Cité, Hôpital Saint-Louis, AP-HP Nord, Laboratoire d'Immunologie, Paris, France; INSERM UMR976, Institut de Recherche St-Louis, Paris, France. (6) Institut Pasteur, Université Paris Cité, INSERM U1223, Dynamics of Immune Responses Unit, équipe Labellisée Ligue Contre le Cancer, 75015 Paris, France. (7) Institut Pasteur, Université Paris Cité, Bioinformatics and Biostatistics HUB, 75015 Paris, France. (8) Université Paris Cité, INSERM, UMRS-1144, Optimisation Thérapeutique en Neuropsychopharmacologie, 75006 Paris, France; Service de Pharmacie, Unité Claude Kellershohn - Radiopharmacie R&D, AP-HP, Hôpital Saint-Louis, 75475 Paris, France. (9) Université Paris Cité, INSERM, UMRS-1144, Optimisation Thérapeutique en Neuropsychopharmacologie, 75006 Paris, France; Service de Pharmacie, AP-HP, Hpital Necker, 75015 Paris, France. (10) Université Paris Cité, INSERM, UMRS-1144, Optimisation Thérapeutique en Neuropsychopharmacologie, 75006 Paris, France; Service de Pharmacie, AP-HP, Hôpital Necker, 75015 Paris, France. (11) Hémato-Oncologie, Hôpital Saint-Louis, AP-HP, Université Paris Cité, Inserm U1153, Paris, France. (12) Université Paris Cité, Hôpital Saint-Louis, AP-HP Nord, Laboratoire d'Immunologie, Paris, France; INSERM UMR976, Institut de Recherche St-Louis, Paris, France. (13) Institut Pasteur, Université Paris Cité, INSERM U1223, Dynamics of Immune Responses Unit, équipe Labellisée Ligue Contre le Cancer, 75015 Paris, France. Electronic address: philippe.bousso@pasteur.fr.
