BACKGROUND: The programmed cell death-1 (PD-1) pathway is a novel therapeutic target in immune checkpoint therapy for cancer. It consists of the PD-1 receptor and its two ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Nivolumab is an anti-PD-1 monoclonal antibody approved for malignant melanoma, advanced non-small cell lung cancer, and advanced renal cell carcinoma in Japan. Thyrotoxicosis and hypothyroidism have both been reported in international Phase 3 studies and national post-marketing surveillance of nivolumab in Japan. METHODS: This study analyzed five consecutive cases with thyroid dysfunction associated with nivolumab therapy. Second, it examined the mRNA and protein expressions of PD-L1 and PD-L2 by reverse transcription polymerase chain reaction and Western blotting. RESULTS: All patients were diagnosed with painless thyroiditis. Thyrotoxicosis developed within four weeks from the first administration of nivolumab and normalized within four weeks of onset in three of the five patients. Hypothyroidism after transient thyrotoxicosis developed in two patients, and preexisting hypothyroidism persisted in one patient. The other two patients were treated with glucocorticoids and discontinued nivolumab therapy for comorbid adverse events. One did not develop hypothyroidism, and the other developed mild, transient hypothyroidism. In addition, it was verified that normal thyroid tissue expresses PD-L1 and PD-L2 mRNA and those proteins. CONCLUSIONS: In the present cases, nivolumab-induced thyrotoxicosis seemed to be associated with painless thyroiditis, while no patient with Graves' disease was observed. A transient and rapid course with subsequent hypothyroidism was observed in nivolumab-induced thyroiditis. In addition, it was verified that PD-L1 and PD-L2 are expressed in normal thyroid tissue. This suggests that nivolumab therapy reduces immune tolerance, even in normal thyroid tissue, and leads to the development of thyroiditis. Treating thyrotoxicosis with only supportive care and considering levothyroxine replacement therapy once subsequent hypothyroidism occurs is proposed. Further investigations are required to confirm whether glucocorticoid therapy and discontinuation of nivolumab therapy prevent subsequent hypothyroidism.
BACKGROUND: The programmed cell death-1 (PD-1) pathway is a novel therapeutic target in immune checkpoint therapy for cancer. It consists of the PD-1 receptor and its two ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Nivolumab is an anti-PD-1 monoclonal antibody approved for malignant melanoma, advanced non-small cell lung cancer, and advanced renal cell carcinoma in Japan. Thyrotoxicosis and hypothyroidism have both been reported in international Phase 3 studies and national post-marketing surveillance of nivolumab in Japan. METHODS: This study analyzed five consecutive cases with thyroid dysfunction associated with nivolumab therapy. Second, it examined the mRNA and protein expressions of PD-L1 and PD-L2 by reverse transcription polymerase chain reaction and Western blotting. RESULTS: All patients were diagnosed with painless thyroiditis. Thyrotoxicosis developed within four weeks from the first administration of nivolumab and normalized within four weeks of onset in three of the five patients. Hypothyroidism after transient thyrotoxicosis developed in two patients, and preexisting hypothyroidism persisted in one patient. The other two patients were treated with glucocorticoids and discontinued nivolumab therapy for comorbid adverse events. One did not develop hypothyroidism, and the other developed mild, transient hypothyroidism. In addition, it was verified that normal thyroid tissue expresses PD-L1 and PD-L2 mRNA and those proteins. CONCLUSIONS: In the present cases, nivolumab-induced thyrotoxicosis seemed to be associated with painless thyroiditis, while no patient with Graves' disease was observed. A transient and rapid course with subsequent hypothyroidism was observed in nivolumab-induced thyroiditis. In addition, it was verified that PD-L1 and PD-L2 are expressed in normal thyroid tissue. This suggests that nivolumab therapy reduces immune tolerance, even in normal thyroid tissue, and leads to the development of thyroiditis. Treating thyrotoxicosis with only supportive care and considering levothyroxine replacement therapy once subsequent hypothyroidism occurs is proposed. Further investigations are required to confirm whether glucocorticoid therapy and discontinuation of nivolumab therapy prevent subsequent hypothyroidism.
Authors: Inmaculada Peiró; Ramón Palmero; Pedro Iglesias; Juan José Díez; Andreu Simó-Servat; Juan Antonio Marín; Laura Jiménez; Eva Domingo-Domenech; Nuria Mancho-Fora; Ernest Nadal; Carlos Villabona Journal: Endocrine Date: 2019-02-25 Impact factor: 3.633
Authors: Priyanka C Iyer; Maria E Cabanillas; Steven G Waguespack; Mimi I Hu; Sonali Thosani; Victor R Lavis; Naifa L Busaidy; Sumit K Subudhi; Adi Diab; Ramona Dadu Journal: Thyroid Date: 2018-10 Impact factor: 6.568
Authors: Petros Fessas; Lucia A Possamai; James Clark; Ella Daniels; Cathrin Gudd; Benjamin H Mullish; James L Alexander; David J Pinato Journal: Immunology Date: 2019-11-19 Impact factor: 7.397
Authors: Jaydira Del Rivero; Lisa M Cordes; Joanna Klubo-Gwiezdzinska; Ravi A Madan; Lynnette K Nieman; James L Gulley Journal: Oncologist Date: 2019-10-10
Authors: Chanjuan Ma; F Stephen Hodi; Anita Giobbie-Hurder; Xiaocheng Wang; Jing Zhou; Amy Zhang; Ying Zhou; Fei Mao; Trevor E Angell; Chelsea P Andrews; Jiani Hu; Romualdo Barroso-Sousa; Ursula B Kaiser; Sara M Tolaney; Le Min Journal: Cancer Immunol Res Date: 2019-05-14 Impact factor: 11.151
Authors: Jaydira Del Rivero; Lisa M Cordes; Joanna Klubo-Gwiezdzinska; Ravi A Madan; Lynnette K Nieman; James L Gulley Journal: Oncologist Date: 2019-10-10