scholarly journals Breaking β Cell Tolerance After 100 Years of Life: Intratumoral Immunotherapy–Induced Diabetes Mellitus

2020 ◽  
Vol 4 (10) ◽  
Author(s):  
Zoe Quandt ◽  
Catherine Coupe ◽  
Mark Anderson ◽  
Alexander Uihlein ◽  
Arabella Young
Keyword(s):  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Autoimmune Diabetes ◽  
High Titer ◽  
Acid Decarboxylase ◽  
Β Cell ◽  
First Case ◽  
Viral Vaccine ◽  
Glutamic Acid Decarboxylase 65 ◽  
Cancer Immunotherapies

Abstract Cancer immunotherapies are changing the landscape of cancer care. Intratumoral talimogene iaherparepvec (T-VEC), an oncolytic viral vaccine, has been approved for treatment of unresectable melanoma with minimal toxicity. We describe the first case of a centenarian who developed autoimmune diabetes while on T-VEC immunotherapy. The patient’s high titer of glutamic acid decarboxylase 65 autoantibodies as well as insulin deficiency are consistent with autoimmune diabetes. Autoimmune diabetes has previously been seen following immune checkpoint inhibitor use; however, it has never been reported with T-VEC. This case highlights that autoimmune diabetes can be a rare but morbid complication of intratumoral T-VEC immunotherapy and can occur in the ultra-elderly.

scholarly journals Checkpoint Inhibitor–Associated Autoimmune Diabetes Is Distinct From Type 1 Diabetes

2019 ◽  
Vol 104 (11) ◽  
pp. 5499-5506 ◽  
Author(s):  
Venessa H M Tsang ◽  
Rachel T McGrath ◽  
Roderick J Clifton-Bligh ◽  
Richard A Scolyer ◽  
Valerie Jakrot ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Checkpoint Inhibitor ◽  
Autoimmune Diabetes ◽  
Case Series ◽  
Acid Decarboxylase ◽  
Risk Haplotype ◽  
Β Cell ◽  
C Peptide

Abstract Context Checkpoint inhibitor–associated autoimmune diabetes mellitus (CIADM) is a rare illness, and little is known about its incidence, clinical features, or pathogenesis. Case Series Description Consecutive patients from a single quaternary melanoma center who developed new-onset insulin-requiring diabetes after commencing anti–programmed cell death-1 (PD-1) immunotherapy were studied to describe CIADM characteristics. Ten (1.9%) of 538 patients with metastatic melanoma treated with anti–PD-1–based immunotherapy from March 2015 to March 2018 developed CIADM. Nine patients had no history of diabetes, and one had pre-existing type 2 diabetes mellitus. Median time from immunotherapy start to CIADM diagnosis was 25 weeks [interquartile range (IQR), 17.5 to 34.5 weeks]. All patients had normal serum C-peptide shortly before CIADM onset and an inappropriately low level when measured soon after. At CIADM diagnosis, median hemoglobin A1c was 7.6% (IQR, 7.15% to 9.75%), median glucose level was 32.5 mmol/L (IQR, 21.6 to 36.7 mmol/L), and median C-peptide concentration was 0.35 nmol/L (IQR, 0.10 to 0.49 mmol/L). Type 1 diabetes (T1D)–associated autoantibodies (DAAs) were present in two patients (both of whom had anti–glutamic acid decarboxylase antibody); all were negative for insulin-associated protein 2, insulin, and ZnT8. Three patients were heterozygous for an HLA class II T1D-risk haplotype; two additional patients also carried protective haplotypes for T1D. All patients continued immunotherapy; eight (80%) had complete or partial oncological response, and all patients required ongoing insulin therapy. Conclusion CIADM is characterized by sudden permanent β-cell failure occurring after immunotherapy. It is distinct from T1D, usually lacks DAA or T1D-associated HLA-risk haplotypes, and is associated with difficult glycemic control from the onset. As such, CIADM represents a new model of auto-inflammatory β-cell failure.

scholarly journals Durvalumab-induced diabetic ketoacidosis followed by hypothyroidism

2019 ◽  
Vol 2019 ◽  
Author(s):  
Shivani Patel ◽  
Venessa Chin ◽  
Jerry R Greenfield
Keyword(s):  
Diabetic Ketoacidosis ◽  
Thyroid Function ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Reference Range ◽  
Checkpoint Inhibitor ◽  
Autoimmune Diabetes ◽  
Inhibitor Therapy ◽  
Thyroid Function Tests ◽  
Checkpoint Inhibitor Therapy

Summary Durvalumab is a programmed cell death ligand 1 inhibitor, which is now approved in Australia for use in non-small-cell lung and urothelial cancers. Autoimmune diabetes is a rare immune-related adverse effect associated with the use of immune checkpoint inhibitor therapy. It is now being increasingly described reflecting the wider use of immune checkpoint inhibitor therapy. We report the case of a 49-year-old female who presented with polyuria, polydipsia and weight loss, 3 months following the commencement of durvalumab. On admission, she was in severe diabetic ketoacidosis with venous glucose: 20.1 mmol/L, pH: 7.14, bicarbonate 11.2 mmol/L and serum beta hydroxybutyrate: >8.0 mmol/L. She had no personal or family history of diabetes or autoimmune disease. Her HbA1c was 7.8% and her glutamic acid decarboxylase (GAD) antibodies were mildly elevated at 2.2 mU/L (reference range: <2 mU/L) with negative zinc transporter 8 (ZnT8) and islet cell (ICA) antibodies. Her fasting C-peptide was low at 86 pmol/L (reference range: 200–1200) with a corresponding serum glucose of 21.9 mmol/L. She was promptly stabilised with an insulin infusion in intensive care and discharged on basal bolus insulin. Durvalumab was recommenced once her glycaemic control had stabilised. Thyroid function tests at the time of admission were within normal limits with negative thyroid autoantibodies. Four weeks post discharge, repeat thyroid function tests revealed hypothyroidism, with an elevated thyroid-stimulating hormone (TSH) at 6.39 mIU/L (reference range: 0.40–4.80) and low free T4: 5.9 pmol/L (reference range: 8.0–16.0). These findings persisted with repeat testing despite an absence of clinical symptoms. Treatment with levothyroxine was commenced after excluding adrenal insufficiency (early morning cortisol: 339 nmol/L) and hypophysitis (normal pituitary on MRI). Learning points: Durvalumab use is rarely associated with fulminant autoimmune diabetes, presenting with severe DKA. Multiple endocrinopathies can co-exist with the use of a single immune checkpoint inhibitors; thus, patients should be regularly monitored. Regular blood glucose levels should be performed on routine pathology on all patients on immune checkpoint inhibitor. Clinician awareness of immunotherapy-related diabetes needs to increase in an attempt to detect hyperglycaemia early and prevent DKA.

scholarly journals Immune checkpoint inhibitor associated reactivation of primary membranous nephropathy responsive to rituximab

2020 ◽  
Vol 8 (2) ◽  
pp. e001287 ◽  
Author(s):  
Jamie S Lin ◽  
Daniel Y Wang ◽  
Omar Mamlouk ◽  
William F Glass ◽  
Maen Abdelrahim ◽  
...  
Keyword(s):  
B Lymphocytes ◽  
Membranous Nephropathy ◽  
Antitumor Immunity ◽  
Antitumor Effect ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Pleural Mesothelioma ◽  
Normal Tissues ◽  
First Case

The same mechanisms that mediate antitumor immunity from checkpoint inhibitors (CPIs) can also lead to unintended targeting of normal tissues, characterized as immune-related adverse events (irAEs). Those with pre-existing autoimmune disease are believed to be particularly vulnerable for exacerbating underlying autoimmunity or inducing severe irAEs. We report the first case of CPI-associated reactivation of primary membranous nephropathy (MN) in a patient with pleural mesothelioma responding to immunotherapy. Due to its specificity in targeting B-lymphocytes, rituximab was used to treat primary MN with the expectation that this would not interfere with the benefits gained from T cell-mediated antitumor immunity. Rituximab was effective in treating CPI-associated reactivation of MN, and the patient was successfully rechallenged with nivolumab and maintained stable kidney function and sustained clinical antitumor effect. While exacerbation of pre-existing autoimmune diseases from CPIs is common, therapy for autoimmune reactivation can be rationally directed by an understanding of the immunosuppressive mechanism with goals of cancer treatment.

scholarly journals 1-25OH2D Mediated Hypercalcemia Secondary to DISR From Immune Checkpoint Inhibitors

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A169-A170
Author(s):  
Domenic Disanti ◽  
Alissa Marr ◽  
Whitney Sears Goldner
Keyword(s):  
Immune Checkpoint ◽  
Fdg Pet ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Inhibitor Therapy ◽  
Mediastinal Lymphadenopathy ◽  
Humoral Hypercalcemia Of Malignancy ◽  
First Case ◽  
Checkpoint Inhibitor Therapy

Abstract Background: Drug induced sarcoid like reactions (DISR) have recently been described as a potential consequence of immune checkpoint inhibitor therapy. However, hypercalcemia associated with DISR has not been reported. Clinical Case: A 72 year old male presented with metastatic melanoma. He initiated therapy with Ipilimumab/Nivolumab (Ipi/Nivo). Three weeks after his first cycle he developed symptomatic hypercalcemia (calcium 14.4 mg/dL), and acute kidney injury (creatinine 3.45mg/dL), PTH 12 pg/mL, 25OHD 51, and PTHrp 0.5. He received IV fluids and IV bisphosphonates and calcium normalized to 9.1 mg/dL and creatinine 1.85 mg/dL. His Ipi/Nivo were stopped due to concern for neurotoxicity. He subsequently switched to Q3week Pembrolizumab (Pembro) and after 2 infusions, he again developed hypercalcemia (calcium 11.8 mg/dL). FDG PET demonstrated a complete radiographic response. Labs showed a 1,25OH2D of 103 pg/mL (reference range 19.9–79.3 pg/mL), PTH of 4 pg/mL and calcium of 11.4 mg/dL. He was treated with prednisone 20 mg QD. After 9 days on prednisone, 1,25OH2D was 26 pg/mL and calcium 9.4 mg/dL. He took prednisone for 3 weeks total. Repeat labs off prednisone for one week were 1,25OH2D of 38 pg/mL and calcium 9.1 mg/dL. He continued on Pembro. After being off steroids for 5 weeks, he developed body aches and swelling of the hands. 1,25OH2D increased to 100 pg/mL and calcium to 10 mg/dL. He restarted prednisone and stopped Pembro. Labs one month later showed a 1,25OH2D of 45 pg/dL while still on prednisone 10 mg qd and a normal calcium in the mid 9’s. Follow up FDG PET showed hypermetabolic bilateral hilar and mediastinal lymphadenopathy not seen on previous imaging. Ultrasound-guided lymph node biopsy revealed granulomatous lymphadenitis. He was diagnosed with DISR, secondary to immunotherapy with checkpoint inhibitors. He continues on prednisone 10 mg per day and calcium and 1,25OH2D levels have remained normal. Conclusion: This is the first case of 1,25OH2D mediated hypercalcemia as a consequence of DISR induced by immune checkpoint inhibitor therapy. Hypercalcemia in the setting of malignancy is more commonly due to humoral hypercalcemia of malignancy from PTHrp or bone metastasis, but DISR needs to be a consideration in persons with hypercalcemia on immune checkpoint inhibitor therapy, with elevated 1,25OH2D levels and low PTH and PTHrp levels.

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