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      Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic lung cancer

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          Abstract

          Background

          Advances in cancer immunotherapy have generated encouraging results in multiple malignancies refractory to standard chemotherapies. As the use of immune checkpoint inhibitors (ICI) proliferates, the incidence of autoimmune side effects associated with these agents, termed immune related adverse events (irAE), is expected to increase. The frequency of significant irAE in ICI treated patients is about 10–20% and early recognition is critical to prevent serious morbidity and even mortality. New onset autoimmune diabetes mellitus (DM) associated with immune checkpoint inhibitor treatment is extremely rare, occurring in less than 1% of patients. Autoimmune DM often presents as diabetic ketoacidosis, a medical emergency requiring immediate treatment. We describe the first reported case of a patient with lung cancer who developed autoimmune diabetes after nivolumab treatment and was found to have three diabetes related (islet) autoantibodies present before ICI treatment and seroconversion of another after ICI treatment and onset of autoimmune DM.

          Case Presentation

          A 34 year old African American woman with metastatic non-small cell lung cancer (NSCLC) was treated with nivolumab in the second line setting after disease progression following standard chemoradiation therapy. After receiving two doses of nivolumab, the patient developed abrupt onset of hyperglycemia and diabetic ketoacidosis. Autoimmune diabetes was diagnosed on the basis of undetectable C-peptide levels, seropositivity of three diabetes related (islet) autoantibodies and absolute insulin dependence. The patient eventually required use of continuous subcutaneous insulin infusion (insulin pump) due to erratic glycemic excursions and multiple readmissions for DKA. Human leucocyte antigen (HLA) genoyping revealed none of the high risk haplotypes associated with the development of type 1 diabetes. Interestingly, a frozen blood sample obtained prior to treatment with nivolumab tested positive for three of the four diabetes related (islet) autoantibodies despite no prior history of diabetes and no family history of diabetes. Notably, at the time of manuscript preparation, the patient is without evidence of NSCLC recurrence with no further treatment since the nivolumab therapy.

          Conclusion

          New onset autoimmune diabetes mellitus associated with nivolumab has been described only in case reports and occurs at rates of < 1% in the large clinical trials which garnered FDA approval in the second line setting for NSCLC. As ICI use continues to expand across a wide variety of malignancies, clinicians must maintain a high index of suspicion for irAE, including autoimmune DM and other endocrinopathies. A multidisciplinary team and thorough education of the patient are recommended to optimize management of new onset adult autoimmune DM. Our patient may have been at greater risk for the development of ICI related autoimmune diabetes due to the presence of three diabetes related autoantibodies prior to therapy; however, about half of the reported cases of autoimmune DM after anti-PD-1 therapy occurred in patients with no detectable diabetes related autoantibodies. Further studies are needed to delineate genetic and immunologic biomarkers that may be useful in identifying patients at risk of developing ICI related autoimmune DM.

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          Most cited references13

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          The Programmed Death-1 (PD-1) Pathway Regulates Autoimmune Diabetes in Nonobese Diabetic (NOD) Mice

          Programmed death-1 (PD-1) receptor, an inhibitory costimulatory molecule found on activated T cells, has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance. We investigated the role of this pathway in the development of autoimmune diabetes. PD-1 or PD-L1 but not PD-L2 blockade rapidly precipitated diabetes in prediabetic female nonobese diabetic (NOD) mice regardless of age (from 1 to 10-wk-old), although it was most pronounced in the older mice. By contrast, cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) blockade induced disease only in neonates. Male NOD mice also developed diabetes after PD-1–PD-L1 pathway blockade, but NOR mice, congenic to NOD but resistant to the development of diabetes, did not. Insulitis scores were significantly higher and frequency of interferon γ–producing GAD-reactive splenocytes was increased after PD-1–PD-L1 pathway blockade compared with controls. Interestingly, PD-L1 but not PD-L2 was found to be expressed on inflamed islets of NOD mice. These data demonstrate a central role for PD-1–PD-L1 interaction in the regulation of induction and progression of autoimmune diabetes in the NOD mouse and provide the rationale to develop new therapies to target this costimulatory pathway in this disease.
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            Genetics of the HLA region in the prediction of type 1 diabetes.

            Type 1 diabetes (T1D) is one of the most widely studied complex genetic disorders, and the genes in HLA are reported to account for approximately 40-50% of the familial aggregation of T1D. The major genetic determinants of this disease are polymorphisms of class II HLA genes encoding DQ and DR. The DR-DQ haplotypes conferring the highest risk are DRB1*03:01-DQA1*05:01-DQB1*02:01 (abbreviated "DR3") and DRB1*04:01/02/04/05/08-DQA1*03:01-DQB1*03:02/04 (or DQB1*02; abbreviated "DR4"). The risk is much higher for the heterozygote formed by these two haplotypes (OR = 16.59; 95% CI, 13.7-20.1) than for either of the homozygotes (DR3/DR3, OR = 6.32; 95% CI, 5.12-7.80; DR4/DR4, OR = 5.68; 95% CI, 3.91). In addition, some haplotypes confer strong protection from disease, such as DRB1*15:01-DQA1*01:02-DQB1*06:02 (abbreviated "DR2"; OR = 0.03; 95% CI, 0.01-0.07). After adjusting for the genetic correlation with DR and DQ, significant associations can be seen for HLA class II DPB1 alleles, in particular, DPB1*04:02, DPB1*03:01, and DPB1*02:02. Outside of the class II region, the strongest susceptibility is conferred by class I allele B*39:06 (OR =10.31; 95% CI, 4.21-25.1) and other HLA-B alleles. In addition, several loci in the class III region are reported to be associated with T1D, as are some loci telomeric to class I. Not surprisingly, current approaches for the prediction of T1D in screening studies take advantage of genotyping HLA-DR and HLA-DQ loci, which is then combined with family history and screening for autoantibodies directed against islet-cell antigens. Inclusion of additional moderate HLA risk haplotypes may help identify the majority of children with T1D before the onset of the disease.
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              Precipitation of Autoimmune Diabetes With Anti-PD-1 Immunotherapy

              Immunotherapy targeting T-cell regulatory molecules is highly effective in multiple cancers refractory to standard chemotherapies. However, blocking inhibitory molecules on activated T cells not only increases tumor cell destruction but also can breach tolerance, enabling pathological T cells to react with self-antigens. Indeed, autoimmune endocrinopathies, including hypophysitis, hypopituitarism, and thyroiditis, have been reported in trials involving anti-CTLA-4 and anti-PD-1 monoclonal antibodies (1–3). But autoimmune diabetes has not been definitively linked to these agents. We describe the development of new-onset insulin-dependent diabetes in five patients after receiving anti-PD-1 antibodies, either as single agent or in combination with other cancer drugs. Clinical history and key laboratory findings are summarized in Table 1. Notably, while the patients presented with diverse cancer types, and some had been treated with other immunological agents, their histories were common for anti-PD-1 antibody exposure prior to developing autoimmune diabetes. Time from drug administration to diabetes onset spanned 1 week to 5 months, when patients presented with severe hyperglycemia or diabetic ketoacidosis (DKA) with elevated HbA1c. Diabetes was a new diagnosis for all but one patient who had preexisting type 2 diabetes controlled with metformin. Most patients exhibited inappropriately low or undetectable C-peptide (Table 1). All were initiated on insulin therapy upon presentation and remained insulin-dependent for glucose control. Table 1 Clinical history and key laboratory findings Patient Age/sex Primary diagnosis Pertinent history Anti-PD-1 drug Other chemotoxins Diabetes presentation Random C-peptide* and glucose Time after anti-PD-1 Antibody positivity/titers^ HLA Diabetes antigen-specific T cells† 1 55/F Melanoma Autoimmune thyroid disease Nivolumab Ipilimumab, prednisone DKA, glucose 532 mg/dL, HbA1c 6.9% (52 mmol/mol) 55 years). Not only do our cases demonstrate temporal correlation between anti-PD-1 treatment and diabetes onset, they also provide the first mechanistic support for cancer immunotherapies targeting T-cell regulatory pathways to precipitate autoimmune diabetes. Other factors that may influence predisposition for hyperglycemia and autoimmunity in our patients included combined use with other immune modulators (patient 1), pancreatic metastases (patient 3), and preexisting type 2 diabetes (patient 4). Nonetheless, the fact that they all developed acute severe hyperglycemia with ketoacidosis or low/undetectable C-peptide levels is strong evidence for a new and insulin-deficient type of diabetes. Diabetes had previously been reported as an adverse event to anti-PD-L1 (2) and one case was reported in 206 subjects treated with nivolumab (3), but there lacked evidence for an autoimmune mechanism. Our report demonstrates humoral and cellular autoimmunity in multiple patients with anti-PD-1–induced diabetes. While it is difficult to estimate the true incidence of this phenomenon, the five patients in our series represent less than 3% of total subjects who have participated in PD-1/PD-L1 trials at our institution. These cases illustrate the importance of recognizing this potential precipitant of autoimmune diabetes in older individuals receiving immunotherapy.
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                Author and article information

                Contributors
                james.godwin@tuhs.temple.edu
                Shuchie.Jain@tuhs.temple.edu
                Imali.Sirisena@tuhs.temple.edu
                Pankaj.Sharda@fccc.edu
                ajay.rao@temple.edu
                rmehra1@jhmi.edu
                colleen.veloski@fccc.edu
                Journal
                J Immunother Cancer
                J Immunother Cancer
                Journal for Immunotherapy of Cancer
                BioMed Central (London )
                2051-1426
                16 May 2017
                16 May 2017
                2017
                : 5
                : 40
                Affiliations
                [1 ]ISNI 0000 0004 0456 6466, GRID grid.412530.1, Department of Hematology/Oncology, , Fox Chase Cancer Center, ; Philadelphia, PA USA
                [2 ]ISNI 0000 0004 0456 652X, GRID grid.412374.7, Department of Medicine, Section of Metabolism, Diabetes and Endocrinology, , Temple University Hospital, ; Philadelphia, PA USA
                [3 ]ISNI 0000 0004 0456 6466, GRID grid.412530.1, Department of Medicine, Section of Endocrinology, , Fox Chase Cancer Center, ; Philadelphia, PA USA
                [4 ]Department of Oncology, Johns Hopkins Hospital/Sidney Kimmel Comprehensive Cancer Center, Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD USA
                Article
                245
                10.1186/s40425-017-0245-2
                5433051
                28515940
                fca1a541-7572-4dab-ba90-f3e0160a8a59
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 18 November 2016
                : 26 April 2017
                Categories
                Case Report
                Custom metadata
                © The Author(s) 2017

                pd-1 inhibitor,nivolumab,non-small cell lung cancer (nsclc),immune related adverse events (irae),autoimmune diabetes,diabetic ketoacidosis (dka)

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