Abstract
Background: Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) is a helper T cell protein receptor that down regulates the immune system when bound to antigen presenting cells. Ipilimumab selectively binds to CTLA-4 inhibiting the immune tolerance to tumour cells and has recently been approved for the treatment of metastatic melanoma. Autoimmune sequelae are side-effects of such immunomodulatory therapies. We describe the first case of ipilimumab induced delayed onset encephalitis. Case: A 71 year-old man with BRAF wild-type metastatic melanoma received ipilimumab as first-line therapy. He presented with generalised weakness and headache following cycle 2 of ipilimumab. Blood analyses confirmed panhypopituitarism and MRI showed lymphocytic infiltration of pituitary gland, confirming autoimmune hypophysitis. Hormone replacement and a course of dexamethasone resolved the initial symptoms. Two months later he developed myoclonic jerks, drowsiness and mood elevation. CSF protein was raised with normal white and no malignant cells. Ipilimumab was stopped and high dose methylprednisolone was intiated resulting in improvement within 24hours. Post methylprednisolone electroencephalogram showed normal background activity with no seizures. Discussion: Gastrointestinal (colitis, nausea), skin (pruritis, rash) and fatigue are the most common (30-40%) ipilimumab induced side effects. Endocrinopathies are reported in 1-2% of patients. CTLA-4 is expressed by pituitary gland thereby being susceptible for lymphocytic hypophysitis following ipilimumab. Neurological side effects are even rarer yet (<1%). Autoimmune encephalitis can be a delayed response and in our case was around 2 months after second dose of ipilimumab therapy. No cases of delayed onset ipilimumab induced encephalitis have been described as yet, but with increasing use of immune therapies which up-regulate T cells, rarer immune sequelae are likely to be on the rise. Conclusion: Ipilimumab caused delayed onset autoimmune encephalitis and hypophysitis that was steroid responsive. Multi-specialty approach with early intervention of a neurologist and endocrinologist is a must for improved identification, treatment and outcomes.
Highlights
Immunomodulatory therapy in the oncological setting has gained interest in recent years and its efficacy is established with improved overall survival in metastatic melanoma [1]
Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) is expressed by pituitary gland thereby being susceptible for lymphocytic hypophysitis following ipilimumab
Ipilimumab is a monoclonal antibody that selectively inhibits CTLA-4 receptor found on helper T-cells and down-regulates the immune tolerance to tumour cells, aiding the cytotoxic T lymphocytes to recognise and destroy tumour cells
Summary
Metastatic melanoma therapy is based on immunotherapy and ipilimumab, a human monoclonal antibody is designed to selectively block CTLA-4 receptor found on helper T-cells thereby down-regulating the immune tolerance to tumour cells and aiding the cytotoxic T lymphocytes to recognise and destroy tumour cells. This approach can cause immune related adverse events (irAEs). With increasing therapeutic use of newer selective monoclonal antibodies, it is likely we will see the emergence of further immune-related complications that we are as yet unaware of The onset of these side effects has mostly been early during induction or a few cycles of therapy with median times of 5-6 weeks [14]. In a recent pooled analysis of 1861 patients on ipilimumab, improved survival of 26% at 3 years follow-up, suggests, with ever improving survival rates there may yet be a possibility in some it can ’reboot’ the immune system and expand the possibility of irAEs
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