title: Case Report of a Fatal Serious Adverse Event Upon Administration of T Cells Transduced With a MART-1-specific T-cell Receptor.
abstract: Here, we describe a fatal serious adverse event observed in a patient infused with autologous T-cell receptor (TCR) transduced T cells. This TCR, originally obtained from a melanoma patient, recognizes the well-described HLA-A*0201 restricted 26-35 epitope of MART-1, and was not affinity enhanced. Patient 1 with metastatic melanoma experienced a cerebral hemorrhage, epileptic seizures, and a witnessed cardiac arrest 6 days after cell infusion. Three days later, the patient died from multiple organ failure and irreversible neurologic damage. After T-cell infusion, levels of IL-6, IFN-γ, C-reactive protein (CRP), and procalcitonin increased to extreme levels, indicative of a cytokine release syndrome or T-cell-mediated inflammatory response. Infused T cells could be recovered from blood, broncho-alveolar lavage, ascites, and after autopsy from tumor sites and heart tissue. High levels of NT-proBNP indicate semi-acute heart failure. No cross reactivity of the modified T cells toward a beating cardiomyocyte culture was observed. Together, these observations suggest that high levels of inflammatory cytokines alone or in combination with semi-acute heart failure and epileptic seizure may have contributed substantially to the occurrence of the acute and lethal event. Protocol modifications to limit the risk of T-cell activation-induced toxicity are discussed.
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, The Netherlands.|Amsterdam Biotherapeutics Unit, Amsterdam, The Netherlands.
authors.forename: Joost H
authors.initials: JH
authors.lastname: van den Berg
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, The Netherlands.
authors.forename: Raquel
authors.initials: R
authors.lastname: Gomez-Eerland
authors.affiliation: Division of Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, The Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: van de Wiel
authors.affiliation: Division of Anesthesiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, The Netherlands.
authors.forename: Lenie
authors.initials: L
authors.lastname: Hulshoff
authors.affiliation: Division of Clinical Chemistry, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, The Netherlands.
authors.forename: Daan
authors.initials: D
authors.lastname: van den Broek
authors.affiliation: Division of Medical Oncology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, The Netherlands.
authors.forename: Adriaan
authors.initials: A
authors.lastname: Bins
authors.affiliation: Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Hanno L
authors.initials: HL
authors.lastname: Tan
authors.affiliation: Immunocore Limited, Oxfordshire, UK.
authors.forename: Jane V
authors.initials: JV
authors.lastname: Harper
authors.affiliation: Immunocore Limited, Oxfordshire, UK.
authors.forename: Namir J
authors.initials: NJ
authors.lastname: Hassan
authors.affiliation: Immunocore Limited, Oxfordshire, UK.
authors.forename: Bent K
authors.initials: BK
authors.lastname: Jakobsen
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, The Netherlands.
authors.forename: Annelies
authors.initials: A
authors.lastname: Jorritsma
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, The Netherlands.|Division of Medical Oncology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, The Netherlands.
authors.forename: Christian U
authors.initials: CU
authors.lastname: Blank
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, The Netherlands.
authors.forename: Ton N M
authors.initials: TN
authors.lastname: Schumacher
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, The Netherlands.|Division of Medical Oncology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, The Netherlands.
authors.forename: John B A G
authors.initials: JB
authors.lastname: Haanen
mesh_terms: D000328:Adult; D064987:Cell- and Tissue-Based Therapy / Q000009:adverse effects* / Q000379:methods; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects* / Q000379:methods; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D058965:MART-1 Antigen / Q000276:immunology* / Q000378:metabolism; D008545:Melanoma / Q000175:diagnosis / Q000235:genetics / Q000276:immunology / Q000628:therapy; D009367:Neoplasm Staging; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D014161:Transduction, Genetic
chemical_list: D058965:MART-1 Antigen; D011948:Receptors, Antigen, T-Cell