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Autoimmune polyendocrine syndrome induced by immune checkpoint inhibitors: a systematic review

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Abstract

Objective

To summarize the clinical characteristics and immunological and genetic features of patients who developed autoimmune polyendocrine syndrome type II (APS-2) after treatment with immune checkpoint inhibitors (ICIs).

Design and methods

Several databases (MEDLINE/EMBASE/Cochrane) were searched for studies published between January 2000 and February 2020 involving patients with two or more endocrine disorders after ICI therapy.

Results

Our final review included 22 articles comprising 23 patients (median age 56 years; 65.2% male patients). Of these patients, 60.9% received anti-programmed cell death 1 (PD-1) therapy, 17.4% received anti-programmed cell death ligand 1 (PD-L1) therapy, and 4.3% received anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) monotherapy. Patients underwent a median of four treatment cycles before the onset of the primary adverse event; the median time of onset was 8.5 weeks. Endocrine organs affected by ICI administration included the thyroid gland (18/23, 78.3%), pancreatic islets (17/23, 73.9%), pituitary gland (11/23, 47.8%), and adrenal gland (2/23, 8.7%). Related autoantibodies were detected in 65.2% of patients. In patients with diabetes, glutamic acid decarboxylase antibody was closely related to the development of diabetes ketoacidosis. The human leukocyte antigen genotype was reported in 34.8% (8/23) of patients, 5 (62.5%) of which had risk genotypes.

Conclusions

As a serious adverse event of ICI treatment, APS-2 is presented with abrupt initiation time and rapid development. Physicians should be aware of potential endocrine disorders and continue monitoring hormone status when treating cancer patients with ICIs.

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Abbreviations

ACA:

Adrenal cortex antibody

APS-2:

Autoimmune polyendocrine syndrome type II

CTLA-4:

Cytotoxic T-lymphocyte antigen 4

DKA:

Diabetes ketoacidosis; FSH, follicle-stimulating hormone

FT4:

Free thyroxine

GAD:

Glutamic Acid Decarboxylase

HLA:

Human leukocyte antigen

ICI:

Immune checkpoint inhibitor

irAE:

Immune-related adverse event

LH:

Luteinizing hormone

NSCLC:

Non-small cell lung cancer

21-OH Ab:

21-Hydroxylase antibody

PD-1:

Programmed cell death 1

PD-L1:

Programmed cell death ligand 1

T1DM:

Type 1 Diabetes Mellitus

TPO:

Thyroid peroxidase antibody

TSH:

Thyroid stimulating hormone

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Funding

This work was supported by the National Natural Sciences Foundation of China (81630097 and 81773718), the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2016-I2M-3–011), the Chinese Academy of Medical Sciences Fundamental Research Funds for the Central Universities (2018RC350002), and the Drug Innovation Major Project (2018ZX09711001-003–005, 2018ZX09711001-008–005, and 2018ZX09711001-003–020).

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Authors and Affiliations

  1. State Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing, 100050, China

    Zhe Zhao, Xiu-qi Bao, Jingwen Ning, Meiyu Shang & Dan Zhang

  2. Department of Thoracic Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Xinfeng Wang

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  1. Zhe Zhao
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Contributions

We declare that all authors made fundamental contributions to the manuscript. All authors contributed to the study conception and design. Database search and data analysis was conducted by WX. Study selection and data extraction were performed by NJ and SM. The manuscript was written by ZZ. BX and ZD reviewed the manuscript. All authors read and approved the final manuscript.

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Correspondence to Dan Zhang.

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Zhao, Z., Wang, X., Bao, Xq. et al. Autoimmune polyendocrine syndrome induced by immune checkpoint inhibitors: a systematic review. Cancer Immunol Immunother 70, 1527–1540 (2021). https://doi.org/10.1007/s00262-020-02699-1

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  • DOI: https://doi.org/10.1007/s00262-020-02699-1

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