Patients With Antithyroid Antibodies Are Prone To Develop Destructive Thyroiditis by Nivolumab: A Prospective Study

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Abstract

Context

Immune checkpoint inhibitors, including anti–programmed cell death-1 (PD-1) antibodies, have become promising treatments for a variety of advanced malignancies. However, these medicines can cause immune-related adverse events (irAEs), including endocrinopathies.

Objective

This study examined the incidence of endocrine irAEs induced by nivolumab.

Patients and Main Outcome Measured

Sixty-six patients treated with nivolumab at Nagoya University Hospital were prospectively evaluated for pituitary hormones, thyroid function, antithyroid antibodies (Abs), and glucose levels every 6 weeks after the initiation of nivolumab for 24 weeks.

Results

Four out of 66 patients developed destructive thyroiditis, and three patients developed hypothyroidism requiring levothyroxine replacement. The prevalence of positive anti-thyroglobulin Abs (TgAbs) and/or anti–thyroid peroxidase Abs (TPOAbs) at baseline was significantly higher in the group that developed destructive thyroiditis (3/4) compared with the group that did not develop thyroiditis (3/62; P = 0.002). There were no significant differences in other clinical variables between the groups. There were no endocrine irAEs other than destructive thyroiditis during the 24 weeks. The prevalence of TgAbs and/or TPOAbs at baseline was not associated with the development of other irAEs, including pneumonitis, colitis, or skin reactions.

Conclusions

Our real-world data showed that destructive thyroiditis was an endocrine irAE that was frequently induced by nivolumab and was significantly associated with positive TgAbs and/or TPOAbs before treatment. Our findings indicate that evaluating these Abs before treatment may help identify patients with a high risk of thyroidal irAEs and may have important clinical benefit.

Abstract

We prospectively examined endocrine irAEs induced by nivolumab and clarified that patients with antithyroid antibodies are prone to develop destructive thyroiditis.

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Most cited references 15

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Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.

Y Iwai, M. Ishida, Y. Tanaka … (2002)

PD-1 is a receptor of the Ig superfamily that negatively regulates T cell antigen receptor signaling by interacting with the specific ligands (PD-L) and is suggested to play a role in the maintenance of self-tolerance. In the present study, we examined possible roles of the PD-1/PD-L system in tumor immunity. Transgenic expression of PD-L1, one of the PD-L, in P815 tumor cells rendered them less susceptible to the specific T cell antigen receptor-mediated lysis by cytotoxic T cells in vitro, and markedly enhanced their tumorigenesis and invasiveness in vivo in the syngeneic hosts as compared with the parental tumor cells that lacked endogenous PD-L. Both effects could be reversed by anti-PD-L1 Ab. Survey of murine tumor lines revealed that all of the myeloma cell lines examined naturally expressed PD-L1. Growth of the myeloma cells in normal syngeneic mice was inhibited significantly albeit transiently by the administration of anti-PD-L1 Ab in vivo and was suppressed completely in the syngeneic PD-1-deficient mice. These results suggest that the expression of PD-L1 can serve as a potent mechanism for potentially immunogenic tumors to escape from host immune responses and that blockade of interaction between PD-1 and PD-L may provide a promising strategy for specific tumor immunotherapy.

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Precipitation of Autoimmune Diabetes With Anti-PD-1 Immunotherapy

Jing Hughes, Nalini Vudattu, Mario Sznol … (2015)

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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Is Open Access

Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management.

Colleen Veloski, Mario Sznol, Michael A. Postow … (2017)

Agents that modulate immune checkpoint proteins, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death receptor-1 (PD-1), have become a mainstay in cancer treatment. The clinical benefit afforded by immune checkpoint inhibitors can be accompanied by immune-related adverse events (irAE) that affect the skin, gastrointestinal tract, liver, and endocrine system. The types of irAEs associated with immune checkpoint inhibitors are generally consistent across tumor types. Immune-related endocrine events can affect the pituitary, thyroid, and adrenal glands, as well as other downstream target organs. These events are unique when compared with other irAEs because the manifestations are often irreversible. Immune-related endocrine events are typically grade 1/2 in severity and often present with non-specific symptoms, making them difficult to diagnose. The mechanisms underlying immune-related target organ damage in select individuals remain mostly undefined. Management includes close patient monitoring, appropriate laboratory testing for endocrine function, replacement of hormones, and consultation with an endocrinologist when appropriate. An awareness of the symptoms and management of immune-related endocrine events may aid in the safe and appropriate use of immune checkpoint inhibitors in clinical practice.

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Author and article information

Contributors

Shintaro Iwama

Journal

Journal ID (nlm-ta): J Endocr Soc

Journal ID (iso-abbrev): J Endocr Soc

Journal ID (publisher-id): jes

Title: Journal of the Endocrine Society

Publisher: Endocrine Society (Washington, DC )

ISSN (Electronic): 2472-1972

Publication date Collection: 01 March 2018

Publication date (Electronic): 06 February 2018

Volume: 2

Issue: 3

Pages: 241-251

Affiliations

[1 ]Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan

[2 ]Research Center of Health, Physical Fitness and Sports, Nagoya University, Nagoya, Japan

[3 ]Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan

[4 ]Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan

[5 ]Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan

[6 ]Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan

[7 ]Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan

[8 ]Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan

Author notes

Correspondence: Shintaro Iwama, MD, PhD, Research Center of Health, Physical Fitness and Sports, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan or Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. E-mail: siwama@ 123456med.nagoya-u.ac.jp .

Article

Publisher ID: js_201700432

DOI: 10.1210/js.2017-00432

PMC ID: 5836529

PubMed ID: 29600292

SO-VID: 80c04757-6272-48d1-8598-b9658159fe3b

License:

This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 07 November 2017

Date accepted : 01 February 2018

Page count

Pages: 11

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Patients With Antithyroid Antibodies Are Prone To Develop Destructive Thyroiditis by Nivolumab: A Prospective Study

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Abstract

Context

Objective

Patients and Main Outcome Measured

Results

Conclusions

Abstract

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Hogrefe: SDG 3 Good Health and Well-being

Most cited references 15

Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.

Precipitation of Autoimmune Diabetes With Anti-PD-1 Immunotherapy

Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management.

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Contributors

Journal

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Author notes

Article

History

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Comments

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Cited by 84

Most referenced authors 903