Journal Article

Perforin-deficient CAR T cells recapitulate late-onset inflammatory toxicities observed in patients

Eckhaus, Michael A., Kohler, M. Eric, Young, Howard A., Shah, Nirali N., Lei, Haiyan, Kondo, Taisuke, Pouzolles, Marie, Fry, Terry J., Chien, Christopher D., Qin, Haiying, Dulau-Florea, Alina, Kuhn, Skyler, Shern, Jack F., Yates, Bonnie, Ombrello, Amanda K., Shalabi, Haneen, Zimmermann, Valérie S., Lichtenstein, Daniel A., Ishii, Kazusa, Taylor, Naomi, Erwin-Cohen, Rebecca A.

2020

Overview

Late-onset inflammatory toxicities resembling hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) occur after chimeric antigen receptor T cell (CAR T cell) infusion and represent a therapeutic challenge. Given the established link between perforin deficiency and primary HLH, we investigated the role of perforin in anti-CD19 CAR T cell efficacy and HLH-like toxicities in a syngeneic murine model. Perforin contributed to both CD8+ and CD4+ CAR T cell cytotoxicity but was not required for in vitro or in vivo leukemia clearance. Upon CAR-mediated in vitro activation, perforin-deficient CAR T cells produced higher amounts of proinflammatory cytokines compared with WT CAR T cells. Following in vivo clearance of leukemia, perforin-deficient CAR T cells reexpanded, resulting in splenomegaly with disruption of normal splenic architecture and the presence of hemophagocytes, which are findings reminiscent of HLH. Notably, a substantial fraction of patients who received anti-CD22 CAR T cells also experienced biphasic inflammation, with the second phase occurring after the resolution of cytokine release syndrome, resembling clinical manifestations of HLH. Elevated inflammatory cytokines such as IL-1β and IL-18 and concurrent late CAR T cell expansion characterized the HLH-like syndromes occurring in the murine model and in humans. Thus, a murine model of perforin-deficient CAR T cells recapitulated late-onset inflammatory toxicities occurring in human CAR T cell recipients, providing therapeutically relevant mechanistic insights.

• Publisher: American Society for Clinical Investigation
• Subject: Animal models / Animals / Antigens / B cells / Biomedical research / Blinatumomab / CD19 antigen / CD22 antigen / CD4 antigen / CD8 antigen / Cell activation / Chimeric antigen receptors / Comparative analysis / Cytokines / Cytokines - biosynthesis / Cytotoxicity / Disease Models, Animal / FDA approval / Gene expression / Health aspects / Histiocytosis / Humans / IL-1β / Immunotherapy, Adoptive - adverse effects / In Vitro Techniques / Inflammation / Inflammation Mediators - metabolism / Interleukin 18 / Leukemia / Life Sciences / Lymphocytes / Lymphocytes T / Lymphocytosis / Lymphohistiocytosis, Hemophagocytic - etiology / Lymphohistiocytosis, Hemophagocytic - immunology / Lymphohistiocytosis, Hemophagocytic - pathology / Macrophage Activation Syndrome - etiology / Macrophage Activation Syndrome - immunology / Macrophage Activation Syndrome - pathology / Macrophages / Mice / Mice, Inbred C57BL / Mice, Knockout / Models, Immunological / Perforin / Perforin - deficiency / Perforin - genetics / Receptors, Chimeric Antigen - immunology / Spleen / Splenomegaly / T cells / T-Lymphocytes - immunology / T-Lymphocytes - pathology / Toxicity