Toxic epidermal necrosis caused by programmed cell death protein 1 inhibitors in a patient receiving chimeric antigen receptor-T cell therapy

To the Editor: Toxic epidermal necrosis (TEN) is a severe dermal-mucous reaction characterized by rashes, blisters, and a generalized laxity of the epidermis.[1] Blockade of the programmed cell death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) pathway could activate and proliferate auto-reactive CD8+ T-cells, which is a crucial step in TEN. The efficacy of anti-CD19 chimeric antigen receptor-T (CAR-T) cells can be inhibited by activating the PD-1/PD-L1 pathway.[2] As a result, the combination of PD-1 blockade and CAR-T cell therapy would increase the functions of CAR-T cells.[3] This case report describes a patient with refractory diffuse large B-cell lymphoma (DLBCL) who had severe TEN after CAR-T cell therapy and PD-1 blockade. A patient in his mid-50s was diagnosed with refractory DLBCL and unsuccessful chemotherapy. In March 2022, the patient provided informed consent to participate in the study of anti-CD19 CAR-T cell therapy, approved by the Ethics Committee of Beijing Tongren Hospital (No. TRECKY2021-225). A positron-emission tomography/computerized tomography before CAR-T cell therapy revealed multiple enlarged lymph nodes [Figure 1A]. After leukapheresis, one cycle of bridging therapy with cytarabine (1 g/day on days 1 and 2) and dexamethasone (40 mg/day on days 1 and 2) was administered, which showed no obvious efficacy. Subsequently, lymphodepletion was performed using fludarabine (25 mg/m2, days –5 to –3) and cyclophosphamide (250 mg/m2, days –5 to –3). On day 0, 2.03 × 108 autologous anti-CD19 CAR-T cells were infused. The anti-CD19 CAR-T cells used in this study were transfected with lentiviral vectors carrying second-generation CAR with 4–1BB costimulatory and CD3ζ signaling domains. The antigen recognition domain of this CAR is a single-chain variable fragment obtained from the murine monoclonal antibody FMC63 (CD19). The absolute count of CAR-T cells in the peripheral blood increased from undetectable on day 4 to 3.81 × 107/L on day 14. However, the cervical mass had no significant changes. No fever, hypotension, or hypoxemia was observed after the infusion of CAR-T cells; thus, no cytokine release syndrome (CRS) or neurologic events occurred at this time. Sintilimab (PD-1 blockade) was administered on day 18 at a dosage of 200 mg to boost the function of CAR-T cells. Encouragingly, the cervical mass significantly shrank, and CAR-T cell expansion continued, rising to 4.14 × 107/L in the peripheral blood on day 21.Figure 1: PET-CT examination. (A) Before CAR-T therapy, bilateral cervical, bilateral supraclavicular, mediastinal, bilateral diaphragmatic foot, para-aortic, and bilateral iliac para-vascular lymph nodes were affected at admission. The larger ones were in the left cervical area and the right diaphragmatic foot, measuring 5.6 cm × 4.7 cm and 7.9 cm × 4.2 cm in size, respectively. The SUVmax measured 29.28. (B) After CAR-T cell therapy and PD-1 blockade, most lymph nodes shrank, and PR was achieved. Clinical manifestations of toxic epidermal necrolysis in different periods. (C) In the early stage of TEN, 13 days after Sintilimab injection, tension vesicles appeared below the epidermis. (D) The laxity of the epidermis appeared on the truck. (E) Necrosis and exfoliation of the epidermis began. (F): Large area of posterior dorsal epidermis exfoliated with bloody exudation. CAR-T: Chimeric antigen receptor-T; PD-1: Programmed cell death protein 1; PET-CT: Positron-emission tomography-computerized tomography; TEN: Toxic epidermal necrosis.Ophthalmalgia and multiple oral ulcers with bleeding developed on day 26. No significant improvement was observed after the topical application of glucocorticoids. Epidermal laxity and volatile blisters appeared on the back [Figure 1C] and spread to the trunk and upper limbs. Meanwhile, interleukin-6 levels in the peripheral blood rose sharply to 1709.29 pg/mL on day 31, and 8 mg/kg of tocilizumab was administered. Drug-related adverse reactions were considered possibly induced by Sintilimab or antibiotics; however, CRS caused by CAR-T cell therapy was not excluded. After consultation with a dermatologist, TEN was diagnosed based on the typical symptoms and signs without a skin biopsy, and the dosage of methylprednisolone was increased to 1 g/day, combined with 40 g of intravenous immunoglobulin per day on day 32. However, the related symptoms did not improve, and diffuse laxity of the skin on the posterior back occurred [Figure 1D]. The epidermis began to exfoliate from the trunk, and the affected area gradually expanded [Figure 1E]. Another PET-CT scan was conducted on day 35 [Figure 1B], which was encouraging with partial remission. However, the skin of the trunk was loosened, and almost all the skin on the back was peeled off, with a bloody discharge exuding from the wound [Figure 1F]. The patient eventually died of septic shock on day 45. Histopathologically, subepidermal bullae with widespread epidermal necrosis and subsequent separation or loss of the entire epidermis were observed, which can be induced by several drugs, such as antibiotics and allopurinol. However, TEN is a rare immune-related adverse reaction caused by PD-1 blockade.[4] The PD-1/PD-L1 signaling pathway mediates T-cell exhaustion and participates in the development of autoimmune tolerance. Blocking this pathway could activate and proliferate autoreactive CD8+ T-cells that target autoantigens. T-cell receptors also play an essential role in the occurrence of TEN. The activation and expansion of drug-specific T-cells is a crucial step. Tumor necrosis factor-α and interferon-γ secreted by activated T cells were correlated with the upregulation of Fas ligand expression in keratinocytes, resulting in Fas- and caspase-8-mediated keratinocyte cell death and skin necrosis. PD-1 blockade restores T-cell function and promotes T-cell proliferation and activation. The rapid amplification of CAR-T cells could also increase the secretion of cytokines[5] which might be associated with the occurrence of TEN. The present case demonstrates the therapeutic value of CAR-T cell therapy combined with PD-1 blockade for refractory DLBCL. Nonetheless, CAR-T cell expansion and activation and immune stimulation of PD-1 blockade would promote the occurrence of rare immune-related adverse events, such as TEN, which needs to be cautioned by both oncologists and dermatologists. Funding This work was supported by grants from the National Natural Science Foundation of China (Nos. 81873450, 82170181), Beijing Hospitals Authority Youth Programme (No. QML20200201), and Beijing Natural Science Foundation (No. 7222027) to Liang Wang. Conflicts of interest The authors declare that they have no competing interests.