Encephalitis After Immunotherapy Detected Early by Blood Test

Encephalitis is one of the most serious and difficult-to-diagnose side effects of immunotherapy.

Immunotherapy with checkpoint inhibitors has enabled completely new opportunities for oncologists to treat patients with various forms of cancer. The treatment means that the patient’s own immune response attacks the cancer cells. The drugs activate the immune response by blocking signaling pathways that normally act as inhibitors of the patient’s T cells.

Oncologists at the Sahlgrenska University Hospital (Goteborg, Sweden) and their rheumatology and clinical neurochemistry colleagues used a simple blood test to detect treatment-triggered encephalitis at an early stage. The scientists took blood samples from an encephalitis patient with metastases of melanoma in the brain, adrenal glands, lung, subcutis, and lymph nodes started double immune checkpoint blockade treatment and also analyzed T cell characteristics in nine checkpoint inhibitor-treated patients with or 12 without other serious immune-related adverse events (irAE).

Peripheral blood mononuclear cells (PBMCs) were separated from heparinized whole blood, stained with fluorochrome-conjugated antibodies and analyzed in a FACSLyric flow cytometer (Beckman Coulter, Brea, CA, USA). CD4 and CD8 T-cell subsets were defined by gating with FlowJo software. The S-100B concentrations in cerebrospinal fluid (CSF) and serum were measured by immunoassay on the cobas Elecsys platform (Roche Diagnostics, Rotkreuz, Switzerland). CSF concentrations of neurofilament light polypeptide (NFL) and glial fibrillary acidic protein (GFAP) were measured with in-house enzyme-linked immunosorbent assays.

CSF tau concentration was measured with a Lumipulse immunoassay (Fujirebio Diagnostics Inc., Tokyo, Japan). Plasma concentrations of NFL, GFAP, and tau were measured with ultrasensitive single-molecule array technology and commercially available kits. CSF and serum concentrations of albumin and IgG were measured by nephelometry on the cobas Elecsys platform. Oligoclonal IgG bands in serum and CSF were visualized by isoelectric focusing in a polyacrylamide gel and silver staining.

The investigators reported that axonal damage marker neurofilament light polypeptide (NFL) and astrocytic damage marker glial fibrillar acidic protein (GFAP) were very high in blood and CSF and gradually normalized after immunosuppression and intensive care. The levels of S-100B in blood rose even before the encephalitis patient exhibited symptoms. The co-stimulatory receptor inducible T cell co-stimulatory receptor (ICOS) was expressed on a high proportion of CD4⁺ and CD8⁺ T cells as encephalomyelitis symptoms peaked and then gradually decreased in parallel with clinical improvement.

Max Levin, MD, PhD, an Associate Professor and Chief Oncologist and co-author of the study said, “In Gothenburg, we now use S-100B and NFL to monitor the risk of encephalitis and we hope to soon be able to include GFAP and Tau. The markers have helped us diagnose three more cases of treatment-triggered encephalitis.”

The authors concluded that their results suggest a potential role for ICOS on CD4⁺ and CD8⁺ T cells in mediating encephalomyelitis and other serious irAE. In addition, brain damaged markers in the blood could facilitate early diagnosis of encephalitis. The study was originally published online on July 2, 2021 in the Journal for ImmunoTherapy of Cancer.

Related Links:
Sahlgrenska University Hospital
Beckman Coulter
Roche Diagnostics
Fujirebio Diagnostics