Objective
To better define the rare adverse event (AE) of diabetes mellitus associated with immune checkpoint inhibitors (ICIs).

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Immune checkpoint inhibitors and type 1 diabetes mellitus: a case report and systematic review.

Aim To conduct a systematic review and meta-analysis to understand the timing and factors associated with anti-programmed cell death protein-1 (PD-1)/anti-programmed cell death protein-1 ligand (PD-L1) inhibitor-induced Type 1 diabetes. Methods We searched MEDLINE, EMBASE, SCOPUS and Cochrane databases (August 2000-2018) for studies of any design on immune checkpoint inhibitors. A total of 71 cases were reviewed from 56 publications. Comparisons were made using Fisher's exact and Student's t-tests. Results The mean ± sd age at Type 1 diabetes presentation was 61.7±12.2 years, 55% of cases were in men, and melanoma (53.5%) was the most frequent cancer. The median time to Type 1 diabetes onset was 49 (5-448) days with ketoacidosis in 76% of cases. The average ± sd HbA1c concentration was 62 ± 0.3 mmol/mol (7.84±1.0%) at presentation. All cases had insulin deficiency and required permanent exogenous insulin treatment. Half of the cases had Type 1 diabetes-associated antibodies at presentation, and those with antibodies had a more rapid onset (P=0.005) and higher incidence of diabetic ketoacidosis (P=0.02) compared to people without antibodies. Conclusions Many people developed Type 1 diabetes within 3 months of initial PD-1/PD-L1 inhibitor exposure. People presenting with Type 1 diabetes-associated antibodies had a more rapid onset and higher incidence of ketoacidosis than those without antibodies. Healthcare providers caring for people receiving these state-of-the-art therapies need to be aware of this potential severe adverse event.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/dme.14050

Immune checkpoint inhibitor-induced Type 1 diabetes: a systematic review and meta-analysis.

Autoimmune diabetes mellitus is a rare but significant side effect of treatment with immune checkpoint inhibitors. Immune checkpoint inhibitor-induced diabetes mellitus (CPI-DM) is characterized by acute onset of dramatic hyperglycemia with severe insulin deficiency and occurrence following exposure to programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors rather than cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors. As a growing number of patients undergo immunotherapy, further understanding of the characteristics of CPI-DM patients is needed for improved prognostic and diagnostic application in order to reduce overall morbidity for this already at-risk population. Additionally, understanding of the features and mechanisms of CPI-DM may contribute to understanding mechanisms of spontaneous type I diabetes mellitus (T1DM). Here, we summarize the clinical features of CPI-DM and interrogate the genetic and cellular mechanisms that may contribute to the disease, as well as the clinical challenges for predicting and treating these patients as increasing cancer immunotherapies reach clinical utility.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/cei.13424

Immune checkpoint inhibitor diabetes mellitus: a novel form of autoimmune diabetes.

Immunotherapy for skin malignancies has ushered in a new era for cancer treatments by demonstrating unprecedented durable responses in the setting of metastatic Melanoma. Consequently, checkpoint inhibitors are now the first-line treatment of metastatic melanoma and widely used as adjuvant therapy for stage III disease. With the observation that higher tumor mutational burden correlates with a better response, checkpoint inhibitors are tested in other skin cancer types of known high tumor mutational burden with promising results and recently became the first-ever FDA-approved treatment for metastatic Merkel cell carcinoma. The emerging new standards-of-care will necessitate more precise biomarkers and predictors for treatment response and immune-related adverse events. Measurable immune-related mediators are currently under investigation as factors that promote or block the response to cancer immunotherapy and may provide insights into the underlying immune response to the tumor. Cytokines and chemokines are such mediators and are crucial for facilitating the recruitment and activation of specific subsets of leukocytes within the microenvironment of skin cancers. The exact mechanisms of how these meditators, both immunological and non-immunological, operate in the tumor microenvironment is an area of active research, so to reliable biomarkers of responses to cancer immunotherapy. Here, we will review and summarize the expanding body of literature for immune-related biomarkers pertaining to Melanoma, Basal cell carcinoma, Squamous cell carcinoma, and Merkel cell carcinoma, highlighting clinically relevant checkpoint inhibitor therapy biomarker advancements.

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Cytokines, Chemokines, and Other Biomarkers of Response for Checkpoint Inhibitor Therapy in Skin Cancer

Immune checkpoint inhibitors (ICIs) belong to a new group of anticancer drugs targeting T-cell proteins involved in the activation of immune response toward malignancies. Their introduction into clinical practice was a milestone in modern cancer treatment. However, the significant advantage of ICIs over conventional chemotherapy in terms of therapeutic efficacy is accompanied by new challenges related to specific side effects. ICI-induced immune system activation could lead to the loss of self-tolerance, presenting as autoimmune inflammation and dysfunction of various tissues and organs. Thus, the typical side effects of ICIs include immune-related adverse events (irAEs), among which endocrine irAEs, affecting numerous endocrine glands, have been commonly recognized. This review aimed to outline the current knowledge regarding ICI-induced endocrine disorders from a clinical perspective. We present updated information on the incidence and clinical development of ICI-induced endocrinopathies, including the most frequent thyroiditis and hypophysitis, the rarely observed insulin-dependent diabetes mellitus and primary adrenal insufficiency, and the recently described cases of hypoparathyroidism and lipodystrophy. Practical guidelines for monitoring, diagnosis, and treatment of ICI-related endocrine toxicities are also offered. Rising awareness of endocrine irAEs among oncologists, endocrinologists, and other health professionals caring for patients receiving ICIs could contribute to better safety and efficacy. As immunotherapy becomes widespread and approved for new types of malignancies, increased incidences of endocrine irAEs are expected in the future.

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Management of endocrine immune-related adverse events of immune checkpoint inhibitors: an updated review.

Context Pembrolizumab (Keytruda; Merck Sharp & Dohme) is a humanized IgG4 monoclonal antibody used in cancer immunotherapy. It targets the programmed cell death-1 (PD-1) receptor, which is important in maintaining self-tolerance. However, immune checkpoint blockade is associated with a risk for immune-related adverse events (irAEs) potentially affecting the endocrine organs. Type 1 diabetes mellitus is a rare irAE of PD-1 inhibitors, occurring in 0.2% of cases. Evidence acquisition Systematic search of four databases (MEDLINE, Embase, Web of Science, and Cochrane Library) using the search terms "diabetes" or "ketoacidosis" and "pembrolizumab," "nivolumab," "PD-1 inhibitor," or "immunotherapy." Included were articles published in English between 1 January 2012 and 1 January 2018. The search was supplemented by bibliographic searches of the complete reference lists of all included papers. Evidence synthesis We provide an overview of all published cases (n = 42) of PD-1 inhibitor-induced type 1 diabetes mellitus to date, including a well-characterized case of islet cell antibody and glutamic acid decarboxylase antibody-positive diabetes mellitus, in a patient with a diabetes-prone HLA genotype. She presented with diabetic ketoacidosis during pembrolizumab therapy for a metastatic uveal melanoma. Furthermore, we discuss potential pathogenic mechanisms, clinical presentation, prognostic markers (β-cell antibodies and HLA type), treatment, and a screening protocol. Conclusions Because the use of immunotherapy will increase, it is essential that all clinicians are aware of diabetic ketoacidosis as a rare and life-threatening side effect of immunotherapy. Blood glucose monitoring during anti-PD-1 therapy is necessary.

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Katrien Clotman

Papers

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus.