Pembrolizumab-Induced Encephalopathy: A Review of Neurological Toxicities with Immune Checkpoint Inhibitors

Abstract

The use of immune checkpoint inhibitor (ICI) therapy in the treatment of solid organ malignancies is becoming increasingly common. This has prompted the recognition of a new class of immune-related adverse effects (irAEs) stemming from the upregulation of T-cell activity causing autoimmunity. Neurological irAEs are a rare complication of ICIs that can lead to long-term morbidity. We report a rare case of encephalopathy after treatment with pembrolizumab, to which the patient achieved durable disease response despite discontinuation of therapy. We also review the pathophysiology, incidence, clinical presentation, diagnosis, and management of neurotoxicity secondary to ICIs. Treatment requires early administration of high-dose corticosteroids, and cessation of ICI therapy is often necessary after grade 3 or 4 irAEs. However, early data suggest that neurological irAEs correlate with a favorable disease response. Consideration should also be given to the optimal duration of ICI therapy to minimize the risk of toxicity and optimize health care expenditure.

Selective inhibition of low-affinity memory CD8+ T cells by corticosteroids

“…1 A, because in some patients with symptomatic brain tumors, such as those with glioblastoma and malignant melanoma, corticosteroids are required to be given concurrently with ICB. Dosing of corticosteroids was selected based on human equivalent dose; low-dose corticosteroids was 20 µg per mouse (0.7-1 µg/g) and high-dose corticosteroids was 2,000 µg per mouse (67-110 µg/g), which is thought to represent a pulse steroid dose (Feng et al, 2017). Early administration of corticosteroids induced a dose-dependent reduction in NY-ESO-1-specific CD8 + T cells in tumors treated with anti-CTLA-4 mAb; CMS5a-NY-ESO-1 tumor progression was not controlled in 40% of mice treated with corticosteroids and anti-CTLA-4 mAb (Fig.…”

A Cascade of Pembrolizumab-Induced Autoimmune Toxicities with Mixed Responses to Corticosteroids

“…EGFR TKIs produce much greater response rates than standard chemotherapy in patients with EGRF mutations; however, in landmark phase III studies complete response is rare, with rates ranging from 0% to 2%. 1 There have been previous published case studies reporting complete response in patients with sustained response 2,3 ; however, they have involved much shorter time scales and the patient received maintenance treatment, whereas our patient received only two cycles and had to stop treatment because of toxicity. However, as of the time of the writing of this letter, which is 4 years since the patient stopped receiving treatment or any further anticancer medication, she has not had any recurrence of her disease.…”

Association of Immune-Mediated Cerebellitis With Immune Checkpoint Inhibitor Therapy

“…4, 7, 9, 10, 11, 12, 13, 14, 15 It is considered a grade 3 or 4 irAE and warrants immediate and permanent discontinuation of ICI therapy. Cases have been reported in patients with various cancer types: non–small cell lung cancer, small cell lung cancer, advanced melanoma, and prostate cancer.…”