Sintilimab-Induced Autoimmune Diabetes in a Patient With the Anti-tumor Effect of Partial Regression

Abstract

Context: Immune checkpoint blockades (ICBs) have been approved widely to treat various malignancies. Autoimmune diabetes mellitus, which can be caused by programmed cell death protein 1 (PD-1) inhibitors, is rare. Sintilimab, a monoclonal anti-PD-1 antibody, has been approved in China for the treatment of Hodgkin's lymphoma and was used in our clinical trial for patients with unresectable hepatocellular carcinoma (HCC). Case Presentation: We present the first case of autoimmune diabetes during Sintilimab treatment in a patient with unresectable HCC, accompanied by a remarkable anti-tumor effect of partial regression. A 56-year-old male with typical symptoms presented with diabetic ketoacidosis (DKA) at 24 weeks after Sintilimab initiation. His fasting plasma glucose level was 22.2 mmol/L, HbA1c was 7.8%, fasting insulin was 1.5 mIU/L, and fasting C-peptide was 1.12 ng/mL, which further decreased to 0.21 ng/mL 4 days later. The patient was diagnosed with new-onset diabetes mellitus using the oral glucose tolerance test. The anti-glutamic acid decarboxylase 65 antibody, anti-islet cell antibody, and anti-insulin antibody tests were all negative. For the type 1 diabetes-associated alleles of human leukocyte antigen (HLA) class I and II, the most relevant type was identified as HLA-A * 0201. A diagnosis of PD-1 inhibitor-induced autoimmune diabetes was made. After rectification of DKA, he was treated with insulin therapy daily, which has since controlled his plasma glucose well. Thereafter, Sintilimab was been continued with sustained therapeutic effect. Conclusion: Due to unpredictability of this rare immune related adverse event (irAE), diabetes-related autoantibodies and C-peptide are recommended to be tested before immunotherapy, and plasma glucose monitoring should be performed. After plasma glucose is well controlled using insulin therapy, PD-1 inhibitor treatment might be continued, especially when the immunotherapy is effective.

Sintilimab: A Promising Anti-Tumor PD-1 Antibody

“…In the study by Xing et al, a 66-yearold lung adenocarcinoma patient received two doses of sintilimab as monotherapy and developed myositis-myasthenia gravis overlap syndrome complicated with myasthenia crisis; the overlap syndrome was cured after supportive therapies such as plasma exchange, mechanical ventilation, and immunosuppressive therapy (78). In an HCC patient, sintilimab administration resulted in autoimmune diabetes at 24 weeks after injection (79). In other reported cases, patients developed cytokine release syndrome, pulmonary fibrosis, hypothyroid myopathy, encephalitis during or after sintilimab administration (80)(81)(82)(83).…”

Immunotherapy-Associated Pancreatic Adverse Events: Current Understanding of Their Mechanism, Diagnosis, and Management

“…Mechanisms of the 3 immunotherapy agents are different from each other and ICIs alone or in combination with chemotherapy are conventional first- or second-line therapies. This has been attributed to favorable survival durations and tolerance for many types of malignancies, including metastatic melanoma ( 6 ), advanced non-small cell lung cancer ( 7 ), Hodgkin lymphoma ( 8 ), metastatic renal cell carcinoma ( 9 ), and unresectable hepatocellular carcinoma ( 10 ). Despite the efficacy of immunotherapy, immune-related adverse events (irAEs), often involving endocrine tissues including pneumonitis, hypophysitis, thyroiditis, colitis, pancreatitis, and autoimmune diabetes, have emerged as potential challenges to patients ( 11 , 12 ).…”

Therapeutic Effectiveness and Safety of Sintilimab-Dominated Triple Therapy in Unresectable Hepatocellular Carcinoma: A Single-Center Retrospective Cohort Study

“…However, this idea will need to be proven by further investigation in future studies. Owing to the small sample size and shortness of follow-up of our study, some immune-related adverse events such as sintilimab-induced autoimmune diabetes (34) and myocarditis (35) were not observed. Another common adverse event was liver dysfunction (11.5% with grade 1-2 and 11.4% with grade 3-4) in the triple group, which might be due to a synergistic hepatotoxicity from sorafenib and TACE.…”