Case report of a serious adverse event following the administration of t cells transduced with a chimeric antigen receptor recognizing ERBB2

Richard A. Morgan, James C. Yang, Mio Kitano, Mark E. Dudley, Carolyn M. Laurencot, Steven A. Rosenberg

Research output: Contribution to journalArticlepeer-review

1281 Scopus citations

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 CD3 signaling moieties was assembled in a γ-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-γ (IFN-γ), granulocyte macrophage-colony stimulating factor (GM-CSF), tumor necrosis factor-α (TNF-α), 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.

Original languageEnglish (US)
Pages (from-to)843-851
Number of pages9
JournalMolecular Therapy
Volume18
Issue number4
DOIs
StatePublished - Apr 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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