Neurological Immune-Related Adverse Events Induced by Immune Checkpoint Inhibitors

Abstract

The use of immune checkpoint inhibitors (ICIs) for the treatment of various advanced and aggressive types of malignancy has significantly increased both survival and long-term remission rates. ICIs block crucial inhibitory pathways of the immune system, in order to trigger an aggravated immune response against the tumor. However, this enhanced immune activation leads to the development of numerous immune-related adverse events (irAEs), which may affect any system. Although severe neurological irAEs are relatively rare, they carry a high disability burden, and they can be potentially life-threatening. Therefore, clinicians must be alert and act promptly when individuals receiving ICIs present with new-onset neurological symptoms. In this narrative review, we have collected all the currently available data regarding the epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of post-ICI neurological irAEs. This review aims to raise physicians' awareness, enrich their knowledge regarding disease pathogenesis, and guide them through the diagnosis and management of post-ICI neurological irAEs.

Keywords: antineuronal antibodies; central nervous system; immune checkpoint inhibitors; neurological immune-related adverse events; neurotoxicity; paraneoplastic neurological syndromes; peripheral nervous system.

Figure 1

Intracellular mechanisms of CTLA-4 action in T lymphocytes. Activation of CTLA-4 inhibits T cell survival via three proposed mechanisms: (1) the inhibition of the RAS/MEK/ERK1/2 pathway by SHP2, (2) the inhibition of ZAP70 phosphorylation by SHP2, blocking the PI3K/AKT/mTOR pathway, (3) the direct inhibition of the PI3K/AKT/mTOR pathway by the YVKM motif. CTLA-4: cytotoxic T lymphocyte-associated antigen 4, CD80: cluster of differentiation 80, TCR: T cell receptor, MHC-II: major histocompatibility complex-II, CD28: cluster of differentiation 28, SHP2: Src homology region 2-containing protein tyrosine phosphatase 2, ZAP70: zeta-chain-associated protein kinase 70, PI3K: phosphoinositide 3-kinase, AKT: protein kinase B (PKB, also known as AKT), mTOR: mammalian target of rapamycin, MEK: mitogen-activated protein kinase/ERK kinase, ERK: extracellular-signal-regulated kinase.

Figure 2

Intracellular mechanisms of PD-1 action in T lymphocytes. Activation of PD-1 decreases T cell proliferation by: (1) inhibiting PLCγ1, leading to the inhibition of the RAS/MEK/ERK1/2 pathway, (2) acting on LCK, inhibiting the phosphorylation of ZAP70 and the activation of the PI3K/AKT/mTOR pathway, and (3) acting on CK2, leading to the phosphorylation of PTEN (presented with an x), inhibiting the PI3K/AKT/mTOR pathway. PD-1: programmed-death 1, PD-L1: programmed death-ligand 1, ITIM: immunoreceptor tyrosine-based inhibitory motif, ITSM: immunoreceptor tyrosine-based switch motif, SHP2: Src homology region 2-containing protein tyrosine phosphatase 2, LCK: lymphocyte-specific protein tyrosine kinase, ZAP70: zeta-chain-associated protein kinase 70, PI3K: phosphoinositide 3-kinase, AKT: protein kinase B (PKB, also known as AKT), mTOR: mammalian target of rapamycin, CK2: casein kinase 2, PTEN: PLCγ1: phospholipase C gamma 1, MEK: mitogen-activated protein kinase/ERK kinase, ERK: extracellular-signal-regulated kinase.

Figure 3

Diagnostic algorithm for individuals receiving ICIs, presenting with new-onset neurological symptoms. ICI: immune checkpoint inhibitor, CSF: cerebrospinal fluid, MG/LEMS: myasthenia gravis/Lambert Eaton myasthenic syndrome, GBS/CIDP: Guillain-Barré syndrome/chronic inflammatory demyelinating polyneuropathy, PRES/MERS: posterior reversible encephalopathy syndrome/mild encephalopathy with reversible splenial lesion, NMO/MS: neuromyelitis optica/multiple sclerosis, CNS: central nervous system.

Figure 4

Treatment options for the most frequently encountered ICI-irAEs, affecting PNS. Treatment options vary among different disorders, and according to disease severity and response to treatment. All currently available treatment options for neurological irAEs affecting the PNS are summarized in this figure. irAEs: immune-related adverse events, ICI: immune checkpoint inhibitor, iv: intravenous, IVIG: intravenous immunoglobulin.

Figure 5

Treatment options for the neurological irAEs, caused by ICI administration, affecting the CNS. Treatment options vary among different disorders, and according to disease severity, personal history, response to treatment, and the presence of autoantibodies. Therefore, the choice of appropriate treatment depends on several factors and should be personalized for each individual. All currently available therapies for CNS irAEs are summarized in this figure. ICI: immune checkpoint inhibitor, CNS: central nervous system, irAEs: immune-related adverse events, iv: intravenous, IVIG: intravenous immunoglobulin, anti-IL6R: interleukin-6 receptor antibody, anti-CD20: cluster of differentiation 20 antibody.