Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Rubin reports no financial relationships relevant to this field of study.
SYNOPSIS: Anti-programmed death 1 antibodies (checkpoint inhibitors) have become a mainstay in the treatment of many types of cancers, and now are known to cause frequent neuromuscular adverse effects that can cause severe disability or death if not recognized or treated promptly.
SOURCE: Kao JC, Liao B, Markovic SN, et al. Neurological complications associated with anti-programmed death 1 (PD-1) antibodies. JAMA Neurol 2017;74:1216-1222.
Anti-programmed death 1 (PD-1) antibodies, originally approved in the United States for the treatment of melanoma in 2014 and for non-small cell lung cancer in 2015, are used for the treatment of solid-organ tumors, including renal cell cancer, head and neck cancer, urothelial cancer, and Hodgkin’s lymphoma. Phase III trials are underway for other tumors, including bladder, ovarian, and brain. Adverse events, as initially reported, were thought to be rare, occurring in < 1% of patients, and included thyroid dysfunction, pneumonitis, colitis, hepatitis, nephritis, hypophysitis, uveitis, type 1 diabetes, and myositis. However, reports of neurological complications associated with anti-PD-1 therapy are increasing, and most often are neuromuscular in nature, including myasthenia gravis, necrotizing myopathy, vasculitic neuropathy, and polyradiculoneuropathy, as well as focal seizures associated with inflammatory cerebral lesions on magnetic resonance imaging, limbic encephalitis, and retinopathy. What are the frequency, phenotype, and severity of neurological complications from PD-1 antibody use?
In a single-center, retrospective, cohort study, undertaken by the departments of Neurology, Oncology, and Pharmacy Services at the Mayo Clinic from September 2014 to May 2016, using the Mayo Cancer Pharmacy Database, patients who received anti-PD-1 monoclonal antibodies (pembrolizumab or nivolumab) for the treatment of malignant melanoma or other solid organ tumor and developed neurologic disorders within 12 months of anti-PD-1 antibody use were identified. Neurologic symptoms attributable to metastatic disease or other cancer treatment were excluded. Severity was measured using the modified Rankin Scale.
Among 347 patients who received anti-PD-1 antibody, 204 received pembrolizumab, 142 received nivolumab, and one received both. Neurologic complications occurred in 10 patients (2.9%), eight men and two women, after a median of 5.5 cycles of anti-PD-1 therapy, seven during pembrolizumab and three during nivolumab treatment. Myopathy (n = 2), one mild and one severe necrotizing, and neuropathy (n = 4), axonal, demyelinating, or mixed, were the most common adverse events, with individual cases of cerebellar ataxia, autoimmune retinopathy, bilateral internuclear ophthalmoplegia, and headache. Time to maximum symptom severity varied from one to 90+ days. One patient died, and nine improved, one spontaneously and eight with immunotherapy, including intravenous immunoglobulin, corticosteroid, and plasma exchange. Non-neurologic, immune-mediated, adverse events occurred in five of these patients as well, including hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Anti-PD-1 neurologic adverse events may be rapid and life threatening, necessitating prompt recognition and withdrawal of the inciting agent.
Cancer immunotherapy, initiated in 1891 when New York surgeon William Coley injected bacterial products into a sarcoma and watched it shrink, has today joined surgery, radiation, and chemotherapy as a pillar of cancer treatment. Initially focused on accelerating T cell activity, today immunotherapy involves immune-checkpoint inhibitors, such as PD-1 monoclonal antibodies, which “release the immune system’s brakes to unleash anti-tumor immune responses.” Discovered in 1992, PD-1 is expressed on B cells and peripheral-activated CD4+ and CD8+ T cells, and suppresses T-cell activation, proliferation, and effector function. Thus, PD-1 blockade activates an antitumor immune system, preferentially recognizing tumor-derived antigens, rather than self-antigens. Immune-related adverse events may occur at any time but most occur during the first four months, with skin, gastrointestinal, and hepatic complications occurring early, within the first two months, and pulmonary, endocrine, and renal adverse events occurring beyond two months. Patients who fail to respond to immunotherapy may lack preexisting antitumor T-cell responses, and combination immune-checkpoint inhibitor therapy trials are underway to address this issue.1
- Iwai Y, Hamanishi J, Chamoto K, Honio T. Cancer immunotherapies targeting the PD-1 signaling pathway. J Biomed Sci 2017;24:26. doi: 10.1186/s12929-017-0329-9.