Neurological Toxicities of Immunotherapy

Mechanism of Action

IL-2 binds to its receptors, expressed on regulatory T cells (Tregs), activated CD8+, CD4+, CD56 high, dendritic cells, and endothelial cells, which leads to signaling via the Janus family tyrosine kinase (JAK). This further activates downstream signaling, causing T and NK cell expansion, T cell effector differentiation, and expansion of CD8+ memory T cells; the increased cytolytic activity of the T and NK cells is responsible for its antitumor effect. Interestingly IL-2 also causes expansion of immunosuppressive Tregs.

Mechanism of Neurotoxicity

Several mechanisms have been proposed for IL-2 medicated neurotoxicity. IL-2 has shown to have effects on neuronal cells, major neurotransmitters, and electrical activity. IL-2 can also lead to increase in the total water content of the brain, likely due to an increase in tumor vascular permeability or due to an overall increase in the total body water content.

Reported Neurotoxicity

Patients on IL-2 can develop delirium, lethargy, fatigue, insomnia, memory loss, dizziness, cognitive decline, and restlessness. In a large study with HDIL-2, multiple events of all-grade neurological toxicity were reported, including coma, somnolence, and dizziness, whereas another study reported grades 3 and 4 neurological toxicity or seizure in about 35% of patients. ^, Mood symptoms are also frequently seen with IL-2. Two studies found a significant increase in depression scores during IL-2 therapy. ^, In one study, patients developed new-onset neurological deficits which were associated with lesions in the white and grey matter. These lesions resolved and the neurological status improved in the majority of the patients once IL-2 therapy was withdrawn. Peripheral nerve entrapment due to fluid retention can be seen. Cases of brachial plexopathy have also been reported.

Mechanism of Action

INF-α works intrinsically on the tumor by decreasing tumor proliferation, inducing apoptosis, and extrinsically by increasing the proliferation and cytotoxicity of T and NK cells, decreasing proliferation of Treg cells, and decreasing the immunosuppressive activity of Treg and myeloid-derived suppressor cells, increasing major histocompatibility complex-1 (MHC-1) and tumor antigen presentation, increasing activation and signaling of dendritic cells, and inducing release of other cytokines.

Mechanism of Neurotoxicity

INF-α acts directly on neurons, leading to a decrease in the length and branching of the dendritic processes via the breakdown of MAP-2 (a cytoskeletal protein), decreasing signal transmission, and through the release of other cytokines. Indirectly, INF-α causes a decrease in levels of dopamine and serotonin and has effects on the hypothalamic-pituitary-adrenal axis.

Reported Neurotoxicities

Psychiatric symptoms are commonly reported with use of INF-α. Utilization of mental health care facilities was found to be more common among patients receiving adjuvant INF-α for melanoma compared with controls, with a higher risk of treatment discontinuation in patients who develop mental health problems. Depressive symptoms have been reported in between 8% and 48% of patients receiving INF-α. Risk factors for depression with INF-α therapy including higher dose and longer duration of treatment, history of psychiatric illness, ongoing psychiatric treatment, and lack of social support. In a clinical trial of patients with melanoma treated with INF, depression, anxiety, and action tremors were more common compared to controls. Other neuropsychiatric symptoms seen with the use of INF-α include mania, suicidal ideation, acute psychosis, difficulty concentrating, impaired memory, and insomnia. New onset seizures have been reported in about 1% of patients treated with INF-α. Development of Parkinson’s disease has also been seen with the use of INF-α.

Mechanism of Action

CTLA-4 present on the T cell surface competes with CD28 to bind with B7 on antigen presenting cells (APCs). Binding of CD28 leads to T cell proliferation by the production of IL-2 and anti-apoptotic factor, an action that is blocked by CTLA-4. Not only does it block CD28, but CTLA-4 also increases inhibitory signaling through tryptophan catabolism. Binding of CTLA-4 leads to downstream signaling inhibition of both CD4+ and CD8+ T cells and enhancement of Treg cells. Blockade of CTLA-4 in vivo has been shown not only to increase T cell activation and proliferation but also cause reduction in tumor growth in several animal models.

PD-1 is a transmembrane receptor which is expressed on mature T and B cells, thymocytes, and macrophages, whereas its ligands, PD-L1 and PD-L2, are expressed on several tissues and tumor cells. Binding of PD-1 with its ligand leads to decrease in T cell proliferation as well as tumor lysis. Blockade of the PD-1/PD-L1 pathway has shown to decrease tumorigenesis, increase proliferation and cytokine production by T helper cells and memory cells, increase cytolytic activity of T effector cells, and increase proliferation of memory cells, as well as other antitumor effects.

Mechanism of Neurotoxicity

Various mechanisms have been proposed to explain the neurological adverse effects seen with ICIs. Perivascular lymphocytic infiltration by both CD4+ and CD8+ T cells observed in this situation supports a T cell-medicated mechanism. On the other hand, development of new-onset myasthenia gravis (MG), the presence of anti-NMDA and anti-HU antibodies in patients with acute encephalitis, and the presence of anti-exosome antibodies in patients with myositis points towards a mechanism of ICI which involves the production of these pathogenic antibodies.

Reported Neurotoxicities

The incidence of any grade adverse effects was 3.8% with anti-CTLA-4 antibodies, 6.1% for anti-PD-1 antibodies, and 12% with the combination of anti-CTLA-4 with anti-PD-1 antibodies. The incidence of grades 3 to 4 adverse effects is less than 1% with all agents, including anti-PD-L1 antibodies. ^, Neurological adverse effects are seen more commonly in men, with a median time of onset 6 weeks after starting therapy, with recovery seen in most patients after a 4-week interruption of treatment. No difference was seen in the incidence of neurological adverse effects when a higher dose of ipilimumab was used. ^, A higher incidence was reported with higher doses of nivolumab, whereas the opposite was seen with pembrolizumab ^,

The most common neurological adverse events are grades 1 to 2 and are nonspecific, such as headache, dysgeusia, sensory impairment, or dizziness. Hypophysitis, which can present with headaches, has also been reported; a higher incidence is seen with the use of anti-CTLA-4 antibodies compared with the anti-PD-1 antibodies. Other central nervous system (CNS) toxicities include encephalitis and aseptic meningitis, which occur in about 0.1% to 0.2% of cases. Cases of cerebral edema, multiple sclerosis, transverse myelitis, posterior reversible encephalopathy (PRES), and CNS vasculitis have also been seen with the use of ICIs. De novo MG, worsening of MG, Guillain-Barre syndrome (GBS)/chronic demyelinating polyneuropathy, radiculopathy, and myositis have also been reported. ^,

Mechanism of Action

CAR T cells are genetically modified T cells that express an antibody-derived single-chain variable region, which attaches to the tumor antigen, and is linked to an intracellular T cell signaling domain (along with other costimulatory molecules in second and third generation CAR T cells) leading to T cell activation.

Mechanism of Neurotoxicity

Neurological toxicity and cytokine release syndrome (CRS) are the most common toxicities with use of CAR T-cell therapy. The major mechanism that has been proposed for neurotoxicity is through activation of endothelial cells and disruption of the blood-brain barrier (BBB). Gust et al. showed a correlation of neurotoxicity with endothelial cell activation, supporting this theory. Increase in angiopoietin (ANG) 2, an enzyme which is released from activated endothelial cells, increased ANG2:ANG1 ratio (ANG1 helps maintain endothelial cell quiescence), and increased von Willebrand factor (which, like ANG2, is stored in endothelial cells and is released upon activation) were found in patients with grade 4 or 5 neurotoxicity. In an animal model, use of CD20 CAR T cell was associated with an increase in multiple proinflammatory cytokines and T cell accumulation in the cerebrospinal fluid (CSF). Similar results have also been seen in humans treated with CD19 CAR T cells, with an increase in proteins and cells in CSF. Gust et al. also showed an increase in the IL-6, INF and tumor necrosis factor (TNF)-α in the CSF. These cytokines have been implicated in the activation of endothelial cells and increase in the BBB permeability. Although CAR T cells may cross-react with normal tissues, to date, CD19 expression has not been described in the nervous system, thus suggesting that CD19 CAR T cells do not cause toxicity by this mechanism. Recent evidence also implicates granulocyte macrophage–colony stimulating factor (GM-CSF), in the development of neurotoxicity and CRS. Lenzilumab, an anti–GM-CSF mAb, not only abrogated neurotoxicity but also improved the antitumor effect of CAR T cells.

Reported Neurotoxicity

In published studies and clinical trials, any grade neurological toxicity has been reported in 28% to 64% of patients, with development of grade 3 or higher toxicity seen in 11% to 28% and a median onset of 4 to 5 days. ^, In a study of 133 patients treated with CD19 CAR T-cell therapy, delirium and headache were the two most commonly reported neurological symptoms. Language disturbances, decreased level of consciousness, memory impairment, ataxia and movement abnormality, seizures, and intracranial hemorrhage were some of the other neurological disorders reported. ^{, ,} Complete resolution of neurotoxicity is seen in most patients. Factors associated with the development of neurological toxicity included young age, B-ALL, high disease burden, higher dose, and peak expansion value of CAR T cells, and preexisting neurological disease. ^, Development of grade 4 or higher CRS was linked to the development of grade 3 or higher neurotoxicity in several studies. Other factors associated with grade 4 or higher neurotoxicity included pre-lymphodepletion higher ANG2:ANG1 ratio, a higher peak of ferritin c-reactive protein (CRP) and other cytokines. Usually there are no changes in the magnetic resonance image (MRI) or computed tomography (CT) scans observed in these patients. ^{, ,} Anatomical changes seen on MRI are a poor prognostic marker as seen in the study by Gust et al., where 4 out of the 7 patients who developed MRI changes died. On electroencephalogram (EEG), generalized slowing is the most common finding. ^,

Mechanism of Action

T-VEC is an attenuated herpes simplex virus-1 encoding for GM-CSF. Tumor cells have disrupted activity of PKR which blocks protein translation in healthy cells. Type 1 INF signaling, which controls multiple transcription factors and cytokines which prevent viral replication, and is also disrupted in tumor cells. In the absence of PKR and INF signaling, the virus undergoes unchecked replication, ultimately leading to cell lysis and subsequent infection of more tumor cells. The release of tumor antigen and release of GM-CSF in the tumor microenvironment augments the action of the vaccine.