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World Journal of Oncology

Review

Volume 14, Number 2, April 2023, pages 109-118

Neurological Adverse Effects of Immune Checkpoint Inhibitors and Chimeric Antigen Receptor T-Cell Therapy

Cancer immunotherapy is at the core of this revolution which targets the immune system of the body and local tumor niche making the tumor more susceptible to immune-mediated killing. The first evidence of targeting the immune system for cancer treatment was the use of bacillus Calmette-Guerin (BCG) vaccine for superficial bladder cancer [1]. Since then, we have gained vast knowledge about the immune system, and the advancement of technology has provided the opportunity to target different aspects of the tumor and immune system interactions for cancer treatment. Immunotherapy mainly acts through increasing the effectiveness of the immune system in recognizing the tumor-specific antigens, by suppressing the checkpoints of immune expressions, by inhibiting the immune-suppressing agents, and by increasing the immune-mediated killing. These mechanisms also act by increasing antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and induction of T-cell immunity through cross-presentation. The main target of immunotherapeutic drugs is to affect the cancer-immunity cycle leading to the generation of self-perpetuating and amplified immune targeting of tumor cells [2].

Immune checkpoint inhibitors (ICPIs) and chimeric antigen receptor (CAR) T-cells therapy are two recent immune targeting treatment strategies with very effective outcomes. Pembrolizumab, ipilimumab, nivolumab are checkpoint inhibitors approved by the Food and Drug Administration (FDA) for melanoma, lung cancer, renal cell cancer and are being investigated for other types of cancer. Checkpoint inhibitors nivolumab and pembrolizumab have been studied in classical Hodgkin lymphoma as well with good efficacy profiles [3]. These therapies have also been found to be having a good efficacy profile in terms of overall survival in patients with renal cell cancer [4]. Similarly, CAR T-cell therapy is approved for B-cell precursor acute lymphoblastic leukemia (ALL), large B-cell lymphoma including diffuse large B-cell lymphoma (DLBCL) arising from follicular lymphoma, multiple myeloma, and mantle cell lymphoma. Although these therapies have led to increased survivability of the patients but also led to incidences of immune-related side effects in around 2-3% of patients.

As ICPIs and CAR-T cell therapy have become an integral part of cancer immunotherapy, it is essential for physicians, oncologists, and neurologists to be aware of its toxic effects succinctly. In this review, we have summarized the etiology, clinical presentation, diagnostic tests, and treatment of various neurological side effects of these immunotherapeutic agents.

The immune system exerts strong selective pressure on tumor cells for survival, and tumor cells adapt by immunoediting and opting for immune tolerance and suppression [5]. Immune checkpoints are the rate-controlling steps that help immune self-tolerance by regulating the amount of immune activation and also help tumor cells in avoiding immune-mediated killing. The first concept of using immune checkpoint blockade against cancer cells was given by Leach et al in 1996, from Allison’s lab, where blockade of the inhibitory effect of cytotoxic T-lymphocyte antigen-4 (CTLA-4) by antibody led to T-cell activation that increases the immune reactivity against the cancer cells [6]. This landmark study led to the development of checkpoint inhibitors as a cancer therapy option. The current checkpoint inhibitors mainly target the two specific molecules, i.e., CTLA-4 and programmed death 1 (PD-1), which are involved with immune regulatory mechanisms and maintaining immune responses in the physiological range.

The antigen-presenting cells (APCs) capture and present tumor antigens to naive T lymphocytes in the lymph nodes. In order to activate the naive T cell, the T-cell receptor (TCR) must interact with the major histocompatibility complex (MHC) molecules on the APCs, as well as costimulatory pathways [6]. Costimulatory and inhibitory signals control the T-cell response. Immunological checkpoints are inhibitory signals that control immune responses and prevent autoimmunity. Antibodies targeting against inhibitory molecules expressed by T cells, such as CTLA-4 and PD-1, and PD-1 ligand expressed by tumor cells, are the basis [7] of ICPI therapy (Table 1) [2-4].

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Table 1. Types of Cancer Immunotherapy, Commonly Used Drugs, Target Sites and Mechanism of Action

Immune-related adverse events (irAEs) are very common with the checkpoint blockade and may be seen in around 25-90% of patients treated with ipilimumab (anti-CTLA-4 antibody), in 70% of patients treated with the PD-1 blockers - nivolumab and pembrolizumab, and around 95% in combination therapy group [8]. Most affected sites are skin, gut, and rarely affected sites are liver, endocrine, and nervous system. Neurological side effects of checkpoint inhibitors vary from simple fatigue to very rare yet complicated adverse reactions of necrotizing encephalitis [9]. Hemophagocytic lymphohistiocytosis (HLH) can also be a treatment complication from these check point inhibitors, but difficulty arises in the etiology as it has an established association with underlying malignancies as well [10].

Although the specific mechanism of ICPI causing neurological irAE is unknown, worsening of pre-existing autoimmunity and potentiation of autoimmune paraneoplastic diseases have been suggested [11]. The increased immune reactivity either acts by increasing the antibodies against the self-antigens, infiltration of clonal T cells similar to that present in tumor or increasing the cytokine level acting against the normal healthy tissue [12].

The incidence of neurological side effects varies according to the therapy used, with 3.8% in anti-CTLA-4, 6.1% in the anti-PD-1 antibodies group, and 12% in patients on combination therapy [13]. The symptoms generally occur within 6 - 12 weeks of starting the ICPI but sometimes may occur immediately after starting the medication or months after discontinuation of ICPI. These side effects were related to the effect of ICPI efficacy and had some relation to anti-PD-1 doses as well [14]. Neurological symptoms are highly heterogenous and vary from grade 1 - 2 adverse effects like headache, fatigue, dysgeusia, dizziness to grade 3 - 4 symptoms, and sometimes even death of the patient. The more complex grade 3 - 4 neurologic adverse events can affect the central nervous system, i.e., hypophysitis, encephalitis, aseptic meningitis, or the peripheral nervous system, i.e., acute demyelinating polyneuropathy, myasthenia gravis (MG), and necrotizing myositis. The Common Terminology Criteria for Adverse Events (CTCAE) rates the severity of irAEs based on clinical severity, ranging from grade 1 with minimal symptoms, grade 2 with moderate symptoms, to grade 3/4 with life-threatening symptoms [15]. Hence, this severity grading can be used to guide management (Table 2) [7, 8, 10, 16-18].

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Table 2. Neurological Side Effects of Cancer Immunotherapy

Antibodies targeting neuromuscular junction or muscle-specific tyrosine kinases cause MG, a B cell-mediated autoimmune disease. ICPI therapy was linked to MG in a case series, with antibodies to acetylcholine receptors being found in around 60% of individuals. The majority of these cases had new-onset MG, and there were fewer cases of disease exacerbation. Pembrolizumab-related MG, for example, had 70% de novo instances, nivolumab had 57.1%, and ipilimumab had 100% de novo cases of all patients [19]. The myasthenic syndrome can present, ranging from ocular symptoms such as ptosis and diplopia to generalized weakness, dyspnea, and dysphagia. Patients should undergo electromyography (EMG) testing for acetylcholine receptor and muscle kinase-specific antibodies. The onset of MG varied between 4.5 and 6 weeks or more on average. The mortality rates can be varied based on the type of immunotherapy used [19]. These patients require early and intensive monitoring due to their severe clinical presentation and rapid decline, which frequently necessitates intensive care unit (ICU) admission. Early treatment with high-dose corticosteroids is recommended, which is especially beneficial when myositis occurs concurrently. Plasma exchange and intravenous immunoglobulin (IVIG) are also used in treatment to escalate therapy [9]. As with other adverse effects, it would be prudent to discontinue the ICPI therapy.

ICPI-induced myositis might be part of an overlapping condition that includes MG and acute inflammatory demyelinating polyneuropathy (AIDP) [9]. Myositis was the most common adverse event reported in a large case series of ICPI-induced neuromuscular side effects. It usually presents with muscle pain and gradual weakening, affecting primarily the proximal limbs [16]. Predominant lymphocytic infiltrates were seen in the histopathology review, with some reports indicating predominating CD4⁺ endomysial lymphocytic infiltrates and others indicating predominating CD8⁺ cells [20]. A creatine kinase (CK) levels, EMG, and myositis antibody panel constitute the workup [7]. It is associated with high levels of CK. Autoantibodies associated with myositis are often negative; however, anti-PL-7, anti-PL-12, anti-SRP, and anti-Ro antibodies have been reported. As a result, early detection and treatment with immunosuppressants are critical [16].

ICPI therapy has been linked to immune-mediated neuropathy such as AIDP and chronic inflammatory demyelinating polyneuropathy (CIDP) [9]. It has a wide range of clinical manifestations that impair the motor, sensory, or autonomic nervous system. Multiple cranial nerves can be affected, with the facial vestibulocochlear, and optic nerves being the most commonly affected [7]. It is also linked to polyradiculopathies, also known as Guillain-Barre syndrome (GBS)-like syndrome, which causes motor and sensory impairments, affecting the extremities. Nerve conduction studies and EMG are vital to differentiate it from cancer-induced neuropathies. In an article by Thaipisu et al, CIDP was shown to be linked to a high level of cerebrospinal fluid (CSF) protein. In this case, the symptoms began 1 month after CPI therapy and progressed over the next 2 months which did not respond to steroids, IVIG, and infliximab, but were later alleviated with tacrolimus [21].

Hypophysitis can affect up to 10% of the patient receiving anti-CTLA-4 antibodies and maybe because of expression of CTLA-4 on pituitary cells, which causes antibody formation, complement deposition, and mononuclear cell infiltration in the pituitary [17]. Patients using anti-PD1/programmed death-ligand 1 (PD-L1) therapy are far less likely to develop this condition. It typically manifests as headaches, neck pain, visual abnormalities, vertigo, and weakness [11]. However, the pituitary’s actions on the adrenal cortex, thyroid, and other organs/glands can cause a wide range of symptoms. If a diagnosis is suspected, hormone levels from the pituitary, thyroid, adrenal, and gonadal glands should be tested. A brain magnetic resonance imaging (MRI) can confirm the diagnosis [22]. Only one hormonal axis may have been affected in some circumstances, while others remain unaffected. Symptoms usually develop 6 weeks after starting therapy; however, symptom remission can take up to 20 weeks and is linked to permanent pituitary dysfunction [23]. Management differs on the basis of grade of toxicity. We may or may not hold off the ICPI therapy in grade I or II toxicity. However, it becomes imperative to hold off on the ICPI therapy in cases of higher grades of toxicity (grade III or IV) until the patient is stabilized on hormone replacement. Corticosteroid therapy should be initiated prior to hormone replacement therapy to treat this condition [18].

Aseptic meningitis and encephalitis have a very low incidence of 0.1-0.2% in patients receiving ICPI with symptoms varying widely in both conditions. Fever, headaches, and neck stiffness are some of the common symptoms of aseptic meningitis [11]. It may co-occur with encephalitis and infectious studies usually come up negative, with lymphocytosis and high opening pressure seen in a CSF analysis. MRI may show diffuse leptomeningeal enhancement. The treatment is high-dose steroids which have shown a good response [9].

The median onset of the presentation of encephalitis was around 55.5 days in a large database analysis. Confusion, aphasia, agitation, altered mental status, and psychiatric symptoms are common signs and symptoms [15]. T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities can be seen on MRI; however, normal findings do not rule out the diagnosis. Many cases of encephalitis were related to paraneoplastic antibodies, including N-methyl-D-aspartate receptor antibodies and contactin-associated protein-like 2 or anti-Hu antibodies; and tests for these antibodies must be conducted in patients suspected of autoimmune encephalitis after ICPI. However, the absence of antibodies does not exclude the diagnosis. Early detection and intervention may increase the likelihood of resolution. The research also revealed that stopping ICPI treatment was linked to better patient outcomes [15]. Patients with a suspected infectious etiology are frequently treated empirically with antibiotics and antiviral treatment until the etiology is ruled out. The majority of patients were treated with intravenous (IV) steroids, and half of them required IVIG due to deteriorating symptoms, according to a review of six cases of CPI-induced encephalitis.

Both aseptic meningitis and encephalitis are graded as mild, when symptoms are not interfering with activities of daily living (ADLs); moderate, when ADLs are moderately compromised, or any cranial nerve is involved and severe when it warrants aid because of limited ability for self-care. Regardless of the severity of symptoms, ICPI should be held and resumed only upon shared decision making with the patient, who understands the risks and benefits of the therapy.

Mild-moderate aseptic meningitis should be empirically treated with IV antivirals (acyclovir) and IV antibacterial therapy until CSF results are negative for infection. The patients may be monitored off antimicrobials thereafter. Oral or IV steroids may be considered for moderate-severe symptoms. For the treatment of mild-moderate encephalitis, patients should empirically receive IV acyclovir, until polymerase chain reaction (PCR) for herpes simplex virus (HSV) is negative along with a trial of methylprednisolone 1 - 2 mg/kg. Symptoms progressing to the severe grade treatment with pulse steroids methylprednisolone 1 g daily for 3 - 5 days along with IVIG 2 g/kg over 5 days may be considered.

Transverse myelitis has also been reported as a side effect of ICPI. This case responded well with treatment with steroids along with discontinuation of ICPI treatment [22]. ICPI therapy has also been linked to multiple sclerosis (MS), which is characterized by demyelinating lesions in the brain and myelin and possible optic nerve involvement [11]. It can lead to MS exacerbation as well as de novo cases. Also, ICPI treatment can also lead to de novo vasculitis [9]. In a systemic review, 20 pathologically confirmed central and peripheral nervous system vasculitis cases were found out of 53 probable cases, with the majority involving medium or large vessels [24] (Table 3) [10, 25-27].

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Table 3. General Investigations and Management of Immune-Related Adverse Events (irAEs)

Immunotherapy, with CAR-expressing T cells has been a major advancement in the management of hematologic malignancies. Autologous or allogeneic T-cells are genetically modified to express a CAR that consists of an extracellular domain that binds to target molecule on tumor cells, a transmembrane domain, and an intracellular domain that signals T-cells activation [28]. This intrinsic activation mechanism makes T-cell activation independent of the need for MHC-epitope presentation [29].

CAR T-cell therapy has shown excellent response rates of 50-80% in refractory B-cell lymphoma [30], and 65-90% in ALL [31]. Currently, there are six FDA-approved CAR T-cell products, tisagenlecleucel used for relapsed/refractory B-cell precursor ALL or large B-cell lymphoma, axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma including DLBCL arising from follicular lymphoma, lisocabtagene marualeucel for relapsed/refractory large B-cell lymphoma, brexucabtagene autoleucel for relapsed/refractory mantle cell lymphoma and recently for relapsed/refractory B-cell precursor ALL, and idecabtagene vicleucel and ciltacabtagene autoleucel for relapsed/refractory multiple myeloma (Table 1) [2-4].

A widely observed toxic effect of CAR T-cell therapy is cytokine release syndrome (CRS), which occurs due to activation of the innate immune system [32]. CRS presents with fever, with or without signs of hemodynamic instability such as hypotension, hypoxemia, tachypnea, and tachycardia [33]. Tocilizumab, anti-interleukin-6 (IL-6) receptor antibody has shown an excellent response in CRS management by mitigating downstream effects of IL-6, which is central to CRS pathophysiology [34].

Apart from CRS, another common adverse effect of CAR T-cell therapy is its neurotoxicity. Initially known as (CAR T-cell related encephalopathy syndrome (CRES), the neurotoxic effects of CAR T-cells are now largely categorized as immune effector cell-associated neurotoxicity syndrome (ICANS). ICANS represents a wider term including neurotoxic effects of other cell therapies and targeted antibodies [35]. In addition to ICANS, other neurologic complications like progressive movement and neurocognitive treatment-emergent adverse events [36], multifocal leukoencephalopathy, posterior reversible encephalopathy syndrome (PRES), and intracranial hemorrhage can also occur after CAR T-cell therapy [37]. It is essential to optimally investigate and manage ICANS, which is a potentially fatal condition.

The incidence of neurotoxicity was found to be 48% in a study of 100 cancer patients being treated with CAR T-cell therapy [25]. Incidence varies depending on the specific CAR T-cell therapy product and underlying disease being treated. For instance, the use of a humanized or murine single-chain variable fragment (scFv), the use of hinge and transmembrane domains derived from either the CD28 or the CD8α molecule, and the use of CD28 costimulatory moieties have been implicated with the occurrence of ICANS [38]. Also, as compared to CAR T-cells targeting CD-19 tumors, a lower incidence of ICANS has been noted for non-CD-19 CAR T-cells targeting hematologic malignancies [26].

In phase I/II clinical trial of ALL patients treated with JCAR014, severe ICANS was associated with several independent factors such as cyclophosphamide and fludarabine lymphodepletion, bone marrow disease burden, and pre-existing neurologic comorbidity. Several clinical indicators, such as high serum IL-6, fever, high monocyte chemoattractant protein-1 (MCP-1) in the first 36-h post-infusion have been associated with grade 4 or higher neurotoxicity with 100% sensitivity and 97% specificity [39]. Other factors such as higher levels of serum C-reactive protein (CRP), various serum cytokines, and CRS symptoms such as fever after beginning CAR T-cell therapy, have also been considered as predictors of ICANS occurrence. In a recent study, patients with clonal hematopoiesis of DNMT3A, TET2, and ASXL1 genes were related to higher incidence of ICANS compared to clonal hematopoiesis negative patients [40].

Pathogenesis of ICANS is not completely understood and there has not been any clear association with imaging or CSF abnormalities. Several studies have considered it to be a result of systemic inflammation which leads to endothelial disruption, consumptive coagulopathy, and a breach in the blood-brain barrier (BBB) [34]. In patients with ICANS, CSF cytokine levels were higher than expected and comparable to the serum cytokine levels, supporting the breach in the BBB as a plausible mechanism [41]. High concentration of IL-6, interferon (IFN)-γ, tumor necrosis factor (TNF)-α along with CAR T-cells are also found inside the CSF. Those high levels of inflammatory cytokines induce endothelial cell activation, resulting in release of angiopoietin-2 (Ang-2) and von Willebrand factor (VWF) from endothelial Weibel-Palade bodies, and the released VWF binds activated endothelium and sequesters platelets. [39]. Increased permeability of the BBB due to the endothelium activation allows a higher concentration of serum cytokines to transit into CSF, including IFN-γ and TNF-α, initiating a feed-forward loop of continued endothelial cell and pericyte activation. This feed-forward loop can cause breakdown of the parenchymal basement membrane and vascular disruption, with cerebral edema, hemorrhage, infarction, and necrosis, and neuronal death. Along with the passage of cytokines, this BBB breach can also lead to the passage of lymphocytes into CNS, as suggested by lymphocyte infiltrates seen in some brain autopsies of ICANS patients [42]. In phase I/II clinical trial of ALL patients treated with JCAR014, endothelial activation, parenchymal necrosis, and microhemorrhages were seen in brain autopsies of patients who developed cerebral edema [43]. Also, high serum ferritin levels have been observed in ICANS, supporting the role of macrophage activation [44].

ICANS can present early simultaneously with CRS, after CRS resolution, or rarely without associated CRS. Although classically, ICANS is thought to present as encephalopathy with preserved alertness, clinical manifestations can be vague and variable in severity [41]. Early symptoms can be mild such as tremors, headache, lethargy, and mild impairment of attention, memory [25]. Mild visual symptoms, mimicking migraine, can also be seen. Language difficulties are very specific to ICANS and are often recognized as the most common sign of severe neurotoxicity. In a phase I trial of CAR T-cell therapy, expressive dysphagia was the first symptom of ICANS in 86% of severely affected patients [41].

Severe symptoms can involve encephalopathy, tremors, agitation, and seizures [32]. Encephalopathy can have waxing and waning symptoms, with or without impulsivity and emotional lability. Patients can also have myoclonus, ataxia, and meningismus [27]. The most devastating complication is cerebral toxicity leading to cerebral edema which could be fatal. However, it has not been a significant feature in multiple major CD-19 CAR T-cell studies. Interestingly, some cases can mimic stroke with focal neurologic deficits like weakness [41] (Table 2) [7, 8, 10, 16-18].

As the symptoms of ICANS are highly nonspecific and mimic other conditions, the diagnostic tests ordered are aimed at ruling out isolated or coexisting conditions such as infections, drug toxicity/induced, neurologic invasion of the primary malignancy, or disease relapse. A full neurological exam including fundoscopy should be done. Workup includes neuroimaging with MRI brain or a computed tomography (CT) scan of the head. An MRI can show white matter hyperintensities, vasogenic edema, microhemorrhages, however it can often be normal even with high-grade ICANS [25].

Further testing with CSF analysis should be carried out if there are no contraindications, which can show elevated protein and mild pleocytosis. Electroencephalography (EEG) can be done in patients suspected to have seizures or nonconvulsive status epilepticus [32]. EEG [28] most commonly shows diffuse or focal slowing, frontal intermittent rhythmic delta activity (Table 3) [10, 25-27].

Although there is no definite guideline for the time to begin CAR T-cell toxicity management, earlier administration of tocilizumab has been shown to reduce the incidence of severe CRS in patients on CTL019 therapy [45]. Performing a neurologic assessment prior to starting CAR T-cell therapy and for 10 days post-infusion is highly recommended. After 10 days, the patient can be transitioned to ambulatory care provided they remain within 1 h of a treatment center for the initial 28 days post-treatment.

Since the development of CAR T-cell therapy, several scoring guidelines have been developed to grade CAR T-cell toxicity. In 2018, CAR T-cell therapy-associated-TOXicity (CARTOX) Working Group provided recommendations for assessment of CAR T-cell-associated neurotoxicity, then known as CRES [28]. In 2019, the American Society for Transplant and Cellular Therapy (ASTCT) group coined the term ICANS and published a modified ICANS grading system [46]. Widely used today, the ICANS grading system is based on assigning a score between 1 to 4 based on these five variables: immune effector cell-associated encephalopathy (ICE) score, level of consciousness, seizure activity, motor activity, and elevation of intracranial pressure (ICP). The ICE score, in turn, analyses orientation, attention, writing, naming, and ability to follow commands [46].

Grade 1 ICANS should be managed supportively. For grade 2 or higher, the mainstay of treatment is corticosteroids, either dexamethasone or methylprednisolone. For grade 3 or more, closer monitoring in ICU is recommended for patients with grade 3 or higher ICANS [32]. For patients with a high risk of ICANS, antiepileptics such as levetiracetam can be given for seizure prophylaxis prior to starting CAR T-cell infusion. For patients who develop seizures, levetiracetam has been widely used as a treatment of choice [26]. Raised ICP can be managed supportively such as by using ICP monitors and hyperosmolar therapies [47].

When concurrent with CRS or in early disease, tocilizumab has been efficacious in treating ICANS. As tocilizumab binds to IL-6 receptors, it can paradoxically elevate IL-6 levels in the CNS and potentially worsen ICANS [26]. Unlike tocilizumab, siltuximab directly binds IL-6 directly (while tocilizumab binds the IL-6 receptors) and can be used; however, no direct comparative studies on their individual efficacy have been done. Anakinra, an IL-1 receptor antagonist can play a role in the management of refractory ICANS or HLH in patients treated with axicabtagene ciloleucel [48]. Similarly, there are limited data on the use of IVIG. Another approach is directed at tuning CAR T-cells itself, such as designing inbuilt mechanisms to turn it off in case of severe toxicity [49].

A vast majority of ICANS cases resolve within 3 - 8 weeks [25]. Up to 10% of patients have ongoing symptoms after developing acute ICANS [50]. Long-term sequelae, such as impaired memory and epilepsy have been noted [51].

ICPIs and CAR T-cell therapies have revolutionized the cancer treatments by enhancing the immune response against cancer cells yet there is a significant restriction in patients who have underlying suppression of immune system as these patients are unable to mount a strong immune reaction against the cancer cells. This poses a significant challenge in clinical decision making by the oncologist in cancer treatment. These challenging conditions include patients with underlying autoimmune conditions, received solid organ or hematological stem cell transplant, chronic viral infections such as human immunodeficiency virus (HIV), hepatitis B and C, and those receiving chronic immunosuppression with high-dose steroids and immunosuppressant. A retrospective study reviewed 30 patients with advanced melanoma with underlying autoimmune conditions including rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus who were treated with ipilimumab. Twenty-seven percent of the patients experienced worsening of autoimmune condition requiring steroid administration [52]. A phase Ib trial evaluated efficacy and safety of ipilimumab in 28 patients with hematological stem cell transplant; 14% of the patients experienced graft-vs-host disease (GVHD) and 21% had irAEs [53]. In the past patients having a chronic viral infection was a near exclusion criteria in immunotherapy trials. Recently, there have been trials evaluating the safety profile of these check point inhibitors in HIV and hepatitis patients. In immunosuppressed patients receiving high-dose steroids or disease-modifying agents for autoimmune diseases, anti PD-1 therapies have been found to be associated with a lower response rate of 15% vs. 44% in patients without immunosuppressant [54]. Therefore, immunotherapy in these patients needs a special consideration and a patient-directed treatment with considering the side effects has to be well thought before starting these therapies.

Recent advances in cancer immunotherapy, especially ICPI and CAR T-cell therapy have shown excellent therapeutic benefits and resulted in increased patient survival rates. However, their use can sometimes be limited due to the accompanying toxicity profile. Both ICPI and CAR T-cell therapy are associated with several neurotoxic effects, most of which are usually manageable if caught early and treated with corticosteroids and other immunosuppressive drugs as needed. However, immunosuppressant use can potentially decrease therapeutic efficacy of these drugs and some cases can be severe and life-threatening. Hence, it is critical to be watchful and have multidisciplinary management of neurological problems.

Acknowledgments

The authors are grateful to the Internal Medicine Department and Hematology Oncology for their continuous support for the research endeavors.

Financial Disclosure

No funding was received from any source for this article.

Conflict of Interest

There is no conflict of interest of any author in this manuscript.

Author Contributions

Farhan Khalid wrote the introduction and did the literature search. Rajshree Gupta wrote the background of ICPIs. Rajvi Gor wrote the neurological manifestations of the ICPIs. Dairya Gor wrote the background of CAR T-cell therapy. Vinit Singh wrote the neurological toxicity of CAR T-cell therapy. Hussam Eltoukhy was the mentor for the study and helped in the final editing of the manuscript.

Data Availability

This review has focused the literature available on the PubMed and clinical trials. The authors declare that data supporting the findings of this study are available within the article.

Abbreviations

ICPI: immune checkpoint inhibitors; CAR: chimeric antigen receptor; irAEs: immune-related adverse events; ALL: acute lymphoblastic leukemia; DLBCL: diffuse large B-cell lymphoma; CTLA-4: cytotoxic T-lymphocyte antigen-4; PD-1: programmed death 1; APCs: antigen-presenting cells; TCR: T-cell receptor; MHC: major histocompatibility complex; CTCAE: Common Terminology Criteria for Adverse Events; MG: myasthenia gravis; EMG: electromyography; ICU: intensive care unit; IVIG: intravenous immunoglobulin; AIDP: acute inflammatory demyelinating polyneuropathy; CIDP: chronic inflammatory demyelinating polyneuropathy; GBS: Guillain-Barre syndrome; MS: multiple sclerosis; ADL: activities of daily living; CRS: cytokine release syndrome; CRES: CAR T cell-related encephalopathy syndrome; ICANS: immune effector cell-associated neurotoxicity syndrome; PRES: posterior reversible encephalopathy syndrome; scFv: single-chain variable fragment; MCP-1: monocyte chemoattractant protein-1; CSF: cerebral spinal fluid; CARTOX: CAR-T-cell therapy-associated-toxicity; ASTCT: American Society for Transplant and Cellular Therapy; ICE: immune effector cell-associated encephalopathy; HLH: hemophagocytic lymphohistiocytosis; BCMA: B-cell maturation antigen; IFN: interferon; TNF: tumor necrosis factor; EEG: electroencephalography; GVHD: graft-vs-host disease

1. Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976;116(2):180-183.
   doi pubmed
2. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1-10.
   doi pubmed
3. Tarekegn K, Colon Ramos A, Singh B, Sequeira Gross HG, Gupta S. Checkpoint inhibitors in relapsed/refractory classical Hodgkin lymphoma. World J Oncol. 2021;12(4):81-84.
   doi pubmed pmc
4. Aly R, Aujla AS, Gupta S, Gupta R, Gupta S, Kalathil S. Evolving paradigms in the management and outcomes of sarcomatoid renal cell carcinoma in the Era of immune checkpoint inhibitors. World J Oncol. 2020;11(5):183-187.
   doi pubmed pmc
5. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol. 2004;22:329-360.
   doi pubmed
6. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271(5256):1734-1736.
   doi pubmed
7. Valencia-Sanchez C, Zekeridou A. Paraneoplastic neurological syndromes and beyond emerging with the introduction of immune checkpoint inhibitor cancer immunotherapy. Front Neurol. 2021;12:642800.
   doi pubmed pmc
8. Sznol M, Postow MA, Davies MJ, Pavlick AC, Plimack ER, Shaheen M, Veloski C, et al. Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management. Cancer Treat Rev. 2017;58:70-76.
   doi pubmed
9. Harrison RA, Tummala S, de Groot J. Neurologic toxicities of cancer immunotherapies: a review. Curr Neurol Neurosci Rep. 2020;20(7):27.
   doi pubmed
10. Rajapakse P, Andanamala H. Hemophagocytic Lymphohistiocytosis Secondary to Immune Checkpoint Inhibitor Therapy. World J Oncol. 2022;13(2):49-52.
    doi pubmed pmc
11. Roth P, Winklhofer S, Muller AMS, Dummer R, Mair MJ, Gramatzki D, Le Rhun E, et al. Neurological complications of cancer immunotherapy. Cancer Treat Rev. 2021;97:102189.
    doi pubmed
12. Osorio JC, Ni A, Chaft JE, Pollina R, Kasler MK, Stephens D, Rodriguez C, et al. Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. Ann Oncol. 2017;28(3):583-589.
    doi pubmed pmc
13. Cuzzubbo S, Javeri F, Tissier M, Roumi A, Barlog C, Doridam J, Lebbe C, et al. Neurological adverse events associated with immune checkpoint inhibitors: Review of the literature. Eur J Cancer. 2017;73:1-8.
    doi pubmed
14. Williams TJ, Benavides DR, Patrice KA, Dalmau JO, de Avila AL, Le DT, Lipson EJ, et al. Association of autoimmune encephalitis with combined immune checkpoint inhibitor treatment for metastatic cancer. JAMA Neurol. 2016;73(8):928-933.
    doi pubmed
15. Larkin J, Chmielowski B, Lao CD, Hodi FS, Sharfman W, Weber J, Suijkerbuijk KPM, et al. Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis. Oncologist. 2017;22(6):709-718.
    doi pubmed pmc
16. Moreira A, Loquai C, Pfohler C, Kahler KC, Knauss S, Heppt MV, Gutzmer R, et al. Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors. Eur J Cancer. 2019;106:12-23.
    doi pubmed
17. Iwama S, De Remigis A, Callahan MK, Slovin SF, Wolchok JD, Caturegli P. Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci Transl Med. 2014;6(230):230ra245.
    doi pubmed
18. Blansfield JA, Beck KE, Tran K, Yang JC, Hughes MS, Kammula US, Royal RE, et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother. 2005;28(6):593-598.
    doi pubmed pmc
19. Makarious D, Horwood K, Coward JIG. Myasthenia gravis: An emerging toxicity of immune checkpoint inhibitors. Eur J Cancer. 2017;82:128-136.
    doi pubmed
20. Suzuki S, Ishikawa N, Konoeda F, Seki N, Fukushima S, Takahashi K, Uhara H, et al. Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan. Neurology. 2017;89(11):1127-1134.
    doi pubmed
21. Thaipisuttikul I, Chapman P, Avila EK. Peripheral neuropathy associated with ipilimumab: a report of 2 cases. J Immunother. 2015;38(2):77-79.
    doi pubmed pmc
22. Bolz S, Ramakrishnan T, Fleischer M, Livingstone E, Stolte B, Thimm A, Kizina K, et al. Detect it so you can treat it: A case series and proposed checklist to detect neurotoxicity in checkpoint therapy. eNeurologicalSci. 2021;22:100324.
    doi pubmed pmc
23. Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691-2697.
    doi pubmed
24. Daxini A, Cronin K, Sreih AG. Vasculitis associated with immune checkpoint inhibitors-a systematic review. Clin Rheumatol. 2018;37(9):2579-2584.
    doi pubmed
25. Rubin DB, Danish HH, Ali AB, Li K, LaRose S, Monk AD, Cote DJ, et al. Neurological toxicities associated with chimeric antigen receptor T-cell therapy. Brain. 2019;142(5):1334-1348.
    doi pubmed
26. Gust J, Finney OC, Li D, Brakke HM, Hicks RM, Futrell RB, Gamble DN, et al. Glial injury in neurotoxicity after pediatric CD19-directed chimeric antigen receptor T cell therapy. Ann Neurol. 2019;86(1):42-54.
    doi pubmed pmc
27. Vitale C, Strati P. CAR T-cell therapy for B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia: clinical trials and real-world experiences. Front Oncol. 2020;10:849.
    doi pubmed pmc
28. Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, Komanduri KV, et al. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47-62.
    doi pubmed pmc
29. Tallantyre EC, Evans NA, Parry-Jones J, Morgan MPG, Jones CH, Ingram W. Neurological updates: neurological complications of CAR-T therapy. J Neurol. 2021;268(4):1544-1554.
    doi pubmed pmc
30. Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, Lin Y, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31-42.
    doi pubmed pmc
31. Frey NV. Chimeric antigen receptor T cells for acute lymphoblastic leukemia. Am J Hematol. 2019;94(S1):S24-S27.
    doi pubmed
32. Neill L, Rees J, Roddie C. Neurotoxicity-CAR T-cell therapy: what the neurologist needs to know. Pract Neurol. 2020;20(4):285-293.
    doi pubmed
33. Curran KJ, Margossian SP, Kernan NA, Silverman LB, Williams DA, Shukla N, Kobos R, et al. Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL. Blood. 2019;134(26):2361-2368.
    doi pubmed pmc
34. Brudno JN, Kochenderfer JN. Recent advances in CAR T-cell toxicity: Mechanisms, manifestations and management. Blood Rev. 2019;34:45-55.
    doi pubmed pmc
35. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, Chau I, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36(17):1714-1768.
    doi pubmed pmc
36. Cohen AD, Parekh S, Santomasso BD, Gallego Perez-Larraya J, van de Donk N, Arnulf B, Mateos MV, et al. Incidence and management of CAR-T neurotoxicity in patients with multiple myeloma treated with ciltacabtagene autoleucel in CARTITUDE studies. Blood Cancer J. 2022;12(2):32.
    doi pubmed pmc
37. Sdrimas K, Diaz-Paez M, Camargo JF, Lekakis LJ. Progressive multifocal leukoencephalopathy after CAR T therapy. Int J Hematol. 2020;112(1):118-121.
    doi pubmed
38. Cao JX, Wang H, Gao WJ, You J, Wu LH, Wang ZX. The incidence of cytokine release syndrome and neurotoxicity of CD19 chimeric antigen receptor-T cell therapy in the patient with acute lymphoblastic leukemia and lymphoma. Cytotherapy. 2020;22(4):214-226.
    doi pubmed
39. Gust J, Hay KA, Hanafi LA, Li D, Myerson D, Gonzalez-Cuyar LF, Yeung C, et al. Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov. 2017;7(12):1404-1419.
    doi pubmed pmc
40. Saini NY, Swoboda DM, Greenbaum U, Ma J, Patel RD, Devashish K, Das K, et al. Clonal hematopoiesis is associated with increased risk of severe neurotoxicity in axicabtagene ciloleucel therapy of large B-cell lymphoma. Blood Cancer Discov. 2022;3(5):385-393.
    doi pubmed pmc
41. Santomasso BD, Park JH, Salloum D, Riviere I, Flynn J, Mead E, Halton E, et al. Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discov. 2018;8(8):958-971.
    doi pubmed pmc
42. Taraseviciute A, Tkachev V, Ponce R, Turtle CJ, Snyder JM, Liggitt HD, Myerson D, et al. Chimeric antigen receptor T cell-mediated neurotoxicity in nonhuman primates. Cancer Discov. 2018;8(6):750-763.
    doi pubmed pmc
43. Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N, Pequignot E, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016;6(6):664-679.
    doi pubmed pmc
44. Rosario C, Zandman-Goddard G, Meyron-Holtz EG, D'Cruz DP, Shoenfeld Y. The hyperferritinemic syndrome: macrophage activation syndrome, Still's disease, septic shock and catastrophic antiphospholipid syndrome. BMC Med. 2013;11:185.
    doi pubmed pmc
45. Kadauke S, Maude S, Gladney W, Motley L, Shenoy V, Callahan C, et al. Early administration of tocilizumab (Toci) for the prevention of grade 4 cytokine release syndrome (CRS) after CD19-directed CAR T-cell therapy (CTL019). Cytotherapy. 2019;21(5):e2-e3
46. Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625-638.
    doi pubmed
47. Yakoub-Agha I, Chabannon C, Bader P, Basak GW, Bonig H, Ciceri F, Corbacioglu S, et al. Management of adults and children undergoing chimeric antigen receptor T-cell therapy: best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE). Haematologica. 2020;105(2):297-316.
    doi pubmed pmc
48. Strati P, Ahmed S, Kebriaei P, Nastoupil LJ, Claussen CM, Watson G, Horowitz SB, et al. Clinical efficacy of anakinra to mitigate CAR T-cell therapy-associated toxicity in large B-cell lymphoma. Blood Adv. 2020;4(13):3123-3127.
    doi pubmed pmc
49. Philip B, Kokalaki E, Mekkaoui L, Thomas S, Straathof K, Flutter B, Marin V, et al. A highly compact epitope-based marker/suicide gene for easier and safer T-cell therapy. Blood. 2014;124(8):1277-1287.
    doi pubmed
50. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439-448.
    doi pubmed pmc
51. Papadouli I, Mueller-Berghaus J, Beuneu C, Ali S, Hofner B, Petavy F, Tzogani K, et al. EMA review of Axicabtagene Ciloleucel (Yescarta) for the treatment of diffuse large B-cell lymphoma. Oncologist. 2020;25(10):894-902.
    doi pubmed pmc
52. Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, Hicks M, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375(18):1749-1755.
    doi pubmed pmc
53. Davids MS, Kim HT, Bachireddy P, Costello C, Liguori R, Savell A, Lukez AP, et al. Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med. 2016;375(2):143-153.
    doi pubmed pmc
54. Menzies AM, Johnson DB, Ramanujam S, Atkinson VG, Wong ANM, Park JJ, McQuade JL, et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol. 2017;28(2):368-376.
    doi pubmed

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