ArticleThe Journal of clinical investigation2020
Perforin-deficient CAR T cells recapitulate late-onset inflammatory toxicities observed in patients.
Article in The Journal of clinical investigation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers, 1 of them a synthesis that pooled it.
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Who cites it
54 citing papers in PubMed, 1 synthesis or guideline pooled it, 67 citations in OpenAlex.
- Immunopathology of and potential therapeutics for secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome: a translational perspective.Experimental & molecular medicine · 2024Pooled it
- The Conflicting Role of Myeloid Cells in CAR T-Cell Therapy.Cancer research · 2026Review
- Chimeric antigen receptor T-cell therapies related to immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome: Diagnosis, high-risk factors, and management.Chinese medical journal · 2026Review
- PD-1: CD28 chimeric receptors enhance phenotypic and functional features of T cell subsets.Research in pharmaceutical sciences · 2026Article
- Rational redesign of antigen binding domain improves in vivo efficacy of the CD22-CAR.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Ten-year experience of CD22 CAR T cells for children and young adults with B-cell acute lymphoblastic leukemia.Blood advances · 2026Article
- Management Practices of CAR T-cell-Related Inflammatory Toxicities: A Survey of Pediatric CAR T-cell Providers.Transplantation and cellular therapy · 2026Article
- The Pleiotropic Roles of Cytokines in Chimeric Antigen Receptor T-cell Therapy.Cancer immunology research · 2026Review
- EomesoderminImmunity · 2025Article
- CAR-T cells in solid tumors: Challenges and breakthroughs.Cell reports. Medicine · 2025Review
- HLA-A2 CAR/IL-2-CISC engineered Treg display robustMolecular therapy. Methods & clinical development · 2025Article
- Article
- Immunological Markers of Cardiovascular Pathology in Older Patients.Biomedicines · 2025Article
- Immune Effector Cell-associated Hemophagocytic Lymphohistiocytosis-like Syndrome (IEC-HS).Hematology/oncology clinics of North America · 2025Review
- Deep insight into cytokine storm: from pathogenesis to treatment.Signal transduction and targeted therapy · 2025Review
- CD22 TCR-engineered T cells exert antileukemia cytotoxicity without causing inflammatory responses.Science advances · 2025Article
- Treating and triggering hyperinflammation: tackling hemophagocytic lymphohistiocytosis and HLH-like syndromes in the pediatric cell therapy and critical care setting.Frontiers in oncology · 2025Review
- Evolving strategies for addressing CAR T-cell toxicities.Cancer metastasis reviews · 2024Review
- New insights into CAR T-cell hematological toxicities: manifestations, mechanisms, and effective management strategies.Experimental hematology & oncology · 2024Review
- Riding the storm: managing cytokine-related toxicities in CAR-T cell therapy.Seminars in immunopathology · 2024Review
Corrections and comments
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Authors and funding
21 authors at 7 institutions in 5 countries.
Funding
Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.