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.

Figure 1

Characteristics of the final infusion product. (a) Phenotypic analysis of infusion product, gated on propidium iodide negative lymphocytes. (b) Functional analysis of T-cell receptor (TCR)-transduced cells. TCR-transduced cells were cultured alone or incubated with HLA-A2⁺ MART-1⁺ Mel624 cells. Intracellular cytokine production was determined after 15 hours of incubation.

Figure 2

Analysis of T-cell infiltration in metastasis, heart, and liver. Upper panel shows H&E staining, lower panel shows CD3 staining.

Figure 3

Blood values during treatment. Dotted line indicates the day of T-cell infusion. Normal reference values are <247 U/l LDH, <31 U/l ASAT, 40–95 µmol/l creatinine, and <8 mg/l for C-reactive protein. ASAH, aspartate aminotransferase; LDH, lactate dehydrogenase.

Figure 4

Flow cytometric analysis of PBMCs, broncho-alveolar lavage (BAL), and ascites samples withdrawn from the patient at day 7 upon T-cell infusion, gated on propidium iodide negative, CD3-positive lymphocytes. PBMC, peripheral blood mononuclear cell.

Figure 5

Cytokine profile in serum samples of patient 1. Only the data point at day -13 was measured in plasma. A previous experiment showed that plasma and serum from the same patient gave the same result. Dotted line indicates time of T-cell infusion.

Figure 6

Lack of reactivity of the T-cell infusion against HLA-A2⁺ induced-pluripotent stem-cell (iPSC)–derived cardiomyocyte (iPSC-CM) cells, as observed by phase contrast microscopy (a) and cytokine analysis (b).