Introduction
Cancer immunotherapy has a rich history. In the late 19th century, William Coley treated sarcoma patients with intratumoral bacteria and bacterial products and demonstrated tumor shrinkage. Over the years, we have added significantly to the “immunological armament” against cancer. In the past two decades, there has been an explosion of immunotherapies which have brought this field to the forefront of oncology. These new agents activate the immune system against cancers but, in the process, create a new set of toxicities including adverse events in both the central and the peripheral nervous systems. In this chapter, we will discuss the major immunological agents, their mechanisms of action, mechanisms of action as pertaining to their neurological toxicities, and major reported neurotoxicities. We will further describe the management of these toxicities.
Agents
INTERLEUKIN
Interleukin 2 (IL-2) has been extensively studied in metastatic melanoma and renal cell carcinoma (RCC). High dose IL-2 (HDIL-2) has been used as monotherapy for metastatic melanoma (MM) and metastatic renal cell carcinoma (mRCC) with objective response rates of 14% to 18% for mRCC and 15% to 16% for MM with few patients showing durable responses of over 10 years.
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.
INTERFERON
Interferon (INF)-α2b has been extensively used as an adjuvant therapy in patients with melanoma. It was also approved for use in RCC, chronic myelogenous leukemia, Kaposi’s sarcoma, and follicular lymphoma. With the advent of better drugs, however, it is no longer commonly used.
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.
IMMUNE CHECKPOINT INHIBITORS
In recent years, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer and have shown efficacy in multiple tumors. The US Food and Drug Administration (FDA) has approved multiple ICIs for various indications. Ipilimumab, a fully humanized immunoglobulin (Ig) G1 monoclonal antibody (mAb) that binds to cytotoxic T cell lymphocyte antigen-4 (CTLA-4), was the first anti-CTLA-4 antibody to be approved for use in melanoma. Tremelimumab is a human IgG2 mAb that also binds CTLA-4. It has been studied in malignant mesothelioma, although a recent phase 2 trial did not show any difference in overall survival when compared with placebo.
■Anti–programmed death-1 (PD-1) antibodies are another group of ICIs. Nivolumab and pembrolizumab are both fully humanized IgG4 antibodies that bind PD-1. They have been FDA–approved for used in melanoma, non–small-cell lung cancer (NSCLC), urothelial carcinoma, head and neck squamous cell cancer, and classic Hodgkin’s lymphoma. Apart from the above indications, pembrolizumab is approved for used in gastric cancer and solid tumors with high microsatellite instability (MSI) and mismatch repair deficiency, whereas nivolumab is approved for use in RCC, colorectal cancer with high MSI, and hepatocellular carcinoma. Cemipilimab, in another anti-PD-1 antibody which has shown activity in patient with advanced cutaneous squamous cell carcinoma, and has been approved for use by the FDA.
■Anti–program death ligand-1 (PD-L1) antibodies also block the PD-1 pathway. Three drugs from this group have been FDA–approved for use. Atezolizumab has been approved for use in NSCLC and urothelial cancer, avelumab has been approved for use in Merkel cell carcinoma and urothelial carcinoma, and durvalumab has been approved for use in urothelial cancer. Anti-PDL1 agents have also shown survival benefit as maintenance therapy in SCLC (atezolizumab and durvalumab), NSCLC (durvalumab) and urothelial carcinoma (avelumab).
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. ,
CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY
Novartis’s CTL019 (tisagenlecleucel) and Kite’s KTE-C19 (axicabtagene ciloleucel) have been approved by the FDA for use in relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) and large B cell lymphoma (BCL) patients who have relapsed after two lines of therapy, respectively. , Several trials have also looked at the use of chimeric antigen receptor (CAR) T cells in solid tumors with disappointing results due to differing antigen densities on the tumor, presence of tumor antigens on normal tissues leading to cross reactivity, and the immunosuppressive tumor microenvironment.
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. ,
ONCOLYTIC VIRUSES
Intralesional talimogene laherparepavec (T-VEC) is the first oncolytic virus to be FDA–approved for use as local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrence after surgery. This approval was based on a phase III trial which showed a greater than 50% decrease in 64% of the injected lesions and in un-injected lesions (34% nonvisceral and 15% visceral), and improvement in durable response rates compared with GM-CSF, although no difference was seen in the overall survival. , T-VEC has also been studied in combination with ICIs and has shown promising results in early phase trials. ,
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.
Mechanism of Neurotoxicity
The mechanism of neurotoxicity associated with oncolytic viruses is not known.
Reported Neurotoxicities
In a phase III trial, fatigue was the most common toxicity and was reported in about 50% of patients. Most of these were low grade with grade 3 or higher toxicity reported in only 2% of patients. Any grade headache was reported in about 19% of patients with 0.7% reporting grade 3 or higher. Other common toxicities include influenza-like illness, injection site pain, chills, nausea, vomiting, nausea, and pyrexia.
BISPECIFIC T CELL ENGAGERS
Bispecific T cell engagers (BiTEs) are a form of immunological agents called bispecific antibodies which have two unique antigen binding sites. Blinatumomab was the first BiTE to be FDA–approved and is currently approved for relapsed/refractory precursor B cell ALL in adult and children. It has also recently gained approval for use in B cell precursor ALL in remission with positive minimal residual disease. Studies have also shown promising results with blinatumomab in relapsed/refractory non-Hodgkin’s lymphoma (NHL). , There are ongoing early phase trials of BiTE cells in acute myelogenous leukemia (AML) and other solid tumors including gastrointestinal adenocarcinoma and prostate cancer.
Mechanism of Action
BiTEs consist of two single-chain variable fragments which are joined together by a linker molecule, one of which binds to T cells, whereas the other binds to a tumor antigen. The simultaneous binding of BiTE cells to T cells and tumor antigens causes T-cell activation and release of cytokines, including γ-interferon, TNF-α, IL-6, and IL-2. BiTE cells also lead to the formation of a cytolytic synapse through which transfer to perforin and granzyme takes place from activated T cells to target tumor cells, leading to apoptosis of the tumor cell.
Mechanism of Neurotoxicity
Blinatumomab causes a transient increase in cytokines including IL-6, TNF-α, and INF-γ, generally with the first cycle of treatment. This increase in cytokines, however, is not reproduced with later cycles. These cytokines have been shown to increase endothelial cell activation and BBB permeability. Interestingly, neurological toxicity is most often reported after the first cycle of blinatumomab. , A study also showed an increase in T cell adhesion to the endothelium with blinatumomab infusion, leading to the redistribution of T cells into neural tissues. Although there is no direct evidence of the mechanism of neurological toxicity from blinatumomab, it appears to be due to the release of cytokines from activated T cells.
Reported Neurotoxicities
Any grade neurological adverse events developed in 47% to 71% of patients. , Severe toxicity developed in about 7% to 22% of patients. , Headache, dizziness, and tremors are the most common neurological toxicities reported, with other adverse effects reported including encephalopathy, seizures, convulsions, apraxia, memory impairment, aphasia, hemiparesis, and cerebral hemorrhage. , Neurological adverse effects are more common in patients aged 65 years or older, although overall adverse effects remain unchanged in this group. The incidence of neurological adverse effects is directly proportional to the dose of blinatumomab administered, as seen in a phase 1 study in NHL where 3 out of 4 patients developed dose-limiting toxicity when treated at the highest dose level. In most patients, neurological adverse events abated after interruption of the drug. , , ,
OTHER MONOCLONAL ANTIBODYS
Antibody-Drug Conjugates
Antibody-drug conjugates (ADCs) are a group of immunological agents where a cytotoxic agent is bound to a mAb targeting a tumor specific antigen. The ADC is internalized by the tumor cell leading to release of the cytotoxic agent and subsequent tumor death. The first drug of this class to be FDA–approved was gemtuzumab ozogamicin (GO), a CD33 binding ADC initially used in patients with AML, but it was later withdrawn from the market due to lack of survival benefit when added to standard therapy, and increased rate of non-hematological grade 4 and fatal toxicity during induction. Although a recent phase III study which used a lower dose of the drug led to its re-approval in the US along with combination chemotherapy or monotherapy. Brentuximab vedotin, another ADC, is approved for use in Hodgkin’s lymphoma, CD30-positive mycosis fungoides, and in systemic and cutaneous large B cell lymphoma in patients who have failed prior systemic chemotherapy. Ado-trastuzumab emtansine is FDA–approved for human epidermal growth factor-2 (HER2)–positive metastatic breast cancer in patients who have received trastuzumab with or without a taxane.
Mechanism of Action.
Brentuximab vedotin (BV) is an anti-CD30 targeting antibody conjugated with monomethyl auristatin-E (MMAE). Upon binding to CD30, the molecule is endocytosed, then cleaved in lysosomes, leading to release of MMAE, a tubulin inhibitor which prevents polymerization of microtubulin, subsequently causing arrest of cell division and growth.
Ado-trastuzumab emtansine (T-DM1) is a HER2-targeting antibody conjugated with a derivative of maytansine (DM-1), which upon internalization, is broken down to release DM-1, a potent tubulin inhibitor, causing inhibition of microtubule assembly leading to cell death. T-DM1 still retains the action of trastuzumab by blocking the HER2 downstream signaling. It inhibits shedding of the extracellular HER2 domain and promotes antibody-dependent cellular cytotoxicity (ADCC).
Gemtuzumab ozogamicin (GO) is a CD33 binding ADC linked to N acetyl-calicheamicin, which, once internalized by myeloid blast cells, releases calicheamicin, a cytotoxic agent that damages DNA by introducing breaks in its structure.
Mechanism of Neurotoxicity.
MMAE, like other tubulin inhibitors, predisposes patients to peripheral neuropathy by disrupting axonal transport in the neuron. Neurons do not express CD30 on their surface ; however, toxicity is likely due to the bystander effect in the surrounding tissue caused by the diffusion of the drug from the tumor cells. T-DM1 likely causes neurotoxicity through a similar mechanism.
Reported Neurotoxicity.
Peripheral neuropathy (PN) is one of the most common toxicities of ADCs and has been reported in 42% to 67% of patients with about 8% to 12% of patients developing grade 3 or higher toxicities. This often leads to treatment discontinuation, treatment delay, and dose reduction in a significant number of patients. Both motor and sensory nerves can be involved, although sensory neuropathy is more common. , Complete resolution has been seen in about 50% of patients, with time to resolution varying from 13 to 41 weeks. , PN can be managed in most cases with dose delays and dose reductions. Cases of progressive multifocal leukoencephalopathy (PML) have also been described with brentuximab vedotin (BV). , Peripheral neuropathy has been reported with T-DM1, although at significantly lower rates when compared with BV. , GO, owing to its action of mechanism which is different from the other ADCs, is well tolerated neurologically and no neurological adverse effects were reported in a phase III trial.
CD20–Directed Antibodies
Rituximab, a chimeric antibody made up of murine variable regions which bind to CD20 and a human Fc region, was the first anti-CD20 mAb to be approved. It is approved for use in several hematological malignancies as well as some autoimmune disorders. Its action is based on antibody-dependent cell-mediated cytoxicity (ADCC), complement-dependent cytotoxicity (CDC), complement-dependent phagocytosis, and direct apoptosis. Ofatumumab and obintuzumab are other CD20-directed antibodies with similar action to that of rituximab. , Ibritumomab tiuxetan contains a CD20-targeting mAb bound to tiuxetan, a chelator, which is further bound to 90Y, a radioactive isotope, which releases high energy beta particles, and causes cytotoxicity by an antibody- and complement-dependent manner as well as directly through beta emmision.
Reported Toxicities.
Neurological adverse effects are uncommon with rituximab, although headache was reported in 16% of patients in one clinical trial. Several cases of PML have been reported with use of rituximab. Other mAbs are also generally well tolerated.
CD52–Directed Antibodies
Alemtuzumab is a mAb which binds to CD52, a CD marker expressed on both T and B cells. Alemtuzumab has been approved for use as monotherapy in chronic lymphocytic leukemia and has shown activity in patients with certain T cell lymphomas and leukemias. Alemtuzumab has also shown activity in the prevention of graft versus host disease (GVHD) after stem cell transplantation.
Reported Toxicity.
Neurological complications are uncommon with alemtuzumab, although a study did report an increase in peripheral neuropathy and myelitis in patients who received alemtuzumab-based reduced-intensity allogeneic transplants. A case of PML has also been reported with alemtuzumab.
CD38–Directed Antibodies and Signal LymphocyticActivation Molecule-7–Directed Antibodies
Daratumumab is a mAB directed against CD38 and has been approved for use in multiple myeloma patients who have progressed through one line of therapy. Like other mAbs, daratumumab also causes ADCC and complement-dependent cytotoxicity (CDC) leading to the lysis of normal and malignant plasma cells.
Elotuzumab is a signal lymphocytic activation molecule (SLAM)-7–directed antibody that has been approved for use in combination with dexamethasone and lenalidomide in patients with multiple myeloma who have received one to three prior therapies. , Elotuzumab is a humanized mAb that binds to SLAM7 and induces ADCC and natural killer (NK) cell–dependent direct cytotoxicity.
Reported Toxicities.
When used as monotherapy, neurological adverse effects due to daratumumab were rare, with one phase II trial reporting headache and dizziness in 3% and 6% of patients, respectively. , Peripheral neuropathy, headache, insomnia, and dizziness have been reported with the combination of elotuzumab with dexamethasone and lenalidomide, although nearly all of these were grade 2 or lower.
Epidermal Growth Factor Receptor–Directed Antibodies
Epidermal growth factor receptor (EFGR) is mutated and/or overexpressed in a number of malignancies and has become a well-exploited target. EGFRs belong to the group of transforming growth factor receptors. Their activation lead to downstream signaling via tyrosine kinases which, in turn, lead to an increase in proliferation, and a decrease in apoptosis. Cetuximab, a chimeric mAb directed against EGFR, not only blocks this downstream signaling but can also cause cell cycle arrest in the G1 phase, decrease angiogenesis, decrease tumor invasion and metastasis, induce apoptosis in tumor cells, and thus can potentiate the action of chemotherapy and radiotherapy. Cetuximab is approved for use in patients with wild-type KRAS metastatic colorectal carcinoma along with irinotecan or as monotherapy, and in head and neck cancers with radiation, in combination with platinum-based chemotherapy or as monotherapy. Panitumumab is a fully humanized antibody against EGFR with a mechanism of action similar to that of cetuximab; in addition, it also causes ADCC and autophagy. Panitumumab is approved for use as monotherapy in wild-type KRAS metastatic colon cancer which does not respond to chemotherapy.
Reported Neurological Toxicity.
When used as monotherapy, headache is the most common neurological adverse effect reported; other neurological adverse effects are uncommon. , Cases of aseptic meningitis have been reported with cetuximab with recovery after symptomatic treatment. Although dermatological toxicities were common, neurological toxicities were not reported in studies with panitumumab as monotherapy. ,
Human Epidermal Growth Factor 2–Directed Antibodies
HER2 is a group of tyrosine kinases, which promote cell growth and proliferation, prevent apoptosis, and are overexpressed in 20% to 30% of patients with invasive breast cancer. Trastuzumab is a humanized IgG1 monoclonal antibody which binds to HER2 and not only prevents downstream signaling but also results in ADCC, prevents angiogenesis, and has been approved for use in HER2 positive breast cancer both in the metastatic and adjuvant settings. Pertuzumab is another HER2-directed mAb and has shown improvement in overall survival when used in combination with trastuzumab and docetaxel in patients with HER2+ metastatic breast cancer.
Reported Neurological Toxicity.
Cardiac toxicity and neutropenia/neutropenic fever are common toxicities reported with HER2-directed therapy. Severe neurological toxicities are uncommon, although fatal cases of cerebrovascular accident (CVA) and hemorrhage have been noted in clinical trials. When used as monotherapy in a phase II trial in patients with ovarian cancer, 14 out of 41 patients developed neurotoxicity, although only one patient developed grade 3 or higher toxicity. Like trastuzumab, the combination of pertuzumab with docetaxel and trastuzumab did not have significant neurotoxicity except headache, which was seen in about 17% of the patients in the combination group compared with 12% of the patients in the control group.
Clinical Approach and Pharmacological Management of Toxicity
INTERLEUKIN-2
Neuropsychiatric symptoms are commonly seen with IL-2. Although some guidelines recommend the use of benzodiazepines for insomnia/irritability, the risk of delirium must be considered prior to administration. Given this, other medications that are known to worsen delirium should be stopped. Antipsychotic medications can be considered in select cases. Progressive changes in personality, hallucinations, hostility, disorientation, and confusion are indications to stop treatment.
In patients with depressive symptoms, escitalopram can be used, as it has shown to decrease depressive symptoms compared with placebo.
Conservative management of peripheral neuropathy with pain medications and dose reduction of IL-2 is usually sufficient as many of these symptoms are self-limiting.
INTERFERON-α
Hypothyroidism is commonly seen with INF use. It can mimic symptoms of depression and should be considered when evaluating patients with neurotoxicity.
Patients with a history of, or who are currently suffering from, psychiatric disorders should be co-managed with the help of a psychiatrist. Pretreatment of patients with paroxetine has shown to decrease the incidence of depression and anxiety in patients treated with INF and can be used prophylactically in patients with high risk of depression. , In patients with new-onset depression, use of drugs that affect both the serotonin and dopaminergic/noradrenergic pathways, including serotonin norepinephrine reuptake inhibitors (SNRIs), psychostimulants like modafinil and methylphenidate, and bupropion, may be more beneficial than selective serotonin reuptake inhibitors (SSRIs), as they can also improve fatigue and other neurovegetative symptoms, such as anorexia and pain, which are commonly seen in patients receiving INF.
Development of mania is an indication to stop INF. However, gabapentin has been successfully used in patients who develop mania and bipolar disorder with INF treatment.
IMMUNE CHECKPOINT INHIBITORS
CNS Involvement
Meningitis/Encephalitis.
Patients with meningitis present with headache, nausea and vomiting, photophobia, and neck stiffness. Encephalitis can present with similar symptoms; in addition, patients may have altered mental status (AMS) or focal neurological deficits. Several pathologies including the metastatic spread of the tumor to CNS/leptomeninges, CVA, infection, autoimmune diseases, and metabolic derangement may present with similar features and should be considered in the differential. In patients presenting with headache with visual disturbances, fatigue, or hypotension, hypophysitis should be considered as a potential etiology.
Testing, including metabolic panel, imaging (usually MRI), and CSF analysis will help in differentiating the underlying cause. In patients presenting with AMS or focal deficits, increased intracranial pressure should be ruled out before attempting a lumbar puncture. Serum cortisol and serum adrenocorticotropic hormone (ACTH) levels should be obtained in patients to evaluate for adrenal insufficiency. Other recommended workup includes erythrocyte sedimentation rate (ESR), CRP, antineutrophil cytoplasmic antibodies (ANCA), thyroid panel, and peripheral smear to evaluate for thrombotic thrombocytopenic purpura (TTP), and inflammatory or autoimmune conditions. Electroencephalogram should be obtained in patients with AMS and neurology consultation should be obtained.
Patients who present with symptoms of meningitis should receive appropriate antibiotic coverage until infectious causes are ruled out. Once infectious etiology has been ruled out, steroids (prednisone 0.5–1 mg/kg or methylprednisolone 1–2 mg/kg for severe disease) are recommended, and further ICIs should be withheld. , The management of patients who present with encephalitis is similar, although in patients with progressive symptoms or presence of oligoclonal bands in CSF, pulse dose steroids (methylprednisolone 1 g/day for 3–5 days) and intravenous immunoglobulin (IVIG) 2 g/kg over 5 days may be considered. A slow taper of steroids over several weeks has been used in most reported cases of ICI-associated encephalitis. , , , Patients with autoimmune encephalopathy showing no improvement with steroids can be considered for plasmapheresis or rituximab therapy. A case of steroid- and IVIG-resistant NMDAR-positive encephalitis successfully treated with rituximab has been reported.
Transverse Myelitis.
Patients with transverse myelitis (TM) usually present with acute or subacute symptoms. A rapid onset over a few hours or a prolonged progressive deficit over weeks is uncharacteristic of TM, and such patients should be considered for alternative diagnoses. TM can involve the entire spinal cord, leading to complete plegia, as well as sensory and autonomic deficits.
MRI of the spine is required for diagnosis. MRI of the brain, serum B12 levels, HIV testing, syphilis serology, TSH, anti-Ro and La antibodies, anti-aquaporin 4-IgG, and CSF analysis, including oligoclonal bands and onconeural antibodies, should also be obtained in patients with suspected TM. , Patients with the involvement of spinal cord of more than three vertebral segments should have an extensive autoimmune workup. Other etiologies of TM include infections, metabolic abnormalities, and autoimmune disorders, all of which should be ruled out depending on the clinical scenario. Interestingly, many malignancies, including lung and ovarian cancer, can also cause paraneoplastic TM and are associated with specific antibodies.
In patients who develop TM, ICIs should be permanently discontinued and patients should be started on high-dose steroids (methylprednisolone 2 mg/kg); pulse dose steroids (1 g/day for 3–5 days) and IVIG (2 g/kg over 5 days) should be considered in these patients. Plasmapheresis has also been recommended in patients not responsive to steroids.
PNS Involvement
Myasthenia Gravis.
Patients with MG classically present with diplopia which gets worse during the day. Other symptoms include ptosis, bulbar muscle weakness leading to dysarthria, dysphagia, and respiratory muscle involvement occurs in severe cases. The Miller-Fischer variant of GBS presents with ophthalmoplegia, ataxia, and absent reflexes, and can often be mistaken for MG.
Neurology consultation should be obtained in patients with suspected MG. , Diagnosis is made based on clinical symptoms and a positive anticholinesterase antibody (AChR). Historically, 80% of patients with a diagnosis of classic MG will have AChR antibody. Interestingly, a case series reported about 40% of patients without AChR antibodies who developed MG during treatment with ICIs. Anti–muscle-specific kinase (MuSK) and lipoprotein-related antibody 4 should be tested in patients with negative AchR. Several patients also have elevated levels of creatinine kinases (CK), unlike non–ICI-mediated MG, which is related to concomitant myositis along with MG. Creatinine phosphokinase, aldolase, ESR, and CRP can be used to help rule out concomitant myositis. Other recommended workup includes MRI brain and/or spine; electrodiagnostic (EDX) studies can be used to help rule out peripheral neuropathy or concomitant myositis. Cardiac involvement can be seen with MG and is often overlooked. In a study of 58 patients with MG and no underlying cardiac abnormalities nearly 60% of patients had new electrocardiogram (ECG) changes and 5 patients had a reduction in their ejection fraction. Creatinine phosphokinase and troponin T should also be obtained in patients with MG and if elevated, further workup with ECG and echocardiogram should be done.
Treatment usually entails pyridostigmine and corticosteroids with cessation of further treatment with ICI. , Patients presenting with grade 2 toxicity should be treated with prednisone (1–1.5 mg/kg) and pyridostigmine starting at 30 mg three times a day, gradually increasing to a maximum 120 mg 4 times a day based on improvement of symptoms. Patients with grade 3–4 disease should be monitored in the ICU, and apart from the above, IVIG 2 g/day or plasmapheresis should be considered along with permanent discontinuation of ICI. Use of other immunosuppressants like azathioprine has been reported. Immunosuppressants have a role in this entity, but the risk of disease progression and toxicity should be weighed with the benefit of the medication. Some medications can worsen MG and should be avoided.
Guillain-Barre Syndrome.
GBS classically presents as an ascending muscle weakness with absent reflexes, which progresses over hours to days. Dysautonomia including cardiac arrhythmias can also occur. Respiratory muscles can also be involved in severe cases and cranial nerve involvement can also be seen. Sensory symptoms like back pain, paresthesias, and meningismus may precede motor symptoms in one-third of cases. Five different variants on GBS exist, all of which have varied clinical presentations.
Diagnostic workup for GBS requires MRI of the spine, EDX, CSF analysis, serum anti-ganglioside antibody testing, and pulmonary function testing. Classic GBS shows an albuminocytological gap without pleocytosis in the CSF. Interestingly, there have been reports of GBS and chronic inflammatory demyelinating neuropathy associated with ICIs with pleocytosis in the CSF, unlike classic GBS. In the same study, the patient with an axonal pattern on EDX, again unlike classic GBS, was seen.
Neurology consultation should be obtained in all patients with suspected GBS. ICIs should be discontinued immediately. IVIG (2 g/kg over 5 days) and plasmapheresis are the main treatment modalities used. Treatment with steroids is generally not useful in classic GBS, but can be used in patients with ICI-mediated GBS. Methylprednisolone (2–4 mg/kg) followed by a taper for patients with grade 2 GBS, and pulse dose steroids (1 g/day for 5 days) for patients with grade 3–4 GBS, can be considered along with the other previously mentioned therapies. Neuropathic pain in this group of patients can be treated with gabapentin or carbamazepine.
Other Toxicities.
Several cases of peripheral nerve involvement have been reported with use of ICIs. This peripheral nerve involvement can have varied presentation including sensory neuropathy, motor neuropathy, and polyradiculitis. , Enteric neuropathy presenting as constipation has also been reported in the literature. Workup of peripheral neuropathy should include EDX as well as evaluation for other potential diagnoses.
Whereas patients with grade 1 peripheral neuropathy can be managed conservatively, patients with grade 2 toxicity should be treated with corticosteroids (prednisone 0.5–1 mg/kg), and patients with grades 3 and 4 toxicity should be managed as mentioned under the GBS section. Patients with autonomic neuropathy can be managed similarly, although grades 3 and 4 toxicity generally require pulse dose steroids followed by a taper.
CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY
Neelapu et al. have proposed a grading system for CNS toxicity which can be used to guide management of patients receiving CAR T-cell therapy, referred to as CARTOX. CARTOX is a 10-point neurological assessment that is done three times a day. Points are assigned for orientation, naming, ability to follow commands, writing, and attention; a score of 10 denotes no impairment, but a lower score denotes grade 2 through 4 immune effector cell–associated neurotoxicity syndrome (ICANS). All patients should have a baseline neurological examination prior to initiation of treatment and should undergo regular CARTOX evaluation. Prophylactic use of levetiracetam 750 mg every 12 hours for 1 month after starting therapy, regular clinical examination, and daily grading of neurotoxicity is recommended. Patients with suspected neurotoxicity should undergo neurology consultation, evaluation for papilledema, EEG, and MRI/CT of the brain, and should be treated with antipyretics, antipsychotics, and ventilator support as required. Of note, use of GM-CSF should be avoided in these patients as it has been implicated in the development of CRS and neurotoxicity. A clinical trial is currently in progress, evaluating the use of lenzilumab in the prevention of neurotoxicity (NCT04314843).
No randomized clinical trial has evaluated the management of neurotoxicity, making this entity an evolving field. CRS can be managed with the use of tocilizumab, an IL-6 receptor antagonist mAb that has been approved by the FDA for this indication. An increase in IL-6 is seen in the CSF of patients who develop neurotoxicity. The use of IL-6 receptor antagonists for neurotoxicity without CRS is not recommended. In mice, use of tocilizumab was unable to prevent delayed lethal neurotoxicity by CAR T cells. Similar results were seen in a study in humans where no benefit in neurological symptoms was seen with use of tocilizumab. This perhaps is due to the inability of tocilizumab to cross the BBB. In patients with neurotoxicity, dexamethasone is the preferred glucocorticoid due to its ability to penetrate the CNS. For patients with severe neurological toxicities, dexamethasone 10 mg every 6 hours is recommended until symptoms improve to grade 1 or lower, , although patients with grade 4 toxicity may need pulse dose steroids followed by a taper. Siltuximab, a IL-6–binding mAb can be used in steroid refractory neurotoxicity, although data for its efficacy is lacking. In mice, use of the IL-1 antagonist, anakinra, has been shown to effectively control neurotoxicity, although similar human studies are lacking. The use of corticosteroids or tocilizumab has not been shown to have an effect on tumor response.
BISPECIFIC T-CELL ENGAGERS
Blinatumomab is infused continuously over a 4-week period followed by a 2-week break. A separate line should be used for infusion. The line should be labeled clearly and should not be flushed as it can cause acute toxicity.
Patients who develop neurological toxicity should be assessed first for underlying infection, CVA, or metabolic etiologies of symptoms. Pretreatment with dexamethasone 20 mg every 6–12 hours before every step has been used successfully to prevent toxicity. Pentosan polysulfate (SP54) is another agent that has been used to prevent toxicity. In patients who develop seizures, antiseizure prophylaxis before re-exposure to blinatumomab has been shown to successfully prevent further seizures. Treatment should be withheld for grade 3 neurotoxicity for at least 72 hours and until symptoms improve to grade 1 or lower. Treatment should be restarted at 9 µg/day. Blinatumomab should be discontinued permanently in patients who experience 2 or more seizures, in patients who experience neurological toxicity that is higher than grade 1 after withholding treatment for 1 week, in patients who develop neurological toxicity at the 9 µg/day dose, and lastly, in patients who develop grade 4 toxicity.
OTHER MONOCLONAL ANTIBODIES
Progressive Multifocal Leukoencephalopathy
Several cases of progressive multifocal leukoencephalopathy (PML) have been reported to be associated with monoclonal antibodies. In a case series of 57 patients who developed PML on rituximab, presenting complaints included confusion, incoordination, speech disturbance, and vision changes, with a median onset of 5.5 months after last rituximab dose. This condition has been associated with a 90% mortality rate. Although plasmapheresis has often been used, its role is controversial and a recent study in patients who developed PML on natalizumab found no benefit of plasmapheresis. Cytarabine, cidofovir, mirtazapine, mefloquine, and risperidone have all been used with sporadic benefit, and no conclusive evidence exists to support the use of these medications. , Cases of PML have also been described with BV. , Notably, JC virus DNA can be negative in the CSF in these patients. This entity is associated with particularly high mortality rates. In a study of 5 patients who developed PML on BV, presenting symptoms were hemiparesis, hemianopsia, aphasia, gait disturbance, and incoordination along with MRI findings of T2 hyperintensity and T1 hypointensity with enhancing lesions. Of five patients, four died and one improved with oral prednisone over 1 year. The role of plasmapheresis is not well defined in this subset of patients.
Aseptic Meningitis
Cases of aseptic meningitis with cetuximab have been reported; however, these patients have had complete recovery after symptomatic treatment and most of these patients had a negative rechallenge test. This can generally be prevented by premedicating patients with antihistamines and dexamethasone 1 hour prior to infusion and utilizing slower infusion rates (5 mg/min with first infusion and 10 mg/min on subsequent infusions).
Nonpharmacological Management of Toxicities
DELIRIUM
Patients and caregivers should be made aware of the potential adverse effects, such as delirium, associated with many medications. Frequent neuro-checks should be done which can help with early detection of delirium. Standard delirium management, such as maintaining a familiar environment and enlisting the help of the caretaker/family members, can be beneficial. Maintenance of normal sleep-wake cycles and prevention of unnecessary disturbance during nighttime may also benefit these patients. In older patients, constipation, urinary retention, and pain are preventable common causes of delirium. In at-risk patients, sedative and medications with anticholinergic activity should be avoided.
NEUROPSYCHIATRIC SYMPTOMS ASSOCIATED WITH INTERFERON-α
The presence of social support has been shown to decrease the incidence of depression in patients receiving low-dose IFN–adjuvant therapy for melanoma. Fatigue is another common complaint associated with IFN-α. Regular physical activity, adequate nutrition, and maintaining a fatigue diary have been described to help patients cope with fatigue.
RESPIRATORY DEPRESSION
Patients with GBS can develop bulbar weakness, increasing their risk of aspiration pneumonia. This risk can be tempered with aggressive chest therapy (pulmonary toilet). Patients should undergo frequent spirometry as it can predict worsening respiratory status and the need for mechanical ventilation.
References
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