Neurological complications of immune checkpoint inhibitors: what happens when you 'take the brakes off' the immune system

Abstract

Patients with advanced malignancies treated with immune checkpoint inhibitors are at increased risk for developing immune-related neurological complications. It is a phenomenon of immunological twist when immunotherapy against co-stimulatory molecules activates previously normal T cells to kill tumor cells but, in so doing, the T cells become unrestrained, triggering other autoimmune diseases for which conventional immunotherapy is needed. The most common autoimmune neurological diseases, usually occurring within 2-12 weeks after immune checkpoint inhibitor initiation, include: inflammatory myopathies, myasthenia gravis, acute and chronic demyelinating polyradiculoneuropathies, vasculitic neuropathies, isolated cranial neuropathies, aseptic meningitis, autoimmune encephalitis, multiple sclerosis and hypophysitis. The neurological events can evolve rapidly, necessitating the need for vigilance at all stages of treatment, even after completion, because early immunotherapeutic interventions are effective. The review addresses these complications and the applied therapies, discusses immune pathomechanisms including triggering preexisting autoimmunity, highlights the distinction between paraneoplastic and autoimmune etiologies, and identifies uncertainties regarding risk factors, use of immune checkpoint inhibitors in patients with known immune diseases or restarting therapy after a neurological event. Although the autoimmune neurological complications are not very common, their incidence will likely increase as the use of immune checkpoint inhibitors in metastatic cancer is growing rapidly.

Keywords: autoimmune neurological disorders; immune checkpoint inhibitors; immune-related neurological complications; immunotherapy; neuro-immunology; neurological side effects.

Figure 1.

Signaling pathways activated by MHC/ T cell receptor (TCR) engagement and effect of immune checkpoint inhibitors. (a) Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) exerts negative, inhibitory signals when bind to their ligands Programmed Cell Death-Ligand 1, and 1 (PD-L1/PDL-2) on APCs and tumor cells and do not attack the tumor. The interaction of TCR with the target antigen presenting cell (APC) (the TCR/MHC complex) activates intracellular phosphotyrosine kinases (ZAP-70) that mediate signaling via phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) and various transduction molecules. T cell activation is meditated via key co-stimulatory factors, based on interactions of CD28/CTLA-4 or PD-1 on T cells with their respective ligands B7-1(CD80)/B7-2 (CD86) or PD-L1/PD-L2 on APCs and tumor cells. CD28, when binding to its CD80(B71)/CD86(B7-2) receptor, exerts positive (+) activating signals; in contrast, the CTLA-4 on activated T cells binds with higher affinity to CD80/CD86 and exerts negative (–) inhibitory signals, blocking T cell activation. This interaction activates sequentially downstream events, leading via the IL-2 promoter and Janus kinases to cell proliferation and T cell differentiation. The application of target-specific immunotherapies in autoimmune diseases is based on therapeutic monoclonal antibodies or fusion proteins directed against the positive activating CD28 and CD80/86 (B7-1,2) signals or in enhancing inhibition, via the CTLA-4 Ig fusion protein, like the drug Abatacept,which is effective in rheumatoid arthritis. (b) Effect of ICPIs: positive co-stimulation and T cell activation. The ICPIs prevent the CTLA-4 or PD-1 from binding to their respective receptors CD80/86 and PDL-1 (noted by *) and, by doing so, they inhibit the inherent ‘inhibitory’ (–) co-stimulatory interactions between T cells and tumor cells. Such inhibition of inhibitory signals results in positive co-stimulation that unleashes a strong and uncontrolled T cell activation ( like ‘taking the brakes off’ the immune system). The ICPI-induced activated T cells enhance Th1 and Th-17 cell responses, increase the production of cytokines, such as IL-6 and IL-17, leading to abnormal T-regulatory (Treg) cell function and altered Treg/Th17 cell axis, which is critical for humoral immunity and development of autoimmune disease. CTLA-4, cytotoxic T lymphocyte antigen; ICAM, intercellular adhesion molecule; ITAM, immunoreceptor tyrosine-based activation motifs; LFA-1, lymphocyte function antigen 1; LFA-3, lymphocyte function antigen 3; NFAT, nuclear factor of activated T cells; PLC, phospholipase C; PTK, protein tyrosine kinase; STAT, signal transducer and activator of transcription; ZAP-70, zeta-chain associated protein 70.