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Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer
Open accessAbstract
Background Programmed cell death protein-1 (PD-1) blockade therapies have demonstrated durable responses and prolonged survival in a variety of malignancies. Treatment is generally well tolerated although immune-related adverse events (irAEs) can occur. Autoimmune thyroid dysfunction is among the most common irAE, but an assessment of the clinical, mechanistic, and immunologic features has not been previously described.Patient and methods Patients with advanced non-small-cell lung cancer (NSCLC) treated with pembrolizumab at Memorial Sloan Kettering Cancer Center (n = 51) as part of KEYNOTE-001 (NCT01295827) were included. Thyroid function test and anti-thyroid antibodies were assessed prospectively at each study visit, beginning before the first treatment. Frequency of development of thyroid dysfunction, association with anti-thyroid antibodies, clinical course, and relationship with progression-free survival and overall survival to treatment with pembrolizumab was evaluated.Results Of 51 patients treated, 3 were hypothyroid and 48 were not at baseline. Ten of 48 [21%, 95% confidence interval (CI) 10% to 35%] patients developed thyroid dysfunction requiring thyroid replacement. Anti-thyroid antibodies were present in 8 of 10 patients who developed thyroid dysfunction, compared with 3 of 38 who did not (80% versus 8%, P < 0.0001). Thyroid dysfunction occurred early (median, 42 days) in the pembrolizumab course, and a majority (6 of 10 patients) experienced brief, transient hyperthyroidism preceding the onset of hypothyroidism; no persistent hyperthyroidism occurred. Both hyperthyroidism and hypothyroidism were largely asymptomatic. Overall survival with pembrolizumab was significantly longer in subjects who developed thyroid dysfunction (hazard ratio, 0.29; 95% CI 0.09-0.94; P = 0.04).Conclusions Thyroid dysfunction during pembrolizumab treatment of NSCLC is common and is characterized by early-onset, frequently preceded by transient hyperthyroidism, closely associated with anti-thyroid antibodies, and may be associated with improved outcomes. The presence of antibody-mediated toxicity in T-cell-directed therapy suggests an under-recognized impact of PD-1 biology in modulating humoral immunity.
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“Two retrospective and two prospective studies reported that positive TPOAb and/or thyroglobulin autoantibodies (TgAb) are associated with a 40 to 70% risk of hypothyroidism during treatment”
From Graves’ Disease during Immune Checkpoint Inhibitor Therapy (A Case Series and Literature Review) (2021) · cites this paper as [56]
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“and that patients who had ICPi-induced hypothyroidism had positive anti-thyroid autoantibodies in 75 to 100% of cases [54,55,56,57].”
From Graves’ Disease during Immune Checkpoint Inhibitor Therapy (A Case Series and Literature Review) (2021) · cites this paper as [56]
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“Note that in the Osorio study [56], survival was better if patients developed ICPi-induced thyroid dysfunction”
From Graves’ Disease during Immune Checkpoint Inhibitor Therapy (A Case Series and Literature Review) (2021) · cites this paper as [56]
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Are anti-CTL4 and anti-PD-1 an effective biomarker in immunotherapy?
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Inibitori dei checkpoint immunitari e patologia tiroidea
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“…a cellule di Merkel Avelumab Ipotiroidismo 6% Morris et al., 2017 [14] Carcinoma a cellule squamose del canale anale Nivolumab Ipotiroidismo 6% Osorio et al., 2017 [15] Carcinoma polmonare non a piccole cellule Pembrolizumab Ipotiroidismo 8% Wolchok et al., 2017 [16] Melanoma Ipilimumab…”
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Autoantibodies: A manifestation of immune related adverse events of cancer immunotherapy
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Endocrine side effects during cancer treatment. Lecture for practitioners
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“Дисфункции щитовидной железы у пациентов, получающих ИКТИО Деструктивный тиреоидит – наиболее частая клиническая форма поражения щитовидной железы на фоне терапии ИКТИО (встречается у 5–50% пациентов) [14, 21, 22] – характеризуется чередованием транзиторной тиреотоксической фазы и последующим стойким исходом в гипотир…”
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Was muss der Internist bei Patienten unter Biologikabehandlung beachten?
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ПОБІЧНА ДІЯ ТЕРАПІЇ ІНГІБІТОРАМИ ИМУННИХ КОНТРОЛЬНИХ ТОЧОК НА ЩИТОПОДІБНУ ЗАЛОЗУ
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Metadata
- Authors
- Osorio, J. C., Ni, A., Chaft, J. E., Pollina, R., Kasler, M. K., Stephens, D., Rodriguez, C., Cambridge, L., Rizvi, H., Wolchok, J. D., Merghoub, T., Rudin, C. M., Fish, S., & Hellmann, M. D.
- Affiliations
- Weill Cornell Medicine (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Hellmann, M.D.
- Venue
- Annals of Oncology
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 28
- Issue
- 3
- Pages
- 583-589
- ISSN
- 0923-7534 (ISSN-L)
- PMC
- PMC5834017
- OpenAlex
- W2561156916
- Cited by
- 659
- References
- 26
- Citations by year
- 2026: 23 · 2025: 50 · 2024: 70 · 2023: 75 · 2022: 102 · 2021: 95 · 2020: 98 · 2019: 77 · 2018: 51 · 2017: 17
- FWCI
- 26.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Annals of Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (P30 CA008748)
- Fiona and Stanley Druckenmiller Center for Lung Cancer Research
- KEYNOTE-001 (NCT01295827)
- Merck Sharp & Dohme, a subsidiary of Merck
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Clinical Neurology › Autoimmune Neurological Disorders and Treatments
- Keywords
- immune-related adverse events, anti-thyroid antibodies, pembrolizumab, anti-PD-1 therapy, non-small cell lung cancer, hypothyroidism, hyperthyroidism, humoral immunity, immune checkpoint inhibitors, progression-free survival, overall survival
- MeSH terms
- Adolescent, Adult, Aged, Antibodies, Monoclonal, Carcinoma, Non-Small-Cell Lung, Female, Humans, Hyperthyroidism, Male, Middle Aged, Neoplasm Staging, T-Lymphocytes, Thyroid Gland, Disease-Free Survival, Programmed Cell Death 1 Receptor, Antibodies, Monoclonal, Humanized, Drug-Related Side Effects and Adverse Reactions
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