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PMID: 20179677 Published · ppublish English Case Reports Journal Article Research Support, N.I.H., Intramural

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

Molecular therapy : the journal of the American Society of Gene Therapy ·Vol. 18 ·No. 4 ·2010-04-00 ·Pages 843-51

Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA

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.

MeSH Terms
Adult Antibodies, Monoclonal/administration & dosage Antibodies, Monoclonal, Humanized CD3 Complex/immunology Colonic Neoplasms/pathology Cytokines/blood,immunology Fatal Outcome Female Genetic Vectors Humans Immunotherapy, Adoptive/adverse effects Liver Neoplasms/secondary,therapy Lung Neoplasms/secondary,therapy Receptor, ErbB-2/immunology Receptors, Antigen, T-Cell/genetics Recombinant Fusion Proteins/genetics Respiratory Distress Syndrome/immunology T-Lymphocytes/transplantation Transduction, Genetic Trastuzumab
Chemicals
Antibodies, Monoclonal Antibodies, Monoclonal, Humanized CD3 Complex Cytokines Receptors, Antigen, T-Cell Recombinant Fusion Proteins ERBB2 protein, human Receptor, ErbB-2 Trastuzumab
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Morgan Richard A
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. [email protected]
Yang James C
Kitano Mio
Dudley Mark E
Laurencot Carolyn M
Rosenberg Steven A
References (61)
61 references, click to expand
  1. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412.
    N Engl J Med. 2006 Sep 7;355(10):1018-28 PMID: 16908486
  2. The interleukin-6 (IL6)-174 G/C promoter genotype is associated with the presence of septic shock and the ex vivo secretion of IL6.
    Int J Immunogenet. 2007 Dec;34(6):413-8 PMID: 18001296
  3. Expression and costimulatory effects of the TNF receptor superfamily members CD134 (OX40) and CD137 (4-1BB), and their role in the generation of anti-tumor immune responses.
    Eur J Immunol. 2002 Dec;32(12):3617-27 PMID: 12516549
  4. Gene polymorphisms and transplantation.
    Curr Opin Immunol. 2001 Oct;13(5):572-6 PMID: 11544006
  5. Phase I trial of 2B1, a bispecific monoclonal antibody targeting c-erbB-2 and Fc gamma RIII.
    Cancer Res. 1995 Oct 15;55(20):4586-93 PMID: 7553634
  6. The emergence of ErbB2 expression in cultured rat hepatocytes correlates with enhanced and diversified EGF-mediated signaling.
    Am J Physiol Gastrointest Liver Physiol. 2006 Jul;291(1):G16-25 PMID: 16769812
  7. Adoptive transfer of autologous, HER2-specific, cytotoxic T lymphocytes for the treatment of HER2-overexpressing breast cancer.
    Cancer Immunol Immunother. 2008 Feb;57(2):271-80 PMID: 17646988
  8. Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma.
    Mol Ther. 2007 Apr;15(4):825-33 PMID: 17299405
  9. Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2.
    Clin Cancer Res. 2004 Sep 1;10(17):5650-5 PMID: 15355889
  10. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer.
    N Engl J Med. 2005 Oct 20;353(16):1673-84 PMID: 16236738
  11. Side-effects of a monoclonal antibody, muromonab CD3/orthoclone OKT3: bibliographic review.
    Toxicology. 1995 Dec 20;105(1):23-9 PMID: 8638282
  12. Targeting tumours with genetically enhanced T lymphocytes.
    Nat Rev Cancer. 2003 Jan;3(1):35-45 PMID: 12509765
  13. The role of cytokine polymorphisms in rejection after solid organ transplantation.
    Genes Immun. 2001 Oct;2(6):297-303 PMID: 11607784
  14. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma.
    J Clin Oncol. 2005 Apr 1;23(10):2346-57 PMID: 15800326
  15. Tumor lysis syndrome.
    Clin J Oncol Nurs. 2004 Aug;8(4):415-6 PMID: 15354929
  16. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer.
    J Clin Oncol. 2005 Jun 1;23(16):3676-85 PMID: 15738535
  17. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma.
    Nat Med. 2008 Nov;14(11):1264-70 PMID: 18978797
  18. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo.
    Mol Ther. 2009 Aug;17(8):1453-64 PMID: 19384291
  19. Presentation of tumor antigens by dendritic cells genetically modified with viral and nonviral vectors.
    J Immunother. 2006 Nov-Dec;29(6):616-27 PMID: 17063124
  20. Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+ T cell-mediated tumor eradication.
    Mol Ther. 2010 Feb;18(2):413-20 PMID: 19773745
  21. Safety of biologics, lessons learnt from TGN1412.
    Curr Opin Biotechnol. 2009 Dec;20(6):673-7 PMID: 19892543
  22. Untangling the ErbB signalling network.
    Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37 PMID: 11252954
  23. "Cytokine storm" in the phase I trial of monoclonal antibody TGN1412: better understanding the causes to improve preclinical testing of immunotherapeutics.
    J Immunol. 2007 Sep 1;179(5):3325-31 PMID: 17709549
  24. Gene amplification, mutation, and protein expression of EGFR and mutations of ERBB2 in serous ovarian carcinoma.
    J Mol Med (Berl). 2006 Aug;84(8):671-81 PMID: 16607561
  25. The T-body approach: redirecting T cells with antibody specificity.
    Handb Exp Pharmacol. 2008;(181):329-42 PMID: 18071952
  26. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells.
    Blood. 2008 Sep 15;112(6):2261-71 PMID: 18509084
  27. The HER-2/neu oncogene in tumors of the gastrointestinal tract.
    Cancer Invest. 2001;19(5):554-68 PMID: 11458821
  28. In vivo cell activation following OKT3 administration. Systemic cytokine release and modulation by corticosteroids.
    Transplantation. 1990 Apr;49(4):697-702 PMID: 2109379
  29. Expression of ERBB2 in human gastric carcinomas: relationship between p185ERBB2 expression and the gene amplification.
    Cancer Res. 1990 Dec 15;50(24):8002-9 PMID: 1979253
  30. Tumor localization of adoptively transferred indium-111 labeled tumor infiltrating lymphocytes in patients with metastatic melanoma.
    J Clin Oncol. 1989 Feb;7(2):250-61 PMID: 2644399
  31. A phase II trial of trastuzumab in combination with low-dose interleukin-2 (IL-2) in patients (PTS) with metastatic breast cancer (MBC) who have previously failed trastuzumab.
    Breast Cancer Res Treat. 2009 Sep;117(1):83-9 PMID: 19051009
  32. Systemic inflammation after trauma.
    Injury. 2007 Dec;38(12):1336-45 PMID: 18048040
  33. A herceptin-based chimeric antigen receptor with modified signaling domains leads to enhanced survival of transduced T lymphocytes and antitumor activity.
    J Immunol. 2009 Nov 1;183(9):5563-74 PMID: 19843940
  34. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains.
    Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3360-5 PMID: 19211796
  35. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer.
    Science. 1989 May 12;244(4905):707-12 PMID: 2470152
  36. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen.
    Blood. 2009 Jul 16;114(3):535-46 PMID: 19451549
  37. Gene modification strategies to induce tumor immunity.
    Immunity. 2005 Apr;22(4):403-14 PMID: 15845446
  38. Recognition of fresh human tumor by human peripheral blood lymphocytes transduced with a bicistronic retroviral vector encoding a murine anti-p53 TCR.
    J Immunol. 2005 Nov 1;175(9):5799-808 PMID: 16237072
  39. A phase I study of interleukin 12 with trastuzumab in patients with human epidermal growth factor receptor-2-overexpressing malignancies: analysis of sustained interferon gamma production in a subset of patients.
    Clin Cancer Res. 2004 Aug 1;10(15):5027-37 PMID: 15297404
  40. The basic biology of HER2.
    Ann Oncol. 2001;12 Suppl 1:S3-8 PMID: 11521719
  41. Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues.
    Oncogene. 1990 Jul;5(7):953-62 PMID: 1973830
  42. Immune regulation by 4-1BB and 4-1BBL: complexities and challenges.
    Immunol Rev. 2009 May;229(1):192-215 PMID: 19426223
  43. Elements related to heterogeneity of antibody-dependent cell cytotoxicity in patients under trastuzumab therapy for primary operable breast cancer overexpressing Her2.
    Cancer Res. 2007 Dec 15;67(24):11991-9 PMID: 18089830
  44. The cytokine storm and factors determining the sequence and severity of organ dysfunction in multiple organ dysfunction syndrome.
    Am J Emerg Med. 2008 Jul;26(6):711-5 PMID: 18606328
  45. Clinical impact of cytokine and growth factor genetic polymorphisms in thoracic organ transplantation.
    Clin Lab Med. 2008 Sep;28(3):423-40, vi PMID: 19028261
  46. Trastuzumab--mechanism of action and use in clinical practice.
    N Engl J Med. 2007 Jul 5;357(1):39-51 PMID: 17611206
  47. Humanization of an anti-p185HER2 antibody for human cancer therapy.
    Proc Natl Acad Sci U S A. 1992 May 15;89(10):4285-9 PMID: 1350088
  48. SnapShot: EGFR signaling pathway.
    Cell. 2007 Nov 30;131(5):1018 PMID: 18045542
  49. Clinical trial results of a HER2/neu (E75) vaccine to prevent recurrence in high-risk breast cancer patients.
    J Clin Oncol. 2005 Oct 20;23(30):7536-45 PMID: 16157940
  50. Immunotherapy of human cancers using gene modified T lymphocytes.
    Curr Gene Ther. 2009 Oct;9(5):396-408 PMID: 19860654
  51. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors.
    Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):720-4 PMID: 8421711
  52. Cancer regression in patients after transfer of genetically engineered lymphocytes.
    Science. 2006 Oct 6;314(5796):126-9 PMID: 16946036
  53. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.
    N Engl J Med. 2001 Mar 15;344(11):783-92 PMID: 11248153
  54. Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience.
    J Clin Oncol. 2006 May 1;24(13):e20-2 PMID: 16648493
  55. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens.
    J Clin Oncol. 2008 Nov 10;26(32):5233-9 PMID: 18809613
  56. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer.
    Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):6106-15 PMID: 17062687
  57. Correlation between NK function and response to trastuzumab in metastatic breast cancer patients.
    J Transl Med. 2008 May 16;6:25 PMID: 18485193
  58. Long term disease-free survival and T cell and antibody responses in women with high-risk Her2+ breast cancer following vaccination against Her2.
    J Transl Med. 2007 Sep 06;5:42 PMID: 17822557
  59. Relationship of p53 overexpression on cancers and recognition by anti-p53 T cell receptor-transduced T cells.
    Hum Gene Ther. 2008 Nov;19(11):1219-32 PMID: 19848582
  60. Interleukin-10-1082 promoter polymorphism in association with cytokine production and sepsis susceptibility.
    Intensive Care Med. 2006 Feb;32(2):260-266 PMID: 16435103
  61. Generation of T-cell immunity to the HER-2/neu protein after active immunization with HER-2/neu peptide-based vaccines.
    J Clin Oncol. 2002 Jun 1;20(11):2624-32 PMID: 12039923
Article Info
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
Abbr.
Mol Ther
ISSN
1525-0024
DOI
10.1038/mt.2010.24
Email
[email protected]
Published
2010-04-00
Epub
2010-00-23
Pages
843-51
Language
English
Region
United States
NLM ID
100890581
PMCID
PMC2862534
Subset
IM
Grants
Intramural NIH HHS · United States
Corrections
CommentIn
PMID: 20357776
External Links
PubMed source DOI: 10.1038/mt.2010.24 PMC Full Text View journal details
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