Immune Checkpoint Inhibitor Related Neuropathic Adverse Effects on Cancer Patients

With the recent development and clinical application, immune checkpoint inhibitors (ICIs) intervention is being increasingly common for multiple malignancies. With these, prospect on focus creates an increasing necessity for an early recognition with proper documentation of upcoming treat-ment-related toxicities. These treatment-related toxicities are generally termed as immune-related adverse effects (irAEs) [1]. It is a known fact that the upregulation of T-cell initiates autoimmunity resulting in these irAEs. The review focuses on increasing events of neuropathy associated with im-munecheckpoint inhibitors, which is one of the rare neurological irAEs, therefore, the least reviewed. The severity and distribution of neurologic toxicities are important deciding factors for its management (CNS vs. PNS), although there is no strong evidence for patients treated with ICIs are specifically affected by the use of immune-modulating interventions. Furthermore, the review discusses on pathophysiology, incidence, clinical presentation, diagnosis, and management of neuropathies as a result of ICIs. Early administration of high-dose corticosteroids is the main management of neuropathies especially for grade 3 or 4 irAEs initial cessation of ICI therapy with contin-ued steroids which are necessary. However, the optimal duration of ICI therapy to minimize the risk of toxicity should be kept under consideration.


Introduction
The specific focus of immune target cells has proved as a revolutionary approach for management of multiple malignancies modulating it into an important branch in the field of Medical Oncology. The upregulation of T-cells pathways lymphoma, etc. (Table 1). In 2011, Ipilimumab, a cytotoxic T lymphocyte associated antigen 4 (CTLA4) targeting antibody was approved for advanced melanoma [2]. Further in 2014, approval of Nivolumab and pembrolizumab, monoclonal antibodies directed against the programed cell death 1 (PD-1), was witnessed. Following in 2016-2017, further approval of anti-PD-1 ligand (PD-L1) agents was witnessed [3]. Nivolumab was approved for metastatic NSCLC, RCC, Hodgkin's lymphoma, metastatic melanoma, and along with Pembrolizumab for metastatic melanoma, lung cancer and metastatic head and neck cancer. Later, Atezolizumab was approved for urothelial carcinoma.
Although through immune activation mechanism, it proves to be a very efficient therapy, concurrently significant immune-related adverse events (IRAEs) pose as a major drawback for the same. Generally termed as IRAEs, it almost affects multiorgan with a wide range of toxicities. Studies for the toxicities are mostly focused on colitis, hepatitis, pneumonitis and other IRAEs whereas there is much less emphasis on peripheral neuropathy [4]. Neuropathies though are rare, are increasing in incidence in recent interventions with ICI. With the above on focus, in this study, we aim to review the literature about IRAE associated neuropathies.

CTLA-4 and PD-1 Pathways
The cancer associated genetic mutations results various tumor associated antigen expression on cancer cells. The Major Histocompatibility Complex (MHC) presents the tumor associated molecules to the Antigen Presenting Cells (APC) on their surface for the T-cell receptor (TCR) recognition as seen in (Figure 1). Henceforth, multiple "non self" tumor-associated antigens induces series of attack on all tumor cells expressing these antigens [5].
However, CTLA-4 is associated with the inhibition of T cell activation and clonal expansion, through targeting CTLA-4 active blocking mechanism, helps to maintain further activation and proliferation of effector T cells ultimately enhancing the tumor immune responses [6]. Unfortunately it also results in inhibition of normal physiological T cell-mediated immunosuppression, thus leading to immune related toxic effects.
Studies show multiple malignancies with PD-1 expression on its tumor-infiltrating lymphocytes. The expression of PD-L1 expression is known to inhibit the T-cell antitumor response which is a major factor for cancer progress [7] [8]. It is noticed the tumor PD-L1 expression to be directly proportional to active tumor immune microenvironment [9]. The long duration of exposure of these antigen could lead to exhaustion or anergy. The focus on the PD-1 blockade may reverse anergy of tumor-specific T cells.

Immune Check Point Inhibitors and IRAEs
Immune checkpoints active blockades, in the maintenance of self-tolerance can have a huge impact on immunological tolerance, which could eventually Figure 1. CTLA4 and PD1 pathway [14].  [12].
Commonly witnessed CTLA4 and PD-1 and PD-L1 adverse effect profiles [10] are fatigue, rash, pruritus and diarrhea. It is noticed PD1 and PDL1 have lower risk of toxicities while compared to the CTLA4. As irAEs can affect nearly every organ in association with checkpoint inhibitors, an early-onset and late-onset recognition of the toxic effects with effective mechanism of identification and management are very crucial for an optimal and efficient application of these immunotherapies [13].

Neuropathies
Despite the efficacy ICI therapy is associated with wide spectrum of im- Regarding the pathogenesis, very less is known for neurological irAEs. It is suggested that checkpoint inhibition could be caused precipitating an underlying autoimmune disorders. For example, ipilimumab can induce myasthenia gravis, disease associated with T-cell-mediated production of acetylcholine receptor antibodies [24].

Incidence of Neuropathy Associated ICIs in Patients with Cancer
Reports on the neuropathy associated with ICI therapies are not much identi-  or the reverse sequence. The result showed Nivolumab followed by ipilimumab (n = 68) a grade four demyelinating polyneuropathy among 1 patient [27]. Study processes are presented in Figure 2 and the selected study is summarized in Table 2.

Immune Related Neuropathy: Management
The   The first line corticosteroid non-responsive or partially responsive patients, alternatives such as IVIg, [20] plasmapheresis (usually 5 -6 sessions], [33] anti-TNF-alpha antibodies (e.g. infliximab], [34] mycofenolatemofetyl [35] and rituximab. [34] These intervention showed few but positive results. Hence, it could be considered according to the type and severity of irAE, although proper care, its relative risks and benefit are to be considered. The immunosuppressants such as Methotrexate and cyclophosphamide also showed efficacy in other dysimmune neurologic disorders. In treatment-refractory patients, alternative immunosuppressive agents are rarely used with toxicity basis involving other organs, proteasome inhibitors (bortezomib), calcineurin inhibitors tacrolimusor IL-17 blockers could be considered.

Discussion
With the rapid regression of tumors, checkpoint blockade has its striking with  ICI after neurological recovery is still under consideration which requires a careful analysis. We suggest further trials assessing the progress of immune disorders to be studied after recontinuing ICI would be vital with regards to its hazards.

Conclusions
With much advancement immune checkpoint inhibitors show a promising, a future perspective in the field of oncology and are increasingly being indicated for first and second line intervention. Unfortunately, there are immune associated toxicities alongside. The upregulation of T-cell activity eventually leads to immune tolerance disruption with autoimmune syndromes. Although it is noticed that irAEs are much lower with PD-1 inhibitors compared with CTLA4 inhibitors, the concern for the toxicities can be severe and cannot be ignored.
Among the toxicities, neurological-irAEs are rare but often can be severe.
Multidisciplinary approach oriented management with early bolus corticosteroids with synchronic supportive care required. However, proper recognition, evaluation and pathophysiology of ICI induced neurotoxicities are still a challenge due to difficulty in identifying biomarkers susceptible to irAEs. This heightens the complexity for optimized management for immune related ad-

Limitation
We would like to notify that our study suffered from several limitations. First the incidence of neuropathies was extracted from large clinical trials. Unfortunately, some trials were poorly characterized, with limited explorations, which could lead to mis-interpretation. Therefore, further studies for the understanding of the neuro-logical AEs especially neuropathies would help to provide optimal management.