Researchers sought to characterize neurological disorders associated with anti-programmed death antibodies for the treatment of metastatic cancers.
One method a tumour may escape destruction by the immune system is to affect the cells that would otherwise destroy it. For the body to distinguish its own normally-functioning cells from abnormal cells and invaders, normal cells display molecules that certain immune cells recognize. These molecules signal the immune cells to forgo an immune response. In the case of programmed cell death protein 1 (PD-1), which white blood cells called T cells use to recognize PD-L1 and PD-L2 on normal cells, a tumour may display PD-L1 or PD-L2 in abundance to prevent certain T cells from taking action against it and causing others to self-destruct.
Anti-Programmed Death Antibodies (Anti-PD-1)
Therapies called anti-programmed death antibodies (anti-PD-1) have been developed. These therapies block PD-1, preventing it from recognizing PD-L1 or PD-L2 and therefore allow T cells to act against the tumor. These drugs, such as pembrolizumab and nivolumab, increase the immune response against cancer cells. However, they are associated with autoimmune disorders (conditions in which the immune system attacks the body’s own cells), including a variety of neurological complications, which are disorders affecting the brain or nervous system. An improved understanding of which neurological complications result from anti-PD-1 therapy and the conditions that cause these complications to arise would enable clinicians to make informed decisions concerning the appropriate use of anti-programmed death antibodies.
Assessing Neurological Disorders Associated with Anti-PD-1
In a recent US study published in JAMA Neurology, researchers investigated the prevalence, types, and severity of neurological disorders associated with the use of PD-1-blocking antibodies (anti-PD-1). Researchers obtained patient data from the Mayo Cancer Pharmacy Database in Rochester, Minnesota. Patients who had received anti-PD-1 therapy for melanoma or solid tumours between September 2014 and May 2016 and developed a neurological disorder within 12 months of antibody use were included in the analysis. Those for whom the neurological condition was attributed to the cancer itself or to other cancer therapies were excluded. Researchers assessed neurological function using nerve and muscle conduction tests, which evaluate their ability to transmit signals. Severity, as measured by a dependence on others to accomplish acts of daily living, was scored from 0 to 6 where 0 represented independence and 6 represented death.
In total, 347 patients were included in the analysis – 204 received pembrolizumab anti-PD-1 therapy, 142 received nivolumab, and one switched from nivolumab to pembrolizumab. Ten (2.9%) of these patients had a neurological condition possibly caused by anti-PD-1 treatment, and none of the participants had a history of neurological or immune dysfunction. Seven had received pembrolizumab and three had received nivolumab.
Results of the Study
There were four cases of weakness in various muscle groups, two cases of nerve dysfunction, and singular cases of inflammation in the cerebellum, which is a part of the brain involved in motor control, autoimmune damage to the retina (a part of the eye which allows us to distinguish shape and colour), impaired eye movement, and headache. Seven of the 10 patients ended treatment after symptoms began. Seven received prednisone daily for an average of 27 days. To manage neurological symptoms, two received immunoglobulin (used to treat autoimmune disorders) with prednisone, and one patient received immunoglobulin alone.
The severity of symptoms decreased in eight patients who received treatment for neurological complications and in one patient who did not receive treatment for neurological complications. Four patients died. Of the four that died, one was taken off of life support shortly after the start of symptoms and the other three passed away due to the progression of their cancer. Two patients remained in remission. Four restarted anti-PD-1 therapy after treatment for their neurological conditions, one stopped due to liver dysfunction, and two continued modified regimens.
Neurological Complications are Rare
The findings suggest neurological complications associated with therapy using anti-programmed death antibodies are rare. Moreover, although neuromuscular disorders were the most common type of complication, there was considerable significant diversity among the conditions. Future observational studies may benefit from a multi-centre study design in order to more accurately determine the frequency of neurological complications and account for the impact of patient differences (e.g. cancer type and the presence of other diseases) and variations in treatment protocols. Conducting clinical studies may also be beneficial as they would permit the collection of data specific to the research questions.
Written by Raishard Haynes, MBS
Kao, J.C. et al. (2017). Neurological Complications Associated With Anti–Programmed Death 1 (PD-1) Antibodies. JAMA Neurol. doi:10.1001/jamaneurol.2017.1912