Immune checkpoint inhibitors and diabetes: Mechanisms and predictors

Youssef, Natalie; Noureldein, Mohamed; Daoud, Georges; Eid, Assaad A.

doi:10.1016/j.diabet.2020.09.003

Cited by 13 publications

(11 citation statements)

References 65 publications

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“…Moreover, PD-1 is not always required for the induction of exhaustion, and some features of exhaustion can even be more severe when PD-1 is absent [ 15 ]. Finally, the role of PD-1 has been highlighted in many other contexts than exhaustion, including autoimmunity [ 55 ], central and peripheric tolerance [ 56 , 57 ], acute infection for memory response [ 58 ], and balance between efficient anti-infectious defense and immunopathology [ 59 ]. In those contexts, PD-1 was not always associated with cellular dysfunction, and it was even sometimes associated with an increased memory response [ 57 , 58 ].…”

Section: The Incomplete Overlap Between the 3 Approaches To Exhaustionmentioning

confidence: 99%

Immunological exhaustion: How to make a disparate concept operational?

2021

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In this essay, we show that 3 distinct approaches to immunological exhaustion coexist and that they only partially overlap, generating potential misunderstandings. Exploring cases ranging from viral infections to cancer, we propose that it is crucial, for experimental and therapeutic purposes, to clarify these approaches and their interconnections so as to make the concept of exhaustion genuinely operational.

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Section: The Incomplete Overlap Between the 3 Approaches To Exhaustionmentioning

confidence: 99%

Immunological exhaustion: How to make a disparate concept operational?

2021

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“…One known mechanism for the onset of IMD is ICI-induced inhibition of the function of PD-L1 expressed on islets. IMD often shows clinicopathological features similar to those of type 1 diabetes mellitus, as they both show absolute insulin deficiency due to pancreatic beta cell destruction by the autoimmune system [32,33]. Concretely, it is not uncommon for patients with IMD to reduce the fasting serum C-peptide levels to below the detection limit and develop complicating diabetic ketoacidosis [32,34].…”

Section: Discussionmentioning

confidence: 99%

“…IMD often shows clinicopathological features similar to those of type 1 diabetes mellitus, as they both show absolute insulin deficiency due to pancreatic beta cell destruction by the autoimmune system [32,33]. Concretely, it is not uncommon for patients with IMD to reduce the fasting serum C-peptide levels to below the detection limit and develop complicating diabetic ketoacidosis [32,34]. In our patient reported herein, the clinical findings suggested sudden insulin deficiency, and autopsy confirmed marked reduction in the beta cells alone in the islets, leading us to diagnose insulin-dependent diabetes arising from absolute insulin deficiency [35].…”

Section: Discussionmentioning

confidence: 99%

Liver Injury and Use of Contrast-Enhanced Ultrasound for Evaluating Intrahepatic Recurrence in a Case of TACE-Refractory Hepatocellular Carcinoma Receiving Atezolizumab-Bevacizumab Combination Therapy: A Case Report

et al. 2021

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A 67-year-old male with type 2 diabetes (T2DM) was diagnosed with postoperative intrahepatic recurrence for hepatocellular carcinoma (HCC). Nine sessions of transarterial chemoembolization (TACE) proved ineffective, and the patient was diagnosed as having TACE-refractory disease and received seven cycles of atezolizumab–bevacizumab combination therapy. After that, the patient developed hyperglycemia with the HbA1c elevation and the marked fasting serum C-peptide reduction and was diagnosed with developed immune-mediated diabetes (IMD) (T2DM exacerbation with insulin-dependent diabetes development). Subsequently, the hepatobiliary enzyme levels, which were high before the systemic therapy, worsened. Thus, we clinically diagnosed an exacerbation of liver injury due to TACE-induced liver injury complicated by drug-induced liver injury such as immune-mediated hepatotoxicity (IMH). Meanwhile, after contrast-enhanced computed tomography revealed complete response, contrast-enhanced ultrasound was performed to assess intrahepatic recurrence. We found that the latter modality allowed earlier and more definitive diagnosis of intrahepatic recurrence of HCC. Subsequently, despite systemic therapy discontinuation and steroids administration, the liver injury worsened, and the patient died. The autopsy revealed intrahepatic recurrence of HCC and extensive arterial obstruction by the beads used for TACE within the liver, which indicated that disturbed circulation was the primary cause of the liver injury and histopathologically confirmed IMD, but not IMH.

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“…The mean age at the time of diagnosis was 66 years, and the median time to disease onset was six cycles of ICI treatment [1]. The pathogenesis of ICI-induced T1DM is not fully understood, although ICI-induced disruption of peripheral immune tolerance to pancreatic β-cells is considered to be a potential contributory factor [2].…”

Section: Discussionmentioning

confidence: 99%

Delayed-onset Fulminant type 1 Diabetes Mellitus after the Discontinuation of Pembrolizumab Immunotherapy: A Case Report

Kitayama¹,

N²,

Iwata³

2021

Preprint

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Introduction:Immune checkpoint inhibitors (ICI) have become an essential component of several cancer therapies, but the increasing use of such drugs has led to an increasing number of reports on immune-related adverse events (IRAEs). Although type 1 diabetes mellitus (T1DM) and its subtype, fulminant T1DM, have been reported as potential IRAEs, the development of these diseases with a delayed onset after the cessation of ICI administration is uncommon. We present the first case of delayed-onset fulminant T1DM precipitated by pembrolizumab, an ICI.Case Presentation:A 75-year-old Japanese man, who received 10 cycles of pembrolizumab as adjuvant chemotherapy for urothelial carcinoma, presented in our emergency department with polyuria and worsening dyspnea nine weeks after the discontinuation of pembrolizumab. The laboratory data showed hyperglycemia (1349 mg/dL), metabolic acidosis, HbA1c 8.1%, and serum β-hydroxybutyrate 13.9 mmol/L. The patient was diagnosed with diabetic ketoacidosis (DKA). His symptoms improved by intravenous hydration and an insulin drip. Additional workup showed his absence of insulin-secreting capacity and negative for anti-glutamic acid decarboxylase antibody.Conclusions:Fulminant T1DM as an IRAE is an oncologic emergency characterized by abrupt-onset ketoacidosis with severe hyperglycemia. In addition to the potential onset of fulminant T1DM during the course of pembrolizumab treatment, clinicians should consider the possibility of delayed-onset fulminant T1DM with DKA, even after the discontinuation of pembrolizumab.

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Immune checkpoint inhibitors and diabetes: Mechanisms and predictors

Cited by 13 publications

References 65 publications

Immunological exhaustion: How to make a disparate concept operational?

Immunological exhaustion: How to make a disparate concept operational?

Liver Injury and Use of Contrast-Enhanced Ultrasound for Evaluating Intrahepatic Recurrence in a Case of TACE-Refractory Hepatocellular Carcinoma Receiving Atezolizumab-Bevacizumab Combination Therapy: A Case Report

Delayed-onset Fulminant type 1 Diabetes Mellitus after the Discontinuation of Pembrolizumab Immunotherapy: A Case Report

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