An autopsy case study of lymphocytic hypophysitis induced by nivolumab treatment for esophageal malignant melanoma.

Immune checkpoint inhibitors such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed death-1 antibodies are effective against malignant tumors. However, they induce unique adverse events known as immune-related adverse events. Hypophysitis is one of the most frequent immune-related adverse events of anti-cytotoxic T-lymphocyte antigen-4 therapies. However, there have been few reports describing the pathological findings of hypophysitis induced by anti-programmed death-1 antibodies. The present case is the first autopsy case of hypophysitis induced by nivolumab monotherapy, an anti-programmed death-1 antibody. Pathologically, lymphocytes infiltrated the anterior lobe of the pituitary gland, and the number of pituitary cells, especially adrenocorticotropic hormone-positive cells, decreased. However, necrosis and remarkable fibrosis were not observed. Immunohistologically, some pituitary cells expressed programmed death-ligand 1. Lymphocytes were predominantly CD8-positive T cells, and CD68-positive macrophages and CD20-positive B-cells were also observed. IgG and C4d were deposited on pituitary cells, but IgG4 (a subclass of nivolumab) was not detected. These findings indicate that type IVc and type II hypersensitivity mechanisms may occur in hypophysitis induced by anti-programmed death-1 antibodies and that the inflammatory mechanisms underlying hypophysitis induced by anti-programmed death-1 and anti-cytotoxic T-lymphocyte antigen-4 antibodies are different.

Evidence for interleukin 17 involvement in severe immune-related neuroendocrine toxicity.

AIM: Severe neurological and endocrine toxicities are well recognised adverse events of immune checkpoint inhibitors. However, the underlying pathophysiology is poorly understood, and classical circulating markers are often non-informative, making it difficult to obtain a precise diagnosis and to initiate timely and effective treatment. Here we investigated immune-modulating activity in the plasma of a mesothelioma patient who developed fatal neuroendocrine toxicity characterised by insulin-dependent diabetes, hypophisitis and a myasthenia-like syndrome while on treatment with the dual PD1 and TIM3 blockade. METHODS: We used an in vitro functional assay for unbiased detection of plasma dendritic cell-modulating activity, followed by cytokine quantification by the Cytokine Bead Array. RESULTS: Immunosuppressive treatment as per established guidelines could not prevent the fatal outcome. Patient's plasma contained a dendritic cell-stimulating activity that induced specific markers (CD25+) compatible with T-helper 17 stimulation. Consistently, elevated levels of interleukin 17 (IL17A), but no other cytokines, were identified in the patient's plasma but not in controls (healthy volunteers and patients treated with immunotherapy without neuroendocrine toxicities). CONCLUSION: If confirmed in larger series, these data suggest IL17 as a candidate diagnostic and therapeutic target in the management of high-grade neuroendocrine immune-related adverse events.

Anti-pituitary antibodies as a marker of autoimmunity in pituitary glands.

Autoimmunity contributes to the pathogenesis of hypophysitis, a chronic inflammatory disease in the pituitary gland. Although primary hypophysitis is rare, the number of pituitary dysfunction cases induced by immune checkpoint inhibitors (ICIs) is increasing. While it is difficult to prove the involvement of autoimmunity in the pituitary glands, circulating anti-pituitary antibodies (APAs) can be measured by indirect immunofluorescence and used as a surrogate marker of pituitary autoimmunity. APAs are present in several pituitary diseases, including lymphocytic adenohypophysitis, lymphocytic infundibulo-neurohypophysitis (LINH), IgG4-related hypophysitis, and pituitary dysfunction induced by ICIs. Mass spectrometry analysis of antigens targeted by APAs clarified rabphilin-3A as an autoantigen in LINH. This demonstrates that APAs can be applied as a probe to identify novel autoantigens in other pituitary autoimmune diseases, including pituitary dysfunction induced by ICIs, which can aid in biomarker discovery.

Autoimmune hypophysitis secondary to therapy with immune checkpoint inhibitors: Four cases describing the clinical heterogeneity of central endocrine dysfunction.

INTRODUCTION: Immune checkpoint inhibitors are becoming increasingly important in oncology. Immune-related adverse events, including autoimmune hypophysitis, have been reported before. CASE REPORT: We present a case series of three males and one female, suffering from either malignant melanoma or renal cell carcinoma, who developed hypophysitis under Nivolumab and/or Ipilimumab. A wide range of clinical manifestations from asymptomatic hypophysitis, headache, general weakness, loss of appetite, visual field impairment, and confusion to acute life-threatening Addison crisis was observed.Management and outcome: All patients received corticosteroids. Immune checkpoint inhibitors were discontinued in three cases until resolution of symptoms. DISCUSSION: The objective of our report is to raise the awareness of physicians, regarding this rare clinical entity, which may become life-threatening, if not promptly recognized and properly treated.

Immunotherapy-induced autoimmune hypophysitis.

Autoimmune hypophysitis is an immune-related adverse event of immune checkpoint inhibitors. In this article, we present the case of a 58-year-old female patient who presented to the emergency room with gradually worsening nonspecific symptoms of headache, nausea, vomiting and decreased oral intake of one week duration. The patient had been diagnosed with relapsed extensive stage small cell lung cancer. She was being treated with a combination of ipilimumab and nivolumab after progression on chemotherapy. Gadolinium-enhanced magnetic resonance imaging of head revealed pituitary enlargement up to 1.5 cm and pituitary stalk enlargement up to 4 mm consistent with hypophysitis. The patient was treated with corticosteroids resulting in rapid resolution of her symptoms. The objective of our report is to highlight this rare but important adverse event associated with checkpoint inhibitors, and discuss its clinical features, diagnostic work-up and treatment.

Hypophysitis and other autoimmune complications related to immune checkpoints inhibitors´ treatment: Spectrum of imaging appearances.

OBJECTIVES: Immune checkpoints inhibitors (ICI) represent a new therapy option for the treatment of several advanced tumors. However, this therapy has been linked to a spectrum of ICI related autoimmune (AI) adverse events. Some may be life threatening and their diagnosis is tricky. The aim of our study was to describe various imaging appearances of ICI related secondary hypophysitis and other coincidental AI diseases. MATERIAL AND METHODS: We included 28 patients (19 females, 9 men, mean aged 58±13 years), who were consecutively treated mostly for advanced stage melanoma by different ICI. All their CT/MRI records and clinical data were reviewed. RESULTS: We found 5 (18%) cases of endocrinology proven secondary hypophysitis; 2 cases of panhypopituitarism and 3 cases of central hypocortisolism. Four cases were MRI positive, 1 case was MRI negative. Three cases were accompanied by other AI diseases: 1 by hemorrhagic colitis and mesenterial lymphadenitis, 1 by AI pancreatitis and 1 by pneumonitis. On MRI pituitary gland was swollen in 3 cases, twice enhanced non-homogenously, once homogenously; infundibular enlargement was present in 2 cases. Those 3 cases reacted to glucocorticoid therapy by hypophyseal shrinkage. In 1 case of MRI positive hypophysitis, the pituitary gland was not enlarged, slightly nonhomogeneous with peripheral contour enhancement; no reaction to glucocorticoids was mentioned. CONCLUSION: Secondary hypophysitis is probably more common ICI related adverse event than reported in the literature. Its MRI appearance is variable. Most of our cases were in coincidence with other AI ICI related events that affected their clinical manifestations.

Critical role of rabphilin-3A in the pathophysiology of experimental lymphocytic neurohypophysitis.

Autoimmune hypophysitis (AH) is thought to be an autoimmune disease characterized by lymphocytic infiltration of the pituitary gland. Among AH pathologies, lymphocytic infundibulo-neurohypophysitis (LINH) involves infiltration of the neurohypophysis and/or the hypothalamic infundibulum, causing central diabetes insipidus resulting from insufficiency of arginine vasopressin secretion. The pathophysiological and pathogenetic mechanisms underlying LINH are largely unknown. Clinically, differentiating LINH from other pituitary diseases accompanied by mass lesions, including tumours, has often been difficult, because of similar clinical manifestations. We recently reported that rabphilin-3A is an autoantigen and that anti-rabphilin-3A antibodies constitute a possible diagnostic marker for LINH. However, the involvement of rabphilin-3A in the pathogenesis of LINH remains to be elucidated. This study was undertaken to explore the role of rabphilin-3A in lymphocytic neurohypophysitis and to investigate the mechanism. We found that immunization of mice with rabphilin-3A led to neurohypophysitis. Lymphocytic infiltration was observed in the neurohypophysis and supraoptic nucleus 1 month after the first immunization. Mice immunized with rabphilin-3A showed an increase in the volume of urine that was hypotonic as compared with control mice. Administration of a cocktail of monoclonal anti-rabphilin-3A antibodies did not induce neurohypophysitis. However, abatacept, which is a chimeric protein that suppresses T-cell activation, decreased the number of T cells specific for rabphilin-3A in peripheral blood mononuclear cells (PBMCs). It ameliorated lymphocytic infiltration of CD3+ T cells in the neurohypophysis of mice that had been immunized with rabphilin-3A. Additionally, there was a linear association between the number of T cells specific for rabphilin-3A in PBMCs and the number of CD3+ T cells infiltrating the neurohypophysis. In conclusion, we suggest that rabphilin-3A is a pathogenic antigen, and that T cells specific for rabphilin-3A are involved in the pathogenesis of neurohypophysitis in mice. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Is autoimmunity the Achilles' heel of cancer immunotherapy?

The emergence of immuno-oncology as the first broadly successful strategy for metastatic cancer will require clinicians to integrate this new pillar of medicine with chemotherapy, radiation, and targeted small-molecule compounds. Of equal importance is gaining an understanding of the limitations and toxicities of immunotherapy. Immunotherapy was initially perceived to be a relatively less toxic approach to cancer treatment than other available therapies-and surely it is, when compared to those. However, as the use of immunotherapy becomes more common, especially as first- and second-line treatments, immunotoxicity and autoimmunity are emerging as the Achilles' heel of immunotherapy. In this Perspective, we discuss evidence that the occurrence of immunotoxicity bodes well for the patient, and describe mechanisms that might be related to the induction of autoimmunity. We then explore approaches to limit immunotoxicity, and discuss the future directions of research and reporting that are needed to diminish it.

Early recognition of ipilimumab-related autoimmune hypophysitis in patients with metastatic melanoma: Case studies and recommendations for management.

Ipilimumab is a human anti-CTLA-4 monoclonal antibody recently approved for the treatment of advanced melanoma. Stimulation of T-cell activity unmasks antitumor activity, but can cause immune-related adverse events. Autoimmune hypophysitis is of particular importance because its presentation can be subtle but life threatening. We present two cases where early recognition of ipilimumab-related autoimmune hypophysitis led to timely intervention and low subsequent morbidity, without compromise of antitumor effects. We provide recommendations for detection and management of this potentially life-threatening complication of ipilimumab.