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      Precipitation of Autoimmune Diabetes With Anti-PD-1 Immunotherapy

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          Abstract

          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) <0.1 ng/mL and 52 mg/dL 5 months None A2.1+, DR4+ 0.35% 2 83/F Non–small-cell lung cancer Remote smoker Nivolumab None DKA, glucose 350 mg/dL, HbA1c 7.7% (61 mmol/mol) <0.1 ng/mL and 336 mg/dL <1 month GAD65/1.2 A2.1+, DR4+ 0.28% 3 63/M Renal cell carcinoma Hypertension Nivolumab Proleukin, bevacizumab, interferon Random glucose 247, 340 mg/dL; HbA1c 8.2% (66 mmol/mol) 1.3 ng/mL and 79 mg/dL 4 months GAD65/1.1, ICA512/1.2, Insulin (IAA)/47 A2.1+, DR4+ 2.01% 4 58/M Small-cell lung cancer Type 2 diabetes Nivolumab Carboplatin/ etoposide, paclitaxel DKA, glucose 749 mg/dL, HbA1c 9.7% (83 mmol/mol) (from 8.5% [69 mmol/mol] prior) <0.1 ng/mL and 284 mg/dL0.6 ng/mL and 523 mg/dL 1 week GAD65/13819 A2.1+ 0.89% 5 64/F Melanoma Autoimmune thyroid disease, psoriasis Pembrolizumab None Ketonuria, glucose 703 mg/dL, HbA1c 7.4% (57 mmol/mol) 0.5 ng/mL and 268 mg/dL <1 month None DR4+ N/A * C-peptide reference range: 1.1–4.4 ng/mL. † Patients 1, 2, 3, and 4 were positive for HLA-A2.1 from screening by flow cytometry using monoclonal antibody BB7.1 (Abcam, Cambridge, MA). HLA-A2.1 tetramers were obtained from the National Institutes of Health Tetramer Core Facility (Atlanta, GA) and loaded with peptides from five diabetes antigens: insulin A chain (GIVEQCCTSI), insulin B chain (HLVEALYLV), preproinsulin (ALWMRLLPL), GAD65 (VMNILLQYVV), and IGRP (LNIDLLWSV) (5). Peripheral blood mononuclear cells (PBMCs) were incubated with the five class I diabetes antigen-containing tetramers. The data shown represent positive staining after subtracting staining with a negative tetramer. PBMCs from HLA-A2.1+ donors without diabetes served as negative control and showed staining (mean ± 2 SD) of 0.5%. PBMCs were also stained with monoclonal antibodies to CD45RO, CCR7, and CD45RA to identify cellular phenotypes. Flow data were analyzed using FlowJo software version 9.6.1 (Tree Star, Ashland, OR). ^ Diabetic autoantibodies to GAD65, ICA512, and insulin were performed at LabCorp, Burlington, NC. Normal GAD65 titers <0.5 U/mL, ICA512 <1.0 U/mL, and IAA <5.0 U/mL. Three of the five patients had positive autoantibodies to diabetes autoantigens, with markedly elevated anti-GAD65 titer in patient 4. Among four HLA-A2+ patients, two had increased diabetes antigen-specific CD8+ T cells, consistent with prior findings of such cells in new-onset type 1 diabetes (4,5). The majority of these cells were CCR7− or + or CD45RO+ effector or memory cells (66%) (data not shown). Interestingly, two patients also developed autoimmune thyroiditis as manifested by thyroid autoantibodies and abnormal thyroid function tests, consistent with heightened autoimmunity from the immune-enhancing monoclonal antibodies. We highlight the fact that our patients exhibited both cellular and humoral diabetes-associated autoimmunity, an otherwise rare finding in this age-group (>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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          Improved Survival with Ipilimumab in Patients with Metastatic Melanoma

          An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)
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            Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer

            Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. In this multicenter phase 1 trial, we administered intravenous anti-PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti-PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression. As of February 24, 2012, a total of 207 patients--75 with non-small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer--had received anti-PD-L1 antibody. The median duration of therapy was 12 weeks (range, 2 to 111). Grade 3 or 4 toxic effects that investigators considered to be related to treatment occurred in 9% of patients. Among patients with a response that could be evaluated, an objective response (a complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with renal-cell cancer, 5 of 49 with non-small-cell lung cancer, and 1 of 17 with ovarian cancer. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up. Antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response rate of 6 to 17%) and prolonged stabilization of disease (rates of 12 to 41% at 24 weeks) in patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell cancer. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00729664.).
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              Nivolumab in Previously Untreated Melanoma withoutBRAFMutation

              Nivolumab was associated with higher rates of objective response than chemotherapy in a phase 3 study involving patients with ipilimumab-refractory metastatic melanoma. The use of nivolumab in previously untreated patients with advanced melanoma has not been tested in a phase 3 controlled study. We randomly assigned 418 previously untreated patients who had metastatic melanoma without a BRAF mutation to receive nivolumab (at a dose of 3 mg per kilogram of body weight every 2 weeks and dacarbazine-matched placebo every 3 weeks) or dacarbazine (at a dose of 1000 mg per square meter of body-surface area every 3 weeks and nivolumab-matched placebo every 2 weeks). The primary end point was overall survival. At 1 year, the overall rate of survival was 72.9% (95% confidence interval [CI], 65.5 to 78.9) in the nivolumab group, as compared with 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; P<0.001). The median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (hazard ratio for death or progression of disease, 0.43; 95% CI, 0.34 to 0.56; P<0.001). The objective response rate was 40.0% (95% CI, 33.3 to 47.0) in the nivolumab group versus 13.9% (95% CI, 9.5 to 19.4) in the dacarbazine group (odds ratio, 4.06; P<0.001). The survival benefit with nivolumab versus dacarbazine was observed across prespecified subgroups, including subgroups defined by status regarding the programmed death ligand 1 (PD-L1). Common adverse events associated with nivolumab included fatigue, pruritus, and nausea. Drug-related adverse events of grade 3 or 4 occurred in 11.7% of the patients treated with nivolumab and 17.6% of those treated with dacarbazine. Nivolumab was associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation. (Funded by Bristol-Myers Squibb; CheckMate 066 ClinicalTrials.gov number, NCT01721772.).
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                Author and article information

                Journal
                Diabetes Care
                Diabetes Care
                diacare
                dcare
                Diabetes Care
                Diabetes Care
                American Diabetes Association
                0149-5992
                1935-5548
                April 2015
                14 March 2015
                : 38
                : 4
                : e55-e57
                Affiliations
                [1] 1Department of Immunobiology, Section of Medical Oncology, Yale University School of Medicine, New Haven, CT
                [2] 2Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, CT
                [3] 3Department of Internal Medicine, Section of Medical Oncology, Yale University School of Medicine, New Haven, CT
                Author notes
                Corresponding author: Kevan C. Herold, kevan.herold@ 123456yale.edu .
                Article
                2349
                10.2337/dc14-2349
                4370325
                25805871
                3b0b901f-e9f0-440d-91ee-6428a42c6b13
                © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
                History
                Page count
                Pages: 3
                Categories
                e-Letters: Observations

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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