Riding the storm: managing cytokine-related toxicities in CAR-T cell therapy.

The advent of chimeric antigen receptor T cells (CAR-T) has been a paradigm shift in cancer immunotherapeutics, with remarkable outcomes reported for a growing catalog of malignancies. While CAR-T are highly effective in multiple diseases, salvaging patients who were considered incurable, they have unique toxicities which can be life-threatening. Understanding the biology and risk factors for these toxicities has led to targeted treatment approaches which can mitigate them successfully. The three toxicities of particular interest are cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and immune effector cell-associated hemophagocytic lymphohistiocytosis (HLH)-like syndrome (IEC-HS). Each of these is characterized by cytokine storm and hyperinflammation; however, they differ mechanistically with regard to the cytokines and immune cells that drive the pathophysiology. We summarize the current state of the field of CAR-T-associated toxicities, focusing on underlying biology and how this informs toxicity management and prevention. We also highlight several emerging agents showing promise in preclinical models and the clinic. Many of these established and emerging agents do not appear to impact the anti-tumor function of CAR-T, opening the door to additional and wider CAR-T applications.

Need for standardization of cytokine profiling in CAR T cell therapy.

With expansion of chimeric antigen receptor (CAR) T cell therapy and broader utilization of anti-cytokine directed therapeutics for toxicity mitigation, the routine assessment of cytokines may enhance understanding of toxicity profiles, guide therapeutic interventions, and facilitate cross-trial comparisons. As specific cytokine elevations can correlate with and provide insights into CAR T cell toxicity, mitigation strategies, and response, we explored the reporting of cytokine detection methods and assessed for the correlation of cytokines to cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) across clinical trials. In this analysis, we reviewed 21 clinical trials across 60 manuscripts that featured a US Food and Drug Administration-approved CAR T cell construct or one of its predecessors. We highlight substantial variability and limited reporting of cytokine measurement platforms and panels used across CAR T cell clinical trials. Specifically, across 60 publications, 28 (46.7%) did not report any cytokine data, representing 6 of 21 (28.6%) clinical trials. In the 15 trials reporting cytokine data, at least 4 different platforms were used. Furthermore, correlation of cytokines with ICANS, CRS, and CRS severity was limited. Considering the fundamental role of cytokines in CAR T cell toxicity, our manuscript supports the need to establish standardization of cytokine measurements as a key biomarker essential to improving outcomes of CAR T cell therapy.

Impact of diagnostic investigations in the management of CAR T-cell-associated neurotoxicity.

ABSTRACT: International guidelines regarding the management of immune effector cell-associated neurotoxicity syndrome (ICANS) recommend several diagnostic investigations, including magnetic resonance imaging (MRI), lumbar puncture (LP), and electroencephalogram (EEG) based on ICANS grade. However, the impact of these investigations has not yet been evaluated. Here, we aimed to describe the role of MRI, LP, and EEG in the management of ICANS in a cohort of real-life patients treated with chimeric antigen receptor (CAR) T cells at the University Hospital of Rennes, France. Between August 2018 and January 2023, a total of 190 consecutive patients were treated with CAR T cells. Among those, 91 (48%) developed ICANS. MRI was performed in 71 patients (78%) with ICANS, with a therapeutic impact in 4% of patients, despite frequent abnormal findings. LP was performed in 43 patients (47%), which led to preemptive antimicrobial agents in 7% of patients, although no infection was eventually detected. Systematic EEG was performed in 51 patients (56%), which led to therapeutic modifications in 16% of patients. Our study shows that EEG is the diagnostic investigation with the greatest therapeutic impact, whereas MRI and LP appear to have a limited therapeutic impact. Our results emphasize the role of EEG in the current guidelines but question the need for systematic MRI and LP, which might be left to the discretion of the treating physician.

Post-CART-T Cell Infection: Etiology, pathogenesis, and therapeutic approaches.

Chimeric antigen receptor (CAR) T cell therapy targeting CD-19 has revolutionized the treatment of refractory B-cell malignancies. However, patients undergoing this therapy face an increased risk of infections due to compromised immune function, lymphodepleting chemotherapy, hospitalization, and therapy-related complications such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome. Patients with systemic corticosteroid use, low immunoglobulin levels, and severe CRS, are at higher risk of infection. This review article highlights the spectrum of infections encountered in CAR T cell therapy, including bacterial, viral, and fungal infections. Following consensus guidelines for vaccination and immunoglobulin replacement is recommended. Clear criteria for antibiotic usage and vaccinating household members against respiratory viruses are crucial. Understanding the risk factors, spectrum of infections, and implementing appropriate prophylactic measures are essential to optimize outcomes in patients undergoing CAR T cell therapy. By prioritizing infection prevention strategies, healthcare professionals can effectively improve patient care.

Complete spectrum of adverse events associated with chimeric antigen receptor (CAR)-T cell therapies.

Chimeric antigen receptor (CAR)-T cell therapies have been approved by FDA to treat relapsed or refractory hematological malignancies. However, the adverse effects of CAR-T cell therapies are complex and can be challenging to diagnose and treat. In this review, we summarize the major adverse events, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and CAR T-cell associated HLH (carHLH), and discuss their pathophysiology, symptoms, grading, and diagnosis systems, as well as management. In a future outlook, we also provide an overview of measures and modifications to CAR-T cells that are currently being explored to limit toxicity.

Delayed-Onset Psychosis Secondary to Tacrolimus Neurotoxicity After Lung Transplant: A Case Report and Systematic Review.

BACKGROUND: Tacrolimus is the most common immunosuppressant used after transplant, yet it can result in moderate-to-severe neurotoxicity in up to 32% of patients. Signs of neurotoxicity can vary from mild (tremor or headache) to severe (posterior reversible encephalopathy syndrome or psychosis. Prompt recognition and management is needed to lead to symptom resolution. OBJECTIVE: The objective of this study is to describe the clinical presentation of tacrolimus-induced psychosis, a type of tacrolimus-inducted neurotoxicity, and distinguish it from other central nervous system disturbances, including delirium. METHODS AND RESULTS: We present a case of delayed onset tacrolimus-induced psychosis with focus on unique clinical features and management strategies. We conducted a systematic review of cases of tacrolimus-induced psychosis using the PubMed database and included 15 manuscripts in our review. CONCLUSIONS: Tacrolimus-induced psychosis is a unique presentation of tacrolimus-related neurotoxicity and can present without the cardinal symptoms of delirium. The data on isolated psychotic symptoms are limited with current literature focusing on more common presentations of tacrolimus-induced neurotoxicity, such as delirium and tremor. Development of psychosis can occur later in the treatment course and at normal tacrolimus serum levels. It can improve with antipsychotic therapies, but primary management should include cross-titration to an alternate immunosuppressant regimen.

Neurotoxicity and management of primary and secondary central nervous system lymphoma after adoptive immunotherapy with CD19-directed chimeric antigen receptor T-cells.

BACKGROUND: Chimeric antigen receptor (CAR) T-cells targeting CD19 have been established as a leading engineered T-cell therapy for B-cell lymphomas; however, data for patients with central nervous system (CNS) involvement are limited. METHODS: We retrospectively report on CNS-specific toxicities, management, and CNS response of 45 consecutive CAR T-cell transfusions for patients with active CNS lymphoma at the Massachusetts General Hospital over a 5-year period. RESULTS: Our cohort includes 17 patients with primary CNS lymphoma (PCNSL; 1 patient with 2 CAR T-cell transfusions) and 27 patients with secondary CNS lymphoma (SCNSL). Mild ICANS (grade 1-2) was observed after 19/45 transfusions (42.2%) and severe immune effector cell-associated neurotoxicity syndrome (ICANS) (grade 3-4) after 7/45 transfusions (15.6%). A larger increase in C-reactive protein (CRP) levels and higher rates of ICANS were detected in SCNSL. Early fever and baseline C-reactive protein levels were associated with ICANS occurrence. CNS response was seen in 31 cases (68.9%), including a complete response of CNS disease in 18 cases (40.0%) which lasted for a median of 11.4 ±â€…4.5 months. Dexamethasone dose at time of lymphodepletion (but not at or after CAR T-cell transfusion) was associated with an increased risk for CNS progression (hazard ratios [HR] per mg/d: 1.16, P = .031). If bridging therapy was warranted, the use of ibrutinib translated into favorable CNS-progression-free survival (5 vs. 1 month, HR 0.28, CI 0.1-0.7; P = .010). CONCLUSIONS: CAR T-cells exhibit promising antitumor effects and a favorable safety profile in CNS lymphoma. Further evaluation of the role of bridging regimens and corticosteroids is warranted.

Valproate overdose leading to hyperammonaemic encephalopathy.

Sodium valproate is a commonly prescribed anticonvulsant medication; however, it can cause uncommon side effects such as hyperammonaemia and encephalopathy. We present the case of a male in his early 50s brought to the emergency department after being found collapsed by his wife, with an empty bottle of sodium valproate tablets. The patient developed hyperammonaemic encephalopathy due to sodium valproate overdose and was treated with supportive care and renal replacement therapy. This case highlights the importance of recognising the potential complications of sodium valproate and its prompt treatment.

Advances in treatments of patients with classical and emergent neurological toxicities of anticancer agents.

The neurotoxicity associated to the anticancer treatments has received a growing body of interest in the recent years. The development of innovating therapies over the last 20years has led to the emergence of new toxicities. Their diagnosis and management can be challenging in the clinical practice and further research is warranted to improve the understanding of their pathogenic mechanisms. Conventional treatments as radiation therapy and chemotherapy are associated to well-known and under exploration emerging central nervous system (CNS) and peripheral nervous system (PNS) toxicities. The identification of the risk factors and a better understanding of their pathogeny through a "bench to bedside and back again" approach, are the first steps towards the development of toxicity mitigation strategies. New imaging techniques and biological explorations are invaluable for their diagnosis. Immunotherapies have changed the cancer treatment paradigm from tumor cell centered to immune modulation towards an efficient anticancer immune response. The use of the immune checkpoints inhibitors (ICI) and CAR-T cells (chimeric antigen receptor) lead to an increase in the incidence of immune-mediated toxicities and new challenges in the neurological patient's management. The neurological ICI related adverse events (n-irAE) are rare but potentially severe and may present with both CNS and PNS involvement. The most frequent and well characterized, from a clinical and biological standpoint, are the PNS phenotypes: myositis and polyradiculoneuropathy, but the knowledge on CNS phenotypes and their treatments is expanding. The n-irAE management requires a good balance between dampening the autoimmune toxicity without impairing the anticancer immunity. The adoptive cell therapies as CAR-T cells, a promising anticancer strategy, trigger cellular activation and massive production of proinflammatory cytokines inducing frequent and sometime severe toxicity known as cytokine release syndrome and immune effector cell-associated neurologic syndrome. Their management requires a close partnership between oncologist-hematologists, neurologists, and intensivists. The oncological patient's management requires a multidisciplinary clinical team (oncologist, neurologist and paramedical) as well as a research team leading towards a better understanding and a better management of the neurological toxicities.

How I treat unique and difficult-to-manage cases of CAR T-cell therapy-associated neurotoxicity.

With growing indications for chimeric antigen receptor (CAR) T-cell therapy, toxicity profiles are evolving. There is an urgent and unmet need of approaches to optimally manage emerging adverse events that extend beyond the standard paradigm of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS). Although management guidelines exist for ICANS, there is little guidance on how to approach patients with neurologic comorbidities, and how to manage rare neurotoxicity presentations, such as CAR T-cell therapy-related cerebral edema, severe motor complications or late-onset neurotoxicity. In this study, we present 3 scenarios of patients treated with CAR T cells who develop unique types of neurotoxicity, and we describe an approach for the evaluation and management based on experience because objective data are limited. The goal of this study is to develop an awareness of emerging and unusual complications, discuss treatment approaches, and help institutions and health care providers establish frameworks to navigate how to best address unusual neurotoxicities to ultimately improve patient outcomes.

Multifocal demyelinating leukoencephalopathy and oligodendroglial lineage cell loss with immune effector cell-associated neurotoxicity syndrome (ICANS) following CD19 CAR T-cell therapy for mantle cell lymphoma.

Immune effector cell-associated neurotoxicity syndrome (ICANS) is a prevalent condition seen after treatment with chimeric antigen receptor T-cell (CAR T) therapy and other cancer cell therapies. The underlying pathophysiology and neuropathology of the clinical syndrome are incompletely understood due to the limited availability of brain tissue evaluation from patient cases, and a lack of high-fidelity preclinical animal models for translational research. Here, we present the cellular and tissue neuropathologic analysis of a patient who experienced grade 4 ICANS after treatment with anti-CD19 CAR T therapy for mantle cell lymphoma. Our pathologic evaluation reveals a pattern of multifocal demyelinating leukoencephalopathy associated with a clinical course of severe ICANS. A focused analysis of glial subtypes further suggests region-specific oligodendrocyte lineage cell loss as a potential cellular and pathophysiologic correlate in severe ICANS. We propose a framework for the continuum of neuropathologic changes thus far reported across ICANS cases. Future elucidation of the mechanistic processes underlying ICANS will be critical in minimizing neurotoxicity following CAR T-cell and related immunotherapy treatments across oncologic and autoimmune diseases.

Aciclovir-induced neurotoxicity.

Aciclovir-induced neurotoxicity results from the accumulation of aciclovir and its metabolite 9-carboxymethoxymethylguanine (CMMG). It occurs predominantly in older patients with impaired renal function and is characterised by a combination of confusion and psychiatric changes. Seizures, myoclonus and dysarthria may also occur. Critically, peritoneal dialysis has little effect on reversing the toxic effects of aciclovir. We describe a woman in her 70s with renal failure who developed confusion and seizures after receiving aciclovir. She was ultimately diagnosed with aciclovir-induced neurotoxicity, confirmed by an elevated serum CMMG concentration. This condition is likely to be underdiagnosed and the neurologist's primary challenge is differentiating aciclovir-induced neurotoxicity from viral encephalitis.

Dose fractionation of CAR-T cells. A systematic review of clinical outcomes.

CAR-T cells are widely recognized for their potential to successfully treat hematologic cancers and provide durable response. However, severe adverse events such as cytokine release syndrome (CRS) and neurotoxicity are concerning. Our goal is to assess CAR-T cell clinical trial publications to address the question of whether administration of CAR-T cells as dose fractions reduces toxicity without adversely affecting efficacy. Systematic literature review of studies published between January 2010 and May 2022 was performed on PubMed and Embase to search clinical studies that evaluated CAR-T cells for hematologic cancers. Studies published in English were considered. Studies in children (age < 18), solid tumors, bispecific CAR-T cells, and CAR-T cell cocktails were excluded. Data was extracted from the studies that met inclusion and exclusion criteria. Review identified a total of 18 studies that used dose fractionation. Six studies used 2-day dosing schemes and 12 studies used 3-day schemes to administer CAR-T cells. Three studies had both single dose and fractionated dose cohorts. Lower incidence of Grade ≥ 3 CRS and neurotoxicity was seen in fractionated dose cohorts in 2 studies, whereas 1 study reported no difference between single and fractionated dose cohorts. Dose fractionation was mainly recommended for high tumor burden patients. Efficacy of CAR-T cells in fractionated dose was comparable to single dose regimen within the same or historical trial of the same agent in all the studies. The findings suggest that administering dose fractions of CAR-T cells over 2-3 days instead of single dose infusion may mitigate the toxicity of CAR-T cell therapy including CRS and neurotoxicity, especially in patients with high tumor burden. However, controlled studies are likely needed to confirm the benefits of dose fractionation.

Wearables, sensors, and smart devices for the detection and monitoring of chemotherapy-induced peripheral neurotoxicity: Systematic review and directions for future research.

Chemotherapy-induced peripheral neurotoxicity (CIPN) diagnosis is largely based on patient reported outcomes. Wearables, sensors, and smart devices may potentially provide early detection and monitoring of CIPN. We systematically reviewed data on wearables, sensors, and smart devices to detect and/or monitor signs and symptoms of CIPN. Moreover, we provide directions and recommendations for future studies. A literature search using PubMed/MEDLINE, Web of Science, IEEE Xplore, and CINHAL databases was conducted from database inception until March 2021. The search was further updated in July 2022 to ensure currency of results. A total of 1885 records were title-abstract screened, 33 full texts were assessed, and 16 were included. The retrieved papers were heterogeneous in terms of study design, sample size, CIPN severity, chemotherapy agents, type of wearable/sensor/device applied, parameters of interest, and purpose. Data are promising and provide preliminary evidence on wearables, sensors, and smart devices for CIPN detection and monitoring. There are several issues and knowledge gaps that should be addressed. We propose a framework for future studies.

Methamphetamine induced neurotoxic diseases, molecular mechanism, and current treatment strategies.

Methamphetamine (MA) is a extremely addictive psychostimulant drug with a significant abuse potential. Long-term MA exposure can induce neurotoxic effects through oxidative stress, mitochondrial functional impairment, endoplasmic reticulum stress, the activation of astrocytes and microglial cells, axonal transport barriers, autophagy, and apoptosis. However, the molecular and cellular mechanisms underlying MA-induced neurotoxicity remain unclear. MA abuse increases the chances of developing neurotoxic conditions such as Parkinson's disease (PD), Alzheimer's disease (AD) and other neurotoxic diseases. MA increases the risk of PD by increasing the expression of alpha-synuclein (ASYN). Furthermore, MA abuse is linked to high chances of developing AD and subsequent neurodegeneration due to biological variations in the brain region or genetic and epigenetic variations. To date, there is no Food and Drug Administration (FDA)-approved therapy for MA-induced neurotoxicity, although many studies are being conducted to develop effective therapeutic strategies. Most current studies are now focused on developing therapies to diminish the neurotoxic effects of MA, based on the underlying mechanism of neurotoxicity. This review article highlights current research on several therapeutic techniques targeting multiple pathways to reduce the neurotoxic effects of MA in the brain, as well as the putative mechanism of MA-induced neurotoxicity.

Stress-another possible mechanism of neurotoxicity in neurodegenerative diseases

Theliteratureassociatesoxidativestresswiththeproductionoffreeradicals,whichleadtoneurodegeneration.Theypresentinnumerablehypotheses,amongwhichareabnormalitiesinthefunctioningofthehypothalamic-pituitary-adrenalaxis,neurotoxiceffectsandneuronaloxidativedamage.ClinicalobservationhasshownthatinneurodegenerativediseasessuchasMultipleSclerosis(MS)andAmyotrophicLateralSclerosis(ALS)thereisareportofprolonged or violent emotionalstressprecedingthesymptoms.Aims:UsingtheCarilloComplexSystemsModel,presentsomepossibilitiesonhowstresscancontributetoneurodegeneration.Methodology:NinecasesofALSandsixcasesofMSwereevaluated,pathologiesalreadyclassifiedasbelongingtosyphilinism.Literaturereviewonstressandneurotoxicitycarriedout.Resultsanddiscussion:Syphilinism is instability with a predominantly intrinsicorigin to the system with a chronic caracter.This diathesis is characterized by a dissipative deficiency, predominantly hepatic, to the processing of certain elements or potentially toxic substances with exogenous origin or endogenous Such non-processed substances are unstable factors in the system, with greater affinity for certain tissues,like the nervous system. Among the toxins, we find alcohol, esters, formaldehyde, aloe, ketones, aldehydes, etc. The final hepatic metabolism of cortisol results in cortic acids and cortol, which use the same enzymatic system as alcohol, and can be considered syphilinic toxins. Ethanol can act directly at the circadian rhythm, disrupting it and generating stressful substances such as cortisol, regardless of an external event, increasing the toxin level. The inflammatory process generated by the production of free radicals and metabolic abnormalities, including the reduction of neuropeptide Y that modulates inflammatory activity in the nervous system, leads to changes that can result in neurodegeneration. Conclusion: Inflammation caused by toxins from prolonged/violent emotional stress can lead to several changes in syphilinic individuals, due to failure in the dissipative process, including neurodegeneration.

Síndrome de neurotoxicidad asociada a células inmunoefectoras: un enfoque terapéutico en el paciente crítico / Immune effector cell-associated neurotoxicity syndrome: A therapeutic approach in the critically ill

La inmunoterapia con células T modificadas con receptor quimérico antígeno-específico (chimeric antigen receptor conocida como [CAR-T]) está emergiendo como un tratamiento prometedor para enfermedades hematológicas. Así, las CAR-T dirigidas contra el complejo de diferenciación 19 han demostrado gran eficacia antitumoral contra neoplasias de células B resistentes a terapias convencionales. Sin embargo, la activación dirigida de la respuesta inmunitaria desata en ciertos casos complicaciones específicas graves y potencialmente mortales. Entre ellas cabe destacar el síndrome de liberación de citoquinas y el síndrome de toxicidad neurológica asociado a la terapia con células inmunoefectoras (Immune-effector cell associated neurotoxicity syndrome conocido como ICANS), siendo este último el objetivo de nuestra revisión. Aunque los mecanismos fisiopatológicos que conducen al ICANS son poco conocidos, existen factores clínicos y biológicos que aumentan el riesgo de desarrollo de neurotoxicidad asociada a la terapia CAR-T. El tratamiento se basa en medidas de monitorización y soporte, tratamiento con anticonvulsivantes, corticosteroides e ingreso en los servicios de medicina intensiva de forma precoz. Este artículo proporciona una revisión exhaustiva de la literatura disponible sobre el ICANS desde una perspectiva multidisciplinar, incluyendo recomendaciones de intensivistas, neurólogos y hematólogos formados en el cuidado de adultos críticamente enfermos (AU)

Immunotherapy with chimeric antigen-specific receptor modified T cells, known as CAR-T, is emerging as a promising approach to hematological malignancies. In this regard, CAR-T against human cluster of differentiation (CD) 19 has demonstrated antitumor efficacy in application to B cell neoplasms resistant to conventional therapy. However, activation of the immune system induces severe and specific complications which can prove life-threatening. These include cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (known as ICANS) - the latter being the subject of the present review. Although the physiopathological mechanisms underlying ICANS are not well known, a number of clinical and biological factors increase the risk of developing neurotoxicity associated to CAR-T therapy. Treatment is based on close monitoring, measures of support, anticonvulsivants, corticosteroids, and early admission to intensive care. The present study offers a comprehensive review of the available literature from a multidisciplinary perspective, including recommendations from intensivists, neurologists and hematologists dedicated to the care of critically ill adults (AU)

Immune effector cell-associated neurotoxicity syndrome: A therapeutic approach in the critically ill.

Immunotherapy with chimeric antigen-specific receptor modified T cells, known as CAR-T, is emerging as a promising approach to hematological malignancies. In this regard, CAR-T against human cluster of differentiation (CD) 19 has demonstrated antitumor efficacy in application to B cell neoplasms resistant to conventional therapy. However, activation of the immune system induces severe and specific complications which can prove life-threatening. These include cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (known as ICANS) - the latter being the subject of the present review. Although the physiopathological mechanisms underlying ICANS are not well known, a number of clinical and biological factors increase the risk of developing neurotoxicity associated to CAR-T therapy. Treatment is based on close monitoring, measures of support, anticonvulsivants, corticosteroids, and early admission to intensive care. The present study offers a comprehensive review of the available literature from a multidisciplinary perspective, including recommendations from intensivists, neurologists and hematologists dedicated to the care of critically ill adults.