title: Possible Compartmental Cytokine Release Syndrome in a Patient With Recurrent Ovarian Cancer After Treatment With Mesothelin-targeted CAR-T Cells.
abstract: Cytokine release syndrome (CRS) is a potentially severe systemic toxicity seen after adoptive T-cell therapy and caused by T-cell activation and proliferation and is associated with elevated circulating levels of cytokines such as C-reactive protein, interleukin-6 (IL-6), and interferon-γ and has previously been described as a systemic response in hematologic malignancies. A 52-year-old woman with BRCA 1 mutation positive heavily pretreated advanced recurrent serous ovarian cancer was treated under a compassionate use protocol with autologous mesothelin-redirected chimeric antigen receptor T cells (CART-meso). Autologous T cells were transduced to express a receptor composed of an extracellular antimesothelin single-chain variable fragment fused to 4-1BB and TCR-zeta signaling domain. This patient was infused with 3×10 CART-meso T cells/m without lymphodepletion and developed compartmental CRS confined to the pleural cavities. The compartmental CRS was evidenced by an increase in IL-6 and accumulation of CART-meso T cells in pleural fluid compared with peripheral blood and was successfully treated the anti-IL6 receptor antagonist tocilizumab on D21 after the T-cell infusion. This is the first description of a compartmental CRS in a patient with solid malignancy. This response could be due to malignant pleural fluid creating an environment where T cells could interact with tumor cells and suggests localized on-target CAR-T-cell activation.
authors.affiliation: *Department of Obstetrics and Gynecology ‡Department of Pathology and Laboratory Medicine, Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia †Department of Obstetrics and Gynecology, Lancaster General Health/Penn Medicine, Lancaster, PA §Department of Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA.
authors.forename: Janos L
authors.initials: JL
authors.lastname: Tanyi
authors.forename: Caitlin
authors.initials: C
authors.lastname: Stashwick
authors.forename: Gabriela
authors.initials: G
authors.lastname: Plesa
authors.forename: Mark A
authors.initials: MA
authors.lastname: Morgan
authors.forename: David
authors.initials: D
authors.lastname: Porter
authors.forename: Marcela V
authors.initials: MV
authors.lastname: Maus
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D002097:C-Reactive Protein / Q000378:metabolism; D002478:Cells, Cultured; D017809:Fatal Outcome; D005260:Female; D005334:Fever; D058851:GPI-Linked Proteins / Q000276:immunology; D006801:Humans; D007022:Hypotension; D016219:Immunotherapy, Adoptive / Q000009:adverse effects* / Q000379:methods; D007371:Interferon-gamma / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D000090204:Mesothelin; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000150:complications / Q000276:immunology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D019947:Receptors, Interleukin-6 / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics; D057127:Single-Chain Antibodies / Q000235:genetics / Q000378:metabolism; D013577:Syndrome; D013601:T-Lymphocytes / Q000502:physiology* / Q000637:transplantation; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D058851:GPI-Linked Proteins; D015850:Interleukin-6; D011948:Receptors, Antigen, T-Cell; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; C505714:TNFRSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; C054979:antigen T cell receptor, zeta chain; D007371:Interferon-gamma; D002097:C-Reactive Protein; C502936:tocilizumab; D000090204:Mesothelin