title: Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2.
abstract: In an attempt to treat cancer patients with ERBB2 overexpressing tumors, we developed a chimeric antigen receptor (CAR) based on the widely used humanized monoclonal antibody (mAb) Trastuzumab (Herceptin). An optimized CAR vector containing CD28, 4-1BB, and CD3zeta signaling moieties was assembled in a gamma-retroviral vector and used to transduce autologous peripheral blood lymphocytes (PBLs) from a patient with colon cancer metastatic to the lungs and liver, refractory to multiple standard treatments. The gene transfer efficiency into autologous T cells was 79% CAR(+) in CD3(+) cells and these cells demonstrated high-specific reactivity in in vitro coculture assays. Following completion of nonmyeloablative conditioning, the patient received 10(10) cells intravenously. Within 15 minutes after cell infusion the patient experienced respiratory distress, and displayed a dramatic pulmonary infiltrate on chest X-ray. She was intubated and despite intensive medical intervention the patient died 5 days after treatment. Serum samples after cell infusion showed marked increases in interferon-gamma (IFN-gamma), granulocyte macrophage-colony stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-10, consistent with a cytokine storm. We speculate that the large number of administered cells localized to the lung immediately following infusion and were triggered to release cytokine by the recognition of low levels of ERBB2 on lung epithelial cells.
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. rmorgan@mail.nih.gov
authors.forename: Richard A
authors.initials: RA
authors.lastname: Morgan
authors.forename: James C
authors.initials: JC
authors.lastname: Yang
authors.forename: Mio
authors.initials: M
authors.lastname: Kitano
authors.forename: Mark E
authors.initials: ME
authors.lastname: Dudley
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Laurencot
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D017252:CD3 Complex / Q000276:immunology; D003110:Colonic Neoplasms / Q000473:pathology*; D016207:Cytokines / Q000097:blood / Q000276:immunology; D017809:Fatal Outcome; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects*; D008113:Liver Neoplasms / Q000556:secondary / Q000628:therapy*; D008175:Lung Neoplasms / Q000556:secondary / Q000628:therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012128:Respiratory Distress Syndrome / Q000276:immunology; D013601:T-Lymphocytes / Q000637:transplantation*; D014161:Transduction, Genetic; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D017252:CD3 Complex; D016207:Cytokines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D000068878:Trastuzumab; C508053:ERBB2 protein, human