Case Report of a Fatal Serious Adverse Event Upon Administration of T Cells Transduced With a MART-1-specific T-cell Receptor

• Published in: Molecular therapy 2015-09, Vol.23 (9), p.1541-1550
• Main Authors: van den Berg, Joost H, Gomez-Eerland, Raquel, van de Wiel, Bart, Hulshoff, Lenie, van den Broek, Daan, Bins, Adriaan, Tan, Hanno L, Harper, Jane V, Hassan, Namir J, Jakobsen, Bent K, Jorritsma, Annelies, Blank, Christian U, Schumacher, Ton N M, Haanen, John B A G
• Format: Article
• Language: English
• Subjects: Adult; Antigens; Cancer; Case reports; Cell- and Tissue-Based Therapy - adverse effects; Cell- and Tissue-Based Therapy - methods; Clinical trials; Cytokines; Epilepsy; Fatal Outcome; Female; Gene therapy; Heart failure; Humans; Immunology; Immunotherapy, Adoptive - adverse effects; Immunotherapy, Adoptive - methods; Lymphocytes; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; MART-1 Antigen - immunology; MART-1 Antigen - metabolism; Melanoma; Melanoma - diagnosis; Melanoma - genetics; Melanoma - immunology; Melanoma - therapy; Neoplasm Staging; Original; Patients; Peptides; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; Response rates; T-Cell Antigen Receptor Specificity - immunology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Target recognition; Toxicity; Transduction, Genetic
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2015.60

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.