Neurological irAEs Research Articles

From ICI to ICU: A systematic review of patients with solid tumors who are treated with immune checkpoint inhibitors (ICI) and admitted to the intensive care unit (ICU).

Immune checkpoint inhibitors (ICIs) have improved the survival of patients with different solid tumors and even resulted in cure of metastatic disease. Since the introduction of ICIs, an increasing number of patients is admitted to the ICU for severe and potentially life-threatening immune related adverse events (irAEs). The outcome of patients who are admitted to the ICU because of severe irAEs is still unknown. The aim of this systematic review is to collect evidence on the outcomes of patients with solid tumors who are admitted to the ICU because of irAEs. Medline, Embase, Cochrane central register of controlled trials and Google Scholar were searched systematically from 1975 to 24 September 2024. Articles were only included when describing patients with solid tumors who were admitted to the ICU because of irAEs after treatment with ICIs. Two independent reviewers extracted the data and assessed the risk of bias. A total of 183 articles were included: two prospective ICU population-based studies, four retrospective ICU population-based studies, 25 retrospective studies describing irAEs with incidental ICU admissions, one review of case reports, and 153 articles with a total of 177 case reports. The six ICU population-based studies contained a total of 169 patients who were admitted to the ICU due to irAEs. In these six studies, the most frequently reported irAEs were pneumonitis and neurological irAEs. Of these 169 patients, 26% of the patients died on the ICU and an additional 8% of patients in the three to six months thereafter due to irAEs or disease progression. In all 183 included articles, various irAEs were described and the reported mortality rate varied from 0 to 53%. The potential favorable outcomes of both the solid tumors and irAEs will probably result in more need for ICU admissions. Prospective clinical trials are needed to optimize the treatment strategy of severe irAEs at the ICU. Based on the favourable outcomes after life-threatening irAEs, ICU admission should definitely be considered for patients with solid tumors who have life-threatening irAEs.

Neurological immune-related toxicity to ipilimumab/nivolumab therapy in malignant melanoma: A challenging case report

Introduction: Malignant melanoma poses a significant threat due to its aggressiveness and high fatality rates. Recent advances in immunotherapy and targeted molecular therapies have transformed the treatment landscape for advanced melanoma, improving overall survival. However, the rising use of immune checkpoint inhibitors (ICIs) introduces complexities, particularly in neurological immune-related adverse events (irAEs), necessitating careful consideration and multidisciplinary management. Case Report: We report the case of a 77-year-old woman with stage IV cutaneous melanoma, which was hospitalized with polyneuropathy following immunotherapy treatment with ipilimumab and nivolumab combination. The complex presentation involved considerations of COVID-19 vaccination, detection of Epstein–Barr virus (EBV) in cerebrospinal fluid, and the challenge of distinguishing infectious from immune-related causes. The multidisciplinary team navigated multiple diagnostic uncertainties. The patient’s clinical evolution, including complications and treatment responses, provided insights into managing severe neurological irAEs associated with immunotherapy. Conclusion: Neurologic immune-related (IR) toxicity is well established, and it may led to severe adverse events, which are complex to diagnose and manage. This case report highlights the challenges and difficulties found, with relevant confounding factors, which arise the relevance of the need of a multidisciplinary team to deal with neurologic immune-related toxicities.

Immune checkpoint inhibitor-induced autoimmune limbic encephalitis with positivity for anti-Hu antibodies in a patient with small-cell lung cancer: A case report and literature review.

In recent years, there has been an increasing number of studies on neurological symptoms induced as paraneoplastic neurological syndrome (PNS) or neurological immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitors (ICIs). Herein, we report a 68-year-old male patient with small-cell lung cancer who developed memory impairment and autonomic nervous system dysfunction after three courses of carboplatin, etoposide, and durvalumab therapy. Brain magnetic resonance imaging revealed hyperintense areas restricted to the bilateral temporal lobes. Moreover, based on the blood test results, the patient was strongly positive for anti-neuronal nuclear antibodies. Hence, he was diagnosed with autoimmune limbic encephalitis (ALE). Corticosteroid pulse therapy was administered. After treatment, the patient exhibited gradual improvement in memory impairment. However, while tapering the prednisolone dose, the patient exhibited relapse of memory disturbance owing to ALE. It is challenging to distinguish PNS from neurological irAEs. However, ICI-induced ALE with positivity for anti-Hu antibodies has an extremely poor prognosis.

Peripheral nervous system immune-related adverse events due to checkpoint inhibition.

Immune checkpoint inhibitors have revolutionized cancer therapy and are increasingly used to treat a wide range of oncological conditions, with dramatic benefits for many patients. Unfortunately, the resulting increase in T cell effector function often results in immune-related adverse events (irAEs), which can involve any organ system, including the central nervous system (CNS) and peripheral nervous system (PNS). Neurological irAEs involve the PNS in two-thirds of affected patients. Muscle involvement (immune-related myopathy) is the most common PNS irAE and can be associated with neuromuscular junction involvement. Immune-related peripheral neuropathy most commonly takes the form of polyradiculoneuropathy or cranial neuropathies. Immune-related myopathy (with or without neuromuscular junction involvement) often occurs along with immune-related myocarditis, and this overlap syndrome is associated with substantially increased mortality. This Review focuses on PNS adverse events associated with immune checkpoint inhibition. Underlying pathophysiological mechanisms are discussed, including antigen homology between self and tumour, epitope spreading and activation of pre-existing autoreactive T cells. An overview of current approaches to clinical management is provided, including cytokine-directed therapies that aim to decouple anticancer immunity from autoimmunity and emerging treatments for patients with severe (life-threatening) presentations.

Safety of immune checkpoint inhibitor rechallenge after severe immune-related adverse events: a retrospective analysis.

Immune checkpoint inhibitors (ICIs) present clinicians with the challenge of managing immune-related adverse events (irAEs), which can range from mild to severe due to immune system activation 1. While guidelines recommend discontinuing ICIs for grade 3 partial and all grade 4 irAEs, there is growing interest in rechallenging patients based on oncological outcomes, particularly for cardiovascular and neurological irAEs where data remains scarce 1,2. We retrospectively evaluated the safety of ICI rechallenge following grade 3-4 irAEs, specifically focusing on cardiovascular and neurological events, in patients discussed at our multidisciplinary immunotoxicity assessment board between 2019 and 2021. Fifteen patients were included, with a median time to severe irAE onset of 49 days. Among them, five patients experienced neurological adverse events (NAEs): aseptic meningitis (3), inflammatory polyradiculoneuropathy (1), and ophthalmoplegia (1), while one patient presented with myocarditis. Of the 15 patients retreated with ICIs after initial severe irAEs, 11 (73%) remained free of subsequent irAEs, two (13%) experienced recurrence of the initial irAE, and two (13%) developed new irAEs distinct from the initial event. The median time to event recurrence was 69 days, occurring no earlier than the initial severe irAE. In the subset analysis focusing on severe cardiovascular and neurological irAEs, rechallenge with ICIs was generally well tolerated. However, one patient treated with anti-PD1 experienced a relapse of grade 2 aseptic meningitis. Overall, our findings suggest that rechallenging with ICIs after severe irAEs, including those affecting the cardiovascular and neurological systems, may be safe, particularly after irAE regression and corticosteroid withdrawal.

Neurological Immune-Related Adverse Events Induced by Immune Checkpoint Inhibitors.

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

Peripheral Neuropathy and Muscle Disorders as Immune-Related Adverse Events

Neurological immune-related adverse events (irAEs) associated with cancer treatment with immune checkpoint inhibitors (ICI) present diverse clinical characteristics. Neurological irAEs affect the peripheral nervous system and muscles more than they affect the central nervous system. Among the various subsets of peripheral neuropathies, polyradiculoneuropathy, which includes Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy, stands out as the most severe form, leading to significant muscle weakness. ICIs can induce dysautonomia, including autoimmune autonomic ganglionopathy. Autonomic neuropathy represents a neurological irAE. Neurological irAEs of neuromuscular junctions include myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS). Diagnosing MG or myositis independently can be challenging when they occur as irAEs. Myocarditis is sometimes observed as an irAE in patients with MG and can cause both severe heart failure and lethal arrhythmias, resulting in fatal outcomes. Anti-Kv1.4 antibodies are biomarkers of the severe form of MG and myocarditis. The administration of ICI in patients with small cell lung cancer increases the risk of LEMS. The distinction between LEMS is an irAE or a manifestation of paraneoplastic neurological syndrome is unclear as both conditions share common immunological mechanisms.

Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations.

The landscape of cancer treatment has undergone a significant transformation with the introduction of Immune Checkpoint Inhibitors (ICIs). Patients undergoing these treatments often report prolonged clinical and radiological responses, albeit with a potential risk of developing immune-related adverse events (irAEs). Here, we reviewed and discussed the mechanisms of action of ICIs and their pivotal role in regulating the immune system to enhance the anti-tumor immune response. We scrutinized the intricate pathogenic mechanisms responsible for irAEs, arising from the evasion of self-tolerance checkpoints due to drug-induced immune modulation. We also summarized the main clinical manifestations due to irAEs categorized by organ types, detailing their incidence and associated risk factors. The occurrence of irAEs is more frequent when ICIs are combined; with neurological, cardiovascular, hematological, and rheumatic irAEs more commonly linked to PD1/PD-L1 inhibitors and cutaneous and gastrointestinal irAEs more prevalent with CTLA4 inhibitors. Due to the often-nonspecific signs and symptoms, the diagnosis of irAEs (especially for those rare ones) can be challenging. The differential with primary autoimmune disorders becomes sometimes intricate, given the clinical and pathophysiological similarities. In conclusion, considering the escalating use of ICIs, this area of research necessitates additional clinical studies and practical insights, especially the development of biomarkers for predicting immune toxicities. In addition, there is a need for heightened education for both clinicians and patients to enhance understanding and awareness.

Chronic Inflammatory Demyelinating Polyneuropathy Induced by Immune Checkpoint Inhibitors: Case Reports

Neurological immune-related adverse events (irAE) are rare but potentially fatal complications associated with the use of immune checkpoint inhibitors (ICI). Recently, there has been a trend towards an increase in the incidence of these cases.
 We present two case reports of demyelinating polyneuropathy in patients with skin melanoma treated with pembrolizumab or nivolumab. Unawareness of neurological irAE induced by ICI leads to delayed diagnosis and medical treatment, and this may result in persistent neurological deficit or even patients’ death. Neurological irAEs include myasthenia gravis, aseptic meningitis, encephalitis, myelitis, inflammatory demyelinating neuropathy, myositis or their combinations, etc. Considering their variability in patients treated with ICI and poor representation in publications, each case report can be of practical value.

Immune checkpoint inhibitor-related myositis and myocarditis: diagnostic pitfalls and imaging contribution in a real-world, institutional case series

BackgroundImmune checkpoint inhibitors (ICIs) are reshaping the prognosis of many cancers, but often cause immune-related adverse events (irAEs). Among neurological irAEs, myositis is the most frequently reported. Our aim is to describe clinical and non-clinical characteristics, treatment and outcome of all irMyositis (skeletal limb-girdle and/or ocular myositis) and irMyocarditis cases in our reference center.MethodsWe retrospectively enrolled all irMyositis/irMyocarditis patients seen between 2018 and 2022. We reviewed demographics, clinical characteristics, biological, neurophysiological, imaging workup, treatment and outcome.ResultsWe included 14 consecutive patients. The most frequent treatments were pembrolizumab (35%) or ipilimumab–nivolumab combination (35%). Limb-girdle, ocular (non-fluctuating palpebral ptosis and/or diplopia with or without ophthalmoparesis) and cardiac phenotypes were equally distributed, overlapping in 40% of cases. Ocular involvement was frequently misdiagnosed; review of brain MRIs disclosed initially missed signs of skeletal myositis in one patient and ocular myositis in 3. Seven patients had other co-existing irAEs. When performed, myography showed a myogenic pattern. CK was elevated in 8/15 patients, troponin-T in 12/12 and troponin-I in 7/9 tested patients. ICI were discontinued in all cases, with further immunosuppressive treatment in nine patients. In most cases, neurological and cardiological outcome was good at last follow-up.ConclusionMyositis is a potentially severe irAE. Despite its heterogeneous presentation, some highly suggestive clinical symptoms, such as ocular involvement, or radiological signs should raise physicians’ attention to avoid misdiagnosis. We thus recommend a multidisciplinary assessment (including complete neuromuscular evaluation) even in case of isolated myocarditis. Our series underlines the importance of an early diagnosis, since suspension of ICI and adequate treatment are usually associated with good functional outcome.

Comparisons of Non-Oral Immune-Related Adverse Events Among Patients With Cancer With Different Oral Toxicity Profiles.

Immune-related adverse events (irAEs) are common. Oral irAEs tend to cluster in patients who experience concurrent toxicities. We aimed to characterize the frequency and trajectory of non-oral irAEs in patients who developed oral irAEs, assess their relationship with non-oral irAEs, and compare those characteristics with patients without oral irAEs. A retrospective chart review was conducted to identify patients who started ICIT between December 11, 2011, and September 15, 2019 (n = 4683) in the Mass General Brigham Registered Patient Data Registry. Demographic information, cancer diagnosis, ICIT regimen, treatment duration, and time and number of infusions to irAE onset were recorded. Non-oral irAEs were categorized into 13 groups. Patients with melanoma, pulmonary cancer, or head and neck cancer who had oral irAEs were then matched with those without oral irAEs to compare the prevalence of concomitant non-oral irAEs. Three hundred and fourteen patients with oral irAEs with a mean age of 65.9 ± 12.6 years (43.3% females) were included. Patients with multiple oral irAEs were more likely to have non-oral irAEs (OR: 2.7, 95% CI, 1.3-3.5), including cutaneous (OR: 1.7, 95% CI, 1.1-3.0), rheumatological (OR: 2.2, 95% CI, 1.1-4.2), thyroid (OR: 2.4, 95% CI, 1.2-4.9), and neurological irAEs (OR: 2.5, 95% CI, 1.0-6.3). Compared to matched patients with non-oral irAEs, patients with oral irAEs were more likely to have cutaneous (OR: 1.7, 95% CI, 1.0-2.8) and thyroid (OR: 2.86, 95% CI, 1.1-7.5) irAEs. The development of oral and non-oral irAEs is often coincidental. Patients who have non-oral irAEs should be monitored for development of oral irAEs for prompt management.

Development and validation of a risk-prediction model for immune-related adverse events in patients with non-small-cell lung cancer receiving PD-1/PD-L1 inhibitors.

Lung cancer remains the leading cause of cancer deaths worldwide and is the most common cancer in males. Immune-checkpoint inhibitors (ICIs) that target programmed cell death protein-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) have achieved impressive efficacy in the treatment of non-small-cell lung cancer (NSCLC) (Pardoll, 2012; Champiat et al., 2016; Gao et al., 2022). Although ICIs are usually well tolerated, they are often accompanied by immune-related adverse events (irAEs) (Doroshow et al., 2019). Non-specific activation of the immune system produces off-target immune and inflammatory responses that can affect virtually any organ or system (O'Kane et al., 2017; Puzanov et al., 2017). Compared with adverse events caused by chemotherapy, irAEs are often characterized by delayed onset and prolonged duration and can occur in any organ at any stage of treatment, including after cessation of treatment (Puzanov et al., 2017; von Itzstein et al., 2020). They range from rash, pneumonitis, hypothyroidism, enterocolitis, and autoimmune hepatitis to cardiovascular, hematological, renal, neurological, and ophthalmic irAEs (Nishino et al., 2016; Kumar et al., 2017; Song et al., 2020). Hence, we conducted a retrospective study to identify validated factors that could predict the magnitude of the risk of irAEs in patients receiving PD-1/PD-L1 inhibitors; our approach was to analyze the correlation between the clinical characteristics of patients at the start of treatment and relevant indicators such as hematological indices and the risk of developing irAEs. Then, we developed an economical, practical, rapid, and simple model to assess the risk of irAEs in patients receiving ICI treatment, as early as possible.

Immune checkpoint inhibitor-induced neurotoxicity is not associated with seroprevalence of neurotropic infections

BackgroundImmune checkpoint inhibitors (ICI) substantially improve outcome for patients with cancer. However, the majority of patients develops immune-related adverse events (irAEs), which can be persistent and significantly reduce quality of life. Neurological irAEs occur in 1–5% of patients and can induce severe, permanent sequelae or even be fatal. In order to improve the diagnosis and treatment of neurological irAEs and to better understand their pathogenesis, we assessed whether previous neurotropic infections are associated with neurological irAEs.MethodsNeurotropic infections that might predispose to ICI-induced neurological irAEs were analyzed in 61 melanoma patients from 3 countries, the Netherlands, Australia and Germany, including 24 patients with neurotoxicity and 37 control patients. In total, 14 viral, 6 bacterial, and 1 protozoal infections previously reported to trigger neurological pathologies were assessed using routine serology testing. The Dutch and Australian cohorts (NL) included pre-treatment plasma samples of patients treated with neoadjuvant ICI therapy (OpACIN-neo and PRADO trials; NCT02977052). In the Dutch/Australian cohort a total of 11 patients with neurological irAEs were compared to 27 control patients (patients without neurological irAEs). The German cohort (LMU) consisted of serum samples of 13 patients with neurological irAE and 10 control patients without any documented irAE under ICI therapy.ResultsThe association of neurological irAEs with 21 possible preceding infections was assessed by measuring specific antibodies against investigated agents. The seroprevalence of all the tested viral (cytomegalovirus, Epstein-Barr-Virus, varicella-zoster virus, measles, rubella, influenza A and B, human herpes virus 6 and 7, herpes simplex virus 1 and 2, parvovirus B19, hepatitis A and E and human T-lymphotropic virus type 1 and 2), bacterial (Borrelia burgdorferi sensu lato, Campylobacter jejuni, Mycoplasma pneumoniae, Coxiella burnetti, Helicobacter pylori, Yersinia enterocolitica and Y. pseudotuberculosis) and protozoal (Toxoplasma gondii) infections was similar for patients who developed neurological irAEs as compared to control patients. Thus, the analysis provided no evidence for an association of described agents tested for seroprevalence with ICI induced neurotoxicity.ConclusionPrevious viral, bacterial and protozoal neurotropic infections appear not to be associated with the development of neurological irAEs in melanoma patients who underwent therapy with ICI across 3 countries. Further efforts are needed to unravel the factors underlying neurological irAEs in order to identify risk factors for these toxicities, especially with the increasing use of ICI in earlier stage disease.

Predictors for the development of neurological immune-related adverse events of immune checkpoint inhibitors and impact on mortality.

Little is known about risk factors for developing neurological immunological adverse events (neuro-irAEs) from immune checkpoint inhibitors (ICIs). We report the incidence, predictors for development, impact on mortality of neuro-irAEs, and impact of ICIs on pre-existing neurological conditions in a large clinical cohort. Patients who received ICIs between January 2011 and December 2018 were identified from a tertiary cancer center registry. Descriptive statistics were used to summarize patient, cancer, and treatment data. Odds ratios from univariable and multivariable logistic regression models were calculated to identify potential predictors for developing a neuro-irAE. Impact of neuro-irAEs on overall survival was estimated by Kaplan-Meier and Cox proportional hazard models. Overall frequency of neurological irAEs was 2.3%. Peripheral nervous system complications were most frequent (53.6%). Melanoma, younger age, prior chemotherapy, prior resection, CTLA-4 ICIs exposure, and combination PD-1 and CTLA-4 ICIs exposure had significantly higher odds for developing a neuro-irAE (p < 0.05) in univariate but not multivariate models. Those with a neuro-irAE were less likely to die at 3 years compared to those without a neuro-irAE (69% vs. 55%, p = 0.004) in univariate but not multivariate model. Flare of pre-existing neurological condition after exposure to ICIs was present (15.4%, 2 of 13 patients) but manageable. One patient was rechallenged with ICIs without recurrent flare. Neuro-irAEs are not associated with increase in overall mortality. Potential predictors for the development of neuro-irAEs are younger age, melanoma, prior chemotherapy and resection, CTLA-4, or combination ICIs exposure.

Nerve Ultrasound of Peripheral Nerves in Patients Treated with Immune Checkpoint Inhibitors.

Background and Objectives: Immune checkpoint inhibitors (ICIs) have enriched tumor therapy, improving overall survival. Immunotherapy adverse events (irAEs) occur in up to 50% of patients and also affect the peripheral nervous system. The exact pathomechanism is unclear; however, an autoimmune process is implicated. Thus, the clinical evaluation of irAEs in the peripheral nervous system is still demanding. We retrospectively analyzed nerve ultrasound (NU) data of polyneuropathies (PNPs) secondary to checkpoint inhibitors. Materials and Methods: NU data of patients with PNP symptoms secondary to ICI therapy were retrospectively analyzed using the Ultrasound Pattern Sum Score (UPSS) as a quantitative marker. Our findings were compared with a propensity score match analysis (1:1 ratio) to NU findings in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and chemotherapy-associated PNP patients. Results: In total, 10 patients were included (4 female, mean age 66 ± 10.5, IQR 60-77), where NU was performed in 80%. The UPSS obtained ranged from 0 to 5 (mean 2 ± 1.6, IQR 1-2.5). The morphological changes seen in the NUs resembled sonographic changes seen in chemotherapy-associated PNP (n = 10, mean UPSS 1 ± 1, IQR 0-2) with little to no nerve swelling. In contrast, CIDP patients had a significantly higher UPSS (n = 10, mean UPSS 11 ± 4, IQR 8-13, p < 0.0001). Conclusions: Although an autoimmune process is hypothesized to cause peripheral neurological irAEs, NU showed no increased swelling as seen in CIDP. The nerve swelling observed was mild and comparable to ultrasound findings seen in chemotherapy-associated PNP.

Neurological Complications of Immune Checkpoint Inhibitors (P12-13.004)

<h3>Objective:</h3> To better understand the risks of neurologic toxicities associated with immune checkpoint inhibitors (ICIs). <h3>Background:</h3> Case reports have described various neurological immune-related adverse events (irAEs). There still exists a dearth of data regarding their incidence and prognosis. <h3>Design/Methods:</h3> A single center retrospective study analyzing patients between ages of 18–85 years old from the dates of 3/1/2011 to 9/30/2018 who received immunotherapy for conditions including urothelial cancer, lung cancer, gastric and colorectal cancer, head and neck cancer, lymphoma, melanoma, and renal cell carcinoma. <h3>Results:</h3> Of the 1914 subjects who received immunotherapy, 276 experienced neurotoxicity from multiple causes. Of those 276 subjects, 11 suffered neurological irAEs directly from ICI use. Of the 940 subjects who received pembrolizumab alone, 4 (0.004%) developed neurotoxicity 165 to 575 days from administration. Of the 534 subjects who received nivolumab alone, 3 (0.00956%) developed neurotoxicity 477 days from administration. Of the 594 subjects who received ipilimumab alone, 1 (0.0016%) developed neurotoxicity 27 days from administration. Of the 101 subjects who received nivolumab and ipilimumab, 1 (0.0099%) developed neurotoxicity 65 days from administration. Of the 140 subjects who received pembrolizumab and ipilimumab, 2 (0.014%) developed neurotoxicity 240 to 343 days from administration. Ninety-two subjects received atezolizumab, 7 received avelumab, and 18 received durvalumab; none of these patients experienced neurological irAEs. The neurological irAEs observed were neuropathy (45.45%), acute inflammatory demyelinating polyneuropathy (9.09%), ataxia (9.09%), seizure disorder (18.18%), autoimmune encephalitis (18.18%), receptive aphasia (9.09%) and myopathy (9.09%). Neurological irAEs were treated with steroids, intravenous immunoglobulin, and symptomatic medications like gabapentin, duloxetine, levetiracetam, and thiamine, with about 36% of subjects achieving symptom control. <h3>Conclusions:</h3> Neurological irAEs were extremely rare in our clinical population, but may correlate to the ICI used. We need larger studies to determine the most effective therapy for each neurological irAE and allow oncologists to recognize and treat them expeditiously. <b>Disclosure:</b> Dr. Babu has nothing to disclose. Dr. Sharda has nothing to disclose. Dr. Kolli has nothing to disclose. Dr. Mora-Rodriguez has nothing to disclose. An immediate family member of Dr. Boldig has received personal compensation for serving as an employee of Custom Wire Technologies. An immediate family member of Dr. Boldig has stock in Custom Wire Technologies. Tyra Gatewood has nothing to disclose. Dr. Shah has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Seagen. Dr. Shah has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for EMD Serono. Dr. Shah has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Exelixis. Dr. Swank has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Iovance Pharmaceuticals. Dr. Swank has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for HOPA. Dr. Pina has nothing to disclose. Dr. Peguero has nothing to disclose. Dr. Jaffer has nothing to disclose. Dr. Mokhtari has nothing to disclose. Neha Verma has nothing to disclose.

Two Cases of Anti-PD1 Antibody Associated Neurological Immune-Related Adverse Effects (P5-4.001)

<h3>Objective:</h3> We present two cases of neurological immune-related adverse events (irAEs) indefinitely triggered by pembrolizumab. <h3>Background:</h3> Recently, immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. Programmed cell death protein 1 (PD-1) is a key immune checkpoint receptor expressed by activated T cells. PD-1/PD-L1 antibody therapy is used to treat multiple malignancies; however, it has been associated with an increasing number of irAEs. Neurological irAEs are highly significant complications of ICI therapy that can cause long-term disability and death. Most commonly, neurological irAEs are neuromuscular complications and occur within 4 months after immunotherapy initiation. The anti-PD-1 agent pembrolizumab is currently approved for treatment of several tumors and has been used increasingly due to its more favorable toxicity profile. <h3>Design/Methods:</h3> NA <h3>Results:</h3> NA <h3>Conclusions:</h3> <h3>Case 1:</h3> Our first case is an 84-year-old man with a history of metastatic colon cancer that was treated with pembrolizumab. This is thought to have elicited myositis with elevated CK as well as acetylcholine receptor antibody-positive myasthenia gravis, causing him diffuse and debilitating weakness and functional limitation. He had multiple exacerbations of these symptoms temporally associated with pembrolizumab administration. With the initiation of maintenance treatment and the cessation of pembrolizumab, he required no further admissions for neurologic irAEs, but ultimately he was transitioned to hospice care for cancer progression. <h3>Case 2:</h3> A 65-year-old man with a history of non-small cell carcinoma of the lung on pembrolizumab and zoledronic acid presented with altered mental status and agitation. He had mild pleocytosis on CSF, MRI brain with left mesial temporal T2 FLAIR hyperintensity and nonspecific encephalopathy markers on continuous EEG. He subsequently had complete recovery with IV high-dose steroids followed by plasmapheresis. His symptoms were therefore suspected to be secondary to autoimmune encephalitis elicited by pembrolizumab administration. His oncologist elected to transition to another treatment regimen, and he has had no relapses to date. <b>Disclosure:</b> Ms. Vitek has nothing to disclose. Dr. Hansra has nothing to disclose.

Stuttering as a signal of encephalopathy associated with toripalimab in a pancreatic ductal adenocarcinoma patient: a case report

BackgroundImmune checkpoint inhibitor (ICI) combined with chemotherapy has exhibited promising results in small sample studies of pancreatic cancer patients. The efficacy of toripalimab, a programmed cell death protein 1 (PD-1) monoclonal antibody has been explored in the previous studies and it was established that immune-related adverse events (irAEs) associated with administration of this drug deserve proper attention and adequate management.Case presentationA 43-year-old female patient with advanced pancreatic ductal adenocarcinoma (PDAC) was treated with toripalimab in combination with gemcitabine and nab-paclitaxel (T-GA) as the first-line treatment. She developed immune-related encephalopathy with stuttering as the main clinical symptom and Magnetic resonance imaging (MRI) showed multiple cerebral white matter demyelination changes, concomitant with asymptomatic cardiac enzyme elevation and hypothyroidism. The symptoms resolved after the discontinuation of toripalimab and corticosteroid treatment.ConclusionsStuttering might be an early sign of neurotoxicity which can be easily neglected during the treatment. These findings provide guidance for the identification of these rare and occult neurological irAEs (n-irAEs) in the clinical practice.

Endocrine and Neurological Toxicities of Immunotherapies.

Immunotherapy has revolutionized cancer care but exposes patients to a new spectrum of complications that mimic autoimmune diseases, which are referred to as immune-related adverse events (irAEs). Endocrine complications are among the most common and involve nearly all endocrine tissues. Corticosteroids are not useful in endocrine irAEs, and definitive hormonal substitution is often indicated. Neurological irAEs can involve the central nervous system, the peripheral nervous system or the neuromuscular junction. Neurological irAEs are among the rarer complications but are associated with a higher morbidity and fatality. Therefore, prompt recognition and treatment are crucial. In this article, we discuss incidence, presentation, work-up, management, and common pitfalls in endocrine and neurological irAEs.

Association of immune-related adverse events with the outcomes of immune checkpoint inhibitors in patients with dMMR/MSI-H metastatic colorectal cancer

BackgroundImmune checkpoint inhibitors (ICIs) show a tremendous activity in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), but a consistent fraction of patients does not respond. Prognostic/predictive markers are needed. Despite...