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

By R. Morgan, Jie Yang, M. Kitano, M. Dudley, C. Laurencot, S. Rosenberg. Molecular Therapy, 2010

2,497 citations recorded by the source corpus.

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.

Subfields: Oncology, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/84e4053a3613f555f6bf8e15184a86990fafc757

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Citations in the corpus

Engineering T cells with Customized Therapeutic Response Programs Using Synthetic Notch Receptors (2016, neutral): “, 2011), which in some cases can be as dangerous as the disease itself (Davila et al., 2014; Lamers et al., 2006; Magee and Snook, 2014; Morgan et al., 2010; Zhao et al., 2009).”
Engineering strategies to overcome the current roadblocks in CAR T cell therapy (2019, methodology): “Much more alarmingly, a patient receiving HER2-directed CAR T cell therapy for metastatic colon cancer developed respiratory distress and pulmonary oedema 15 minutes after cell infusion, which progressed to multiorgan failure and death 85 .”
Chimeric Antigen Receptor Therapy (2018, neutral): “HER2/neu CAR: lethal cytokine release syndrome Morgan et al.(62)”
PD-1– and CTLA-4–Based Inhibitory Chimeric Antigen Receptors (iCARs) Divert Off-Target Immunotherapy Responses (2013, background): “These include B cell aplasia in chronic lymphocytic leukemia patients treated with T cells expressing anti-CD19 CAR (7–9), fatal acute respiratory distress syndrome after anti-ERBB2 CAR T cell infusion thought to result from cross-reactivity on lung epithelium (10), and TCR-induced fatalities from c”
TRUCKs: the fourth generation of CARs (2015, background): “For instance, ‘on-target off-tumor’ toxicity upon targeting solid tumors by anti-ErbB2 (Her2/neu) CAR T cells produced severe tissue damage when activated against normal epithelial tissues including lung and heart resulting in the patient’s death soon after T-cell transfer [21].”
Toxicities of chimeric antigen receptor T cells: recognition and management. (2016, positive): “CAR T cells may damage normal tissues by unexpectedly cross-reacting with a protein that is not expressed on tumor cells.(32,33) Acute anaphylaxis and tumor lysis syndrome (TLS) have occurred following infusion of CAR T cells.”