Microglial cell, illustration
Credit: Juan Gaertner / Science Photo Library

The neurotoxic side effects of anti-PD-1 immunotherapy have been a mystery, but new research has revealed a possible drug target that could help alleviate these effects. These side effects have reduced the efficacy of this revolutionary cancer treatment. Anti-PD1 immunotherapy causes neurotoxicity in mice by activating microglia, according to a study by researchers from the University of Freiburg.

The researchers found that spleen tyrosine kinase (Syk) activity was up in these activated microglia. Entospletinib, a Syk inhibitor that the FDA is currently studying in clinical trials, improved neurocognitive function without reducing the effectiveness of immunotherapy against cancer. The results, published in Science Translational Medicine, are intriguing because they show that anti-PD-1 treatment in patients increases surface marker expression, indicating microglia activation. This suggests that these findings could be applied to treating human patients.

How to block immunotherapy-mediated neurotoxicity

Immunotherapeutic strategies that involve blocking immune checkpoints, specifically programmed cell death protein/ligand 1 (PD-1/ PD-L1) and cytotoxic T lymphocyte–associated protein 4 (CTLA-4), have greatly enhanced the effectiveness of cancer treatment for various types of cancer. However, immune checkpoint inhibition treatment is associated with autoimmune-like disorders in patients, and neurological symptoms are found in one to twelve percent of patients. Unfortunately, it is difficult to distinguish between neurotoxicity and infection-related adverse events, so this percentage may be lower than the actual occurrence.

Neuroinflammation can develop unexpectedly as a side effect of immune checkpoint inhibitors. It can manifest with a wide range of symptoms, including fever, headaches, tremors, altered mental state, cognitive decline, seizures, encephalopathy, hypophysitis, meningitis, and encephalitis. Neuropathies, myasthenia gravis, Guillain-Barré syndrome, and other neuromuscular complications have also been reported. Additionally, demyelinating disorders similar to multiple sclerosis have been reported in some patients who have taken immune checkpoint inhibitors.

The present method for deciding which treatments to use for immune-mediated side effects after anti-PD-1 immunotherapy relies more on expert judgment and smaller case series than on prospective clinical trials. Current treatments for immune-mediated neurotoxicity tend to depend on nonselective immunosuppression, which has serious side effects, including invasive infections and other complications. As a result, a targeted treatment that considers the biological components of immune-mediated neurotoxicity caused by anti-PD-1 is seriously needed. 

Sick and tired of being syk and tired

The research team, which included Bertram Bengsch, MD, PhD, Marco Prinz, MD, and Robert Zeiser, MD, examined various mouse models and contrasted their findings with postmortem examination of the central nervous system (CNS) of patients who received anti-PD-1 therapy. Microglia activation was studied in both tumor-free and melanoma-stricken mice following anti-PD-1 treatment. This included observing changes in the physical structure of microglia and increased expression of MHC-II. A decrease in microglia counts but no change in T cell counts was associated with improved neurocognitive function following anti-PD-1 therapy.

An unbiased kinase activity analysis showed that anti-PD-1 treatment activated the spleen tyrosine kinase (Syk). Improvements in neurocognitive function were also observed after genetic deletion of microglia and pharmacological inhibition of Syk with entostainib. Finding increased microglial activation in patients treated with anti-PD-1 as compared to the control group further supports the interpretation of these results. Clinical trials are required to determine whether the results seen in mice, where Syk inhibition reduced microglia activation and anti-PD-1 treatment-induced neurocognitive impairments, are applicable to humans. 

This study has limitations, one of which is that it only looks at microglia. Although not specifically addressed in this study, astrocytes may contribute to the progression of anti-PD-1-induced neuroinflammation alongside other cell types.

The finding that inhibiting Syk improved neurocognitive function and reduced microglia activation without affecting the anti-melanoma effects of anti-PD-1 antibody treatment is highly significant from a clinical perspective. The reason is that a clinical trial could test entospletinib on people whose neurocognitive function has been impaired due to anti-PD-1 medication. This inhibitor is undergoing clinical trials for acute myeloid leukemia (ClinicalTrials.gov identifier: NCT05020665) and chronic lymphocytic leukemia, which streamlines the necessary investigational processes for its clinical application.

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