Hypothyroidism in Cancer Patients on Immune Checkpoint Inhibitors with anti-PD1 Agents: Insights on Underlying Mechanisms

Abstract

Background: Immune therapy using monoclonal antibodies against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death 1 receptor (PD-1) for various cancers have been reported to cause thyroid dysfunction. Little is known, however, about the underlying pathogenic mechanisms and the course of hypothyroidism that subsequently develops. In this report, we use the change in thyroglobulin and thyroid antibody levels in patients on immune therapy who develop hypothyroidism to better understand its pathogenesis as well as examine the status of hypothyroidism in the long term.

Methods: We report a case series of 10 patients who developed hypothyroidism after initiation of immune therapy (either anti-PD-1 alone or in combination with anti-CTLA-4). Available thyroid antibodies including anti-thyroglobulin (anti-Tg), anti-thyroid peroxidase (anti-TPO), and thyroid stimulating immunoglobulin (TSI) were noted during the initial thyroiditis phase as well as the hypothyroid phase. Persistence or remission of hypothyroidism was noted at 6 months.

Summary: During the thyroiditis phase, 50% of the patients had elevated Tg titers, 40% had elevated anti-Tg, and 40% had elevated TSI. All of these titers decreased during the hypothyroid phase. Permanent hypothyroidism was noted in 80% of the cases.

Conclusion: Hypothyroidism following initiation of immune therapy has immunologic and non-immunologic mediated mechanisms and is likely to be persistent.

Key words

hypothyroidism - immunotherapy - oncology - thyroiditis - immune phenomena

• References

• 1 Luke J, Ott P. PD-1 pathway inhibitors: The next generation of immunotherapy for advanced melanoma. Oncotarget 2015; 6: 3479-3492
• 2 Ascierto P, Marincola F. The year of anti-PD-1/PD-L1s against melanoma and beyond. ebiomedicine 2015; 2: 92-93
• 3 Ryder M, Callahan M, Postow M et al. Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. Endocr Relat Cancer 2014; 21: 371-381
• 4 Abbas AK, Lichtman AH, Pillai S. Immunity to tumors. In: Abbas AK, Lichtman AH, Pillai S. eds. Cellular and Molecular Immunology. 8^th ed. Elsevier; Philadelphia: 2014: 383-397
• 5 Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45: 228-247
• 6 Orlov S, Salari F, Kashat L et al. Induction of painless thyroiditis in patients receiving programmed death 1 receptor immunotherapy for metastatic malignancies. J Clin Endocrinol Metab 2015; 100: 1738-1741