Neurological complications of current and emerging CAR-T cell therapies.

Introduction

Immune therapies and cellular based therapies are becoming effective and standard therapies for many cancers. Many therapies exist and are in development. Chimeric antigen receptor T-cells (CAR-T) are engineered to target the immune system to antigens expressed on cancer cells, with the goal of utilizing the power and specificity of T-cells to fight cancer and potentially other serious illnesses [ 1 ]. Moreover, other cellular based therapies have been developed, such as tumor infiltrating lymphocytes (TILs) and bi-specific T cell engagers (BiTES), which are being used in solid and hematologic cancers with promising results and with the advantage of being used off-the-shelf (not manufactured for each individual patient) [ 2 , 3 ]. In this review, we will focus on CAR therapies and their potential neurologic complications, as these are presently the most widely used cell-based therapies, acknowledging the rapidly growing and expanding landscape of immune therapies for both oncologic and non-oncologic disease.

CAR-T cell therapies were first approved for use in hematologic cancers, and these therapies have been remarkable treatments for difficult to treat diseases including refractory leukemias and lymphomas [ 4 ]. Complications to these therapies include a systemic immune response causing cytopenias, fevers, and elevated inflammatory markers termed cytokine release syndrome (CRS) and a high incidence of neurologic dysfunction usually in the form of cognitive impairment with encephalopathy and motor dysfunction termed immune effector cell-associated neurotoxicity syndrome (ICANS) [ 5 ]. Neurologic complications range in severity from mild, reversible deficits to chronic neurologic deficits and even death [ 6 ]. To limit the incidence and severity of potential neurologic complications, there is ongoing work on improving CAR-T engineering and design along with work on optimizing treatment, which is reviewed below.

Additionally, CAR-T are currently being developed for non-hematologic malignancies, including tumors of the central nervous system (CNS) and non-oncologic indications such as refractory auto-immune disease [ [7] , [8] , [9] , [10] , [11] , [12] ]. With new clinical applications, new toxicities have been observed, including tumor-inflammation associated neurotoxicity (TIAN), which can be seen in patients receiving CAR-T cells for CNS tumors including glioma and CNS lymphoma [ 13 , 14 ]. Further work is needed to better understand the efficacy of these promising therapeutics, to maximize their clinical effect while minimizing toxicity to patients.

Overall, CAR-T therapies have become essential tools in the treatment of hematologic cancers and are promising therapies for solid tumors and auto-immune diseases. The prevention and treatment of neurologic toxicities is essential to maximize longevity and quality of life for patients as these therapies become more widely adopted and used for broad clinical indications.

Neurologic complications of CAR-T cells for hematologic cancers

Immune effector cell associated neurotoxicity syndrome (ICANS)

The classic neurologic toxicity from CAR-T therapies is termed immune effector cell associated neurotoxicity syndrome (ICANS). ICANS typically presents as an encephalopathy syndrome with impaired consciousness, disorientation, language abnormalities, and impaired motor function; it often develops in an acute to subacute fashion and presents in most patients 3–10 days after CAR-T infusion [ 5 ]. However, ICANS has also been described to occur up to a few weeks after CAR-T in rare cases, so it should be considered in the differential for patients with neurologic changes outside of this early period [ 15 , 16 ]. ICANS classically develops shortly after the onset of cytokine release syndrome (CRS), which is characterized by an enhanced immune response with fevers and elevated inflammatory markers, potentially affecting cardiovascular and other organ functions [ 17 ]. Severe forms of ICANS include cerebral edema and seizures [ 5 , 18 ]. Multiple mechanisms are likely involved in the development of ICANS, including systemic immune activation leading to supraphysiological cytokine release, blood brain barrier disruption, immune cells and CAR-T cells trafficking to the CNS to alter brain function [ 5 , 19 , 20 ].

In clinical practice, ICANS is assessed and monitored by a bedside scale termed the immune effector cell associated encephalopathy (ICE) score, with a grading scale ranging from 0 to 10 and with 10 being a normal score [ 17 ]. ICANS can be graded based on the ICE score, the level of consciousness, evidence of cerebral edema on imaging, and evidence of seizures [ 17 ]. Studies have identified ICANS as a common complication of CAR-T cells, and with a frequency ranging from 20 to 80%, depending on the product used and the tumor treated, and 5–10% of patients will develop grade 3 or higher ICANS [ 6 , [21] , [22] , [23] , [24] , [25] , [26] ]. With supportive treatment, most patients will eventually fully recover, though severe illness and death can occur [ 27 ].

Motor and neurocognitive treatment emergent adverse events (MNT)

A unique neurologic complication from CAR-T cell therapies targeting the B-cell maturation antigen (BCMA) used in multiple myeloma has been initially termed motor and neurocognitive treatment emergent adverse events (MNT). MNT typically presents later than ICANS, and classically is encountered 3–4 weeks post treatment, but in isolated cases it has also been reported to develop several months post treatment [ 21 , [28] , [29] , [30] , [31] , [32] ]. The clinical presentation is characterized by a picture of parkinsonism, with rigidity, tremor, bradykinesia, and cognitive dysfunction [ 32 ]. MNT has not been found to be dopamine responsive, when using carbidopa/levodopa, suggesting a different pathophysiology than idiopathic Parkinson's disease [ 21 , 31 ]. BCMA has been found to be expressed in neurons and astroglia, including in the basal ganglia, suggesting that MNT may be an off-tumor but on-target effect of BCMA-directed CAR-T therapies [ 33 ]. However, it is important to note there are some conflicting data about levels of expression of BCMA in the adult brain and more work is needed to elucidate the precise mechanisms of MNT with BCMA-targeted CAR-T [ 34 ].

MNT is overall much less common than ICANS and develops in ∼5% of patients treated with BCMA targeted therapies for multiple myeloma [ 32 ]. It was initially reported in 5 of 97 patients in the initial study of ciltacabtagene autoleucel (CARTITUDE-1) but subsequently in only one patient out of 208 in the phase 3 trial after implementation of a prevention program that prioritized reducing tumor burden prior to CAR-T and aggressive treatment of ICANS and CRS (CARTITUDE-4) [ 30 , 35 ].

Other neurologic complications

While ICANS is the most common neurologic toxicity seen after CAR-T therapies, several other neurologic toxicities have been described (please see Ref. [ 36 ] for a detailed review and consensus recommendations). These other neurologic toxicities have mostly been reported at the case report or case series level, with a need for continued monitoring and reporting from larger patient cohorts. Neurovascular events, including ischemic strokes and hemorrhage, have also been described [ [37] , [38] , [39] , [40] ]. At least 24 cases of myelopathy after CAR-T have been reported, with mechanisms for this complication hypothesized to include direct toxicity on the spinal cord from inflammatory molecules, spinal cord infarction, and on-target, off-tumor toxicity on mural cells (which can express CD19) or oligodendrocytes (which can express CD22) [ 41 ]. In addition, cranial nerve palsies occurred in 6.3% (31 of 332) of patients in trials of CAR-T targeting BCMA, classically affecting the facial nerve, and usually recovering over time [ 30 , 42 , 43 ]. Autonomic dysfunction, peripheral neuropathies, and other more complex polyradiculoneuropathies, such as Guillain-Barre Syndrome have [ 44 ] also been described post CAR-T [ 45 , 46 ], though the underlying mechanisms of such neurological adverse events are unknown.

Toxicity from associated therapies

It is important to note that CAR-T therapies are rarely given in isolation. Beyond the many previous treatments including traditional chemotherapies and radiation that most patients have received prior to proceeding with CAR-T cells, other treatments are administered as part of the CAR-T preparation process; these treatments can carry their own neurotoxicity potential. Lymphodepleting chemotherapy, classically involving fludarabine and cyclophosphamide, is given to reduce the patient's native T cells and to limit the patient's immune response against the CARs themselves. Fludarabine has been associated with a delayed onset leukoencephalopathy syndrome that can be fatal [ [47] , [48] , [49] ]. Groups are also researching further modulation of the immune system through depletion of B cells with therapies like rituximab or enhancing the immune response through immune checkpoint inhibitors (ICIs) [ 50 , 51 ]. These additional therapies have the potential of neurotoxicity themselves, so will require close monitoring when used in combination with CARs. For example, rituximab has been associated progressive multifocal leukoencephalopathy (PML), posterior reversible encephalopathy syndrome (PRES), headache, and peripheral neuropathy [ 52 ]. ICIs can cause a whole range of central and peripheral neurotoxicities including encephalitis, paraneoplastic syndromes, peripheral neuropathies, myositis, and myasthenia gravis [ 53 ].

Long-term neurologic complications from CAR-T

While the acute and subacute neurologic effects of CAR-T, including ICANS, are well described, longer term complications from CAR-T, including impact on neurocognitive function, are less well studied. Pre-clinical studies in mice suggest CAR-T can impair cognition through microglial activation, inflammatory changes and dysregulation of oligodendroglial cells [ 54 ]. Human studies, especially long-term studies are limited by patient attrition which may not be random [ 55 ]; plus, assessing any chronic changes to be caused by CAR-T therapy is complicated by the fact that patients are at risk of disease relapse and are often treated with many other therapies. When evaluated with formal neuropsychological testing, cognition appears to be stable at the population level 6–12 months after CAR-T compared to pre-CAR-T levels [ 23 , [56] , [57] , [58] ]. However, patient reported outcomes or measures of subjective cognition over time appear to have more mixed and controversial results, with some patients reporting worsening cognition and some patients reporting improving cognition over time after CAR-T [ [59] , [60] , [61] , [62] ]. Ultimately, studies of larger numbers of patients with longer follow up are needed to better assess the long-term neurologic and neurocognitive outcomes following CAR-T therapies.

Neurologic complications of CAR-T for CNS tumors

An exciting area of ongoing investigation is the use of CAR-T therapies for CNS tumors, including glioblastoma, diffuse midline glioma (DMG), and primary and secondary CNS lymphoma (PCNSL and SCNSL). While the CAR-T products for CNS solid tumors are still in early research stages, in February 2026 the FDA approved the use of axicabtagene ciloleucel (CAR-T targeting CD19) for recurrent/refractory PCNSL [ 63 ]. ICANS can also occur with CAR-T cells for CNS tumors [ 8 , 64 ]. Additionally, another neurologic complication termed tumor inflammation associated neurotoxicity (TIAN) has been described [ 14 ]. TIAN usually occurs early within the first few days of CAR-T therapy for CNS tumors (median of 3.5 days for CNS lymphoma in one cohort); an earlier onset of TIAN after intraventricular administration of CARs has been postulated when compared after intravenous administration in some solid CNS tumors [ 13 , 65 ]. It is important to note that data from clinical trials of CARs for CNS tumors, especially solid tumors, is still maturing so exact timing of onset and duration of TIAN is not well known.

TIAN is usually reversible, though can result in fatal outcome [ 13 ]. TIAN is characterized by local inflammation, and two types of TIAN have been described. In Type 1 TIAN, peri-tumoral edema and CNS inflammation can cause increased intracranial pressure, with herniation and death in its most severe form; patients can experience headaches and altered consciousness [ 14 ]. In Type II TIAN, neuronal dysfunction and circuit disruption from inflammation can cause focal neurological symptoms based on the tumor's location in the brain [ 14 ]. While cranial imaging may show no changes, some studies have reported increased edema and mass effect on CT imaging, and MRI may resemble pseudoprogression , with increased enhancement and T2/FLAIR changes that can improve with time and supportive treatment [ 14 ].

As mentioned above, TIAN occurs in CNS lymphoma patients treated with CAR-T with a frequency of ∼15–20%, with larger tumor volume pre-treatment identified as a risk factor for development of TIAN [ 13 ]. Noteworthy, patients with TIAN also appear to have improved outcomes, suggesting a link of inflammation following CAR-T cells and improved treatment response [ 13 ]. Data on rates of TIAN and other neurotoxicity have not been fully reported for solid CNS tumors as these trials remain in early stages. A phase I trial of an experimental CAR-T therapy targeting GD2 for diffuse midline glioma (DMG) found a frequency of TIAN in 100% of patients who received the therapy intraventricularly and in 91% of the patients who received it intravenously [ 8 ]. The phase I experimental CAR-T therapy targeting B7–H3 for DMG did not explicitly quantify rates of TIAN but noted 17 (81%) of patients to develop headaches and one patient to develop hydrocephalus, which could be consistent with TIAN [ 64 ]. Additionally, one patient developed grade 4 intratumoral hemorrhage. Both ICANS and TIAN have been reported in patients treated with EGFR targeted CAR-T for glioblastoma [ 7 , 9 , 66 ]. As future patients with CNS malignancies are treated with CAR-T, standardized grading for ICANs, TIAN, and other neurologic toxicities including intracerebral hemorrhage will remain important to determine the risks of these promising therapies and the best ways to treat these toxicities.

Neurologic complications of novel CAR-T for other solid cancers

As of February 2026, there are no FDA approved CAR-T therapies for solid tumors, as CAR-T therapies so far have not been as effective against solid tumors compared with their application in hematologic cancers; however, international efforts have made progress in improving these technologies to target solid tumors outside the CNS with promising results. The therapies that have published results in humans so far do not suggest that CAR-T therapies against solid tumors result in significant neurologic toxicity, though the number of patients treated has been low ( Table 1 ). The largest clinical trial published as of today is a phase 2 trial of a CAR-T product targeting CLDN18.2 for patients with gastric or esophageal cancer, with 104 patients randomized to the CAR-T group, and so far with no reported cases of ICANS [ 67 ]. Table 1 Selected sample of neurotoxicity reported for CAR therapies for solid tumors. Table 1 Paper Cancer type CAR-T target antigen Number of patients treated with CAR-T Neurologic toxicities reported Qi et al. 2025 Gastric and esophageal cancer CLDN18.2 104 0 cases of ICANS or neurologic toxicity reported Bufalo et al. 2023 Neuroblastoma GD2 and 4-1BB 27 0 cases of ICANS 1 grade 4 brain hemorrhage 6 grade 2 peripheral neurotoxicity/pain Chen et al. 2024 Colorectal cancer CD19 and GCC 15 1 grade 4 neurotoxic effect (not further described) Narayan et al. 2023 Prostate cancer PSMA 13 1 grade 3 encephalopathy within 12 h of infusion, attributed to ICANS Mackensen et al. 2023 Solid tumor of any type with CLDN6 expression CLDN6 22 1 grade 1 ICANS Hegde et al. 2024 Sarcoma HER2 13 0 cases of ICANS or neurotoxicity reported Adusumilli et al. 2021 Malignant pleural disease Mesothelin CAR-T + pembrolizumab 27 0 cases of ICANS or neurotoxicity reported (note was administered intrapleurally) Pang et al. 2021 Hepatocellular carcinoma; pancreatic carcinoma; ovarian carcinoma GPC3 or mesothelin 6 0 cases of ICANS or neurotoxicity reported Steffin et al. 2024 Solid tumors with GPC3 expression GPC3 and IL15 24 0 cases of ICANS 1 grade 1 dizziness 3 grade 1 headache 1 grade 3 agitation Shah et al. 2023 Melanoma and breast carcinoma cMET 7 0 cases of ICANS 1 grade 1 dizziness 1 grade 1 headache Pinto et al. 2024 Pediatric solid tumors B7–H3 9 0 cases of ICANS 1 grade 1 headache 1 grade 1 paresthesias Pal et al. 2024 Renal cell carcinoma CD79 (allogenic CAR-T) 16 0 cases of ICANS or neurotoxicity reported

Other targets and cancers are also being investigated with novel CAR-T applications ( Table 1 ). For example, CAR-T targeting GD2 has been used for patients with neuroblastoma, with promising efficacy signal and without reports of ICANS in a series of 27 patients without CNS involvement; of note, one patient developed altered mental status from a brain hemorrhage and 6 developed pain or peripheral neurotoxic effects (the nature and pattern of these peripheral neurotoxic effects was not further specified) [ 39 ]. One grade 4 neurologic toxicity that was not further described but resolved within 30 days with steroids was noted in a study on GCC19-targeted CAR-T therapy for patients with colorectal cancer [ 68 ]. Grade 3 ICANS was reported in 1 patient out of 13 treated with CAR-T targeted against PSMA for prostate cancer [ 69 ], and Grade 1–2 ICANS was reported in 1 patient out of 22 treated with CAR-T targeted against CLDN6 for CLDN-6 positive solid tumors [ 70 ].

Other groups have published phase 1 clinical trial results for CAR-T against HER2 for advanced sarcoma [ 71 ], mesothelin for malignant pleural diseases [ 72 ], GPC3 for hepatic cell carcinoma or pediatric solid tumors [ 73 , 74 ], cMET for melanoma and breast cancer [ 75 ], B7–H3 for pediatric solid tumors [ 76 ], and against CD70 for renal cell carcinoma [ 77 ], without any grade 3–5 neurologic toxicities or any grade of ICANS reported ( Table 1 ). While ICANS has not been a significant toxicity in these preliminary trials, it will be important to continue to monitor for potentially delayed neurologic toxicities, as further patients are treated with CAR-T for solid tumors, including those with metastatic disease to the brain or spinal cord.

Neurologic complications from novel CAR products

Beyond CAR-T therapies, which are created from T cells from the patient, there has been progress in creating allogenic CARs and CARs from other cells besides T cells [ 78 ]. Allogenic CAR-Ts provide the hope of lowering cost and production time, as an “off-the-shelf” option, but with the added potential risk of graft versus host disease (GVHD). Allogenic CARs can be created from donor peripheral blood cells, cord blood cells, or stem cells including induced pluripotent stem cells [ 78 ]. Early trials so far have shown continued risk of ICANS with allogenic CAR-T therapies for treatment of various hematologic malignancies including B-ALL (targeting CD19 or CD22) and MM (targeting BCMA) [ [79] , [80] , [81] ]. Reassuringly, they have not reported novel neurologic toxicities or higher rates of serious ICANS than the autologous CAR-T currently approved for and used in clinical practice [ [79] , [80] , [81] ]. For example, in the UNIVERSAL Phase 1 trial, 43 patients with relapsed/refractory multiple myeloma were treated with an allogenic CAR-T targeting BCMA, and 6 (14%) developed neurotoxicity, but none were of higher grade (≥ grade 3).

CARs using natural killer cells (NK cells), invariant natural killer T cells (NKT cells), and gamma delta T cells (γδ T cells) are also in development, with some early trial results suggesting efficacy, with minimal neurologic toxicity or ICANS [ 82 , 83 ]. As these cells do not induce GVHD, there is promise for improved safety of an allogenic product without requiring extensive matching of donor to patient [ 78 ]. One phase 1 trial of CAR-NK cells for patients with non-Hodgkin's lymphoma or CLL showed no neurotoxicity in 11 patients, with an impressive complete remission in 7 out of 11 patients [ 82 ]. Another recent study of 86 patients who received an allogenic CAR-NK targeted against CD19 for B cell lymphoma also reported no cases of neurotoxicity; efficacy data is still maturing [ 83 ]. CAR-NKT therapies are being studied in neuroblastoma, also with promising efficacy data without reports of neurotoxicity [ 84 ]. Allogenic CARs using various immune cells, not just T cells, remain an exciting area for further research.

Neurologic complications from CAR-T for non-oncologic disease

Recent promising work has extended the use of CAR-T therapeutics to autoimmune diseases, recognizing the potential power of CAR-T cells to modulate the immune system. Many autoimmune diseases are hypothesized to result from hyperactive B cells and antibodies targeting the patient's own antigens [ 85 ]. There are multiple ongoing phase 1 and phase 2 trials targeting various antigens on B cells for patients with autoimmune diseases including systemic lupus erythematous (SLE), myasthenia gravis (MG), multiple sclerosis (MS), and inflammatory myopathies or myositis [ 85 ]. Because CAR-T targeting CD19 leads to B cell destruction and thus aplasia, CAR-T cells targeting CD19 have been a preferred strategy. In one case series, CD19 targeted CAR-T cells were given to patients with severe SLE, idiopathic inflammatory myositis, or systemic sclerosis [ 12 ]. After an average of 15 months of follow up, all patients had stopped immunosuppressive therapy and had clinical improvement in their autoimmune disease. Reassuringly, only 1 of the 15 patients developed grade 1 ICANS, suggesting that CAR-T for autoimmune diseases is likely safe neurologically. Other case series describing patients treated with CD19 directed CAR-T for autoimmune disease also suggest there is not a significant neurologic toxicity risk, though the number of patients treated so far remains low [ [86] , [87] , [88] ]. Of note, one preliminary trial has used allogenic CAR-T for 2 patients with systemic sclerosis and one with necrotizing myopathy, reinforcing the cutting-edge nature of this work [ 87 ]. Many studies published have excluded patients with active CNS disease, but there is ongoing work in patients with MS and other nervous system autoimmune disease, with promising results and minimal or no neurotoxicity reported so far [ 89 ].

Other antigens being targeted include BCMA, sometimes with a dual target involving CD19 [ 90 ]. BCMA targeted CAR-T has been used for patients with MG; 14 patients treated in one study had improvement in symptoms and quality of life without neurotoxicity [ 91 ]. There have not been reports of MNT developing in these patients, but the numbers treated has been much lower than those treated with BCMA targeted-CAR-T for multiple myeloma. Overall, longer follow up and greater numbers of patients treated are important next steps in determining the efficacy and safety of CAR-T for autoimmune diseases, including those diseases that affect the nervous system.

Treatment options for neurologic complications of CAR-T

First line treatments

With any change in neurologic status, it is essential to first stabilize the patient and treat any active issues like seizures, or manage increased intracranial pressure (ICP). Additionally, while neurologic decline can result from CAR-T, ICANS, and TIAN, concurrent workup for alternative causes including infection, hemorrhage, medication toxicity, electrolyte abnormalities, or cancer progression is paramount. Grade 1 ICANS is typically managed with supportive care and close monitoring per the American National Comprehensive Cancer Network (NCCN) Guidelines and expert recommendations; a trial of high-dose glucocorticoids (e.g., dexamethasone 10 mg intravenously for one dose), can be considered [ 18 , 92 , 93 ]. First line treatment for grade 2 or higher ICANS is typically high-dose glucocorticoids (often dexamethasone at a dose of 10 mg every 6–12 h until clinical benefit) [ 18 , 92 ]. Higher grade ICANS may require close monitoring in an intensive care unit; methylprednisolone at high doses (1 mg/kg) every 12 h or continued high-dose dexamethasone every 6 h can be considered [ 92 ]. Steroids may only be needed for a few doses, but if there is refractory or recurrent ICANS, a taper over a few days to a few weeks, depending on the clinical situation can be considered [ 18 ]. As in other oncologic and neurologic conditions, the lowest dose of steroids for the least amount of time needed clinically is preferred, to lower the risk of side effects including immune suppression and to limit potential effects on CAR efficacy [ 94 ].

Beyond corticosteroids, immune modulatory agents are often added. Anakinra (an IL-1 receptor antagonist) is typically recommended for patients with grade 3 or higher ICANS [ 18 , 92 , 95 ]. Tocilizumab (an IL-6 receptor blocker) can be considered if there is concurrent CRS(92), but is generally avoided in the absence of CRS as it may worsen ICANS in patients without CRS [ 96 ]. The potential worsening of ICANS in patients without systemic CRS is hypothesized to occur because tocilizumab does not effectively cross the blood–brain barrier. As a result, blockade of peripheral IL-6 receptors can increase circulating IL-6 concentrations, potentially exacerbating CNS inflammation and neurotoxicity [ 97 ].

First line treatment for TIAN involves ICP management and close neurologic monitoring, potentially in the intensive care unit setting [ 13 , 14 ]. Corticosteroids and immune modulation, such as by using anakinra, are often employed [ 13 ]. Other rarer neurologic complications, including MNT, are usually treated similarly to ICANS, with glucocorticoids and immune modulation [ 93 , 97 ]. MNT has not been found to be responsive to dopamine modulation with levodopa/carbidopa in multiple case reports and is not recommended in this setting by the most recent NCCN guidelines [ 21 , 31 , 92 ].

Chemotherapy

With refractory ICANS, treatment with chemotherapy may aim to reducing the number of circulating CAR-T cells, such as with the use of cyclophosphamide and cytarabine [ 93 ], recognizing that this may also limit the otherwise desired anti-cancer effects of the immunotherapy. Some groups have used intrathecal chemotherapy (including methotrexate and cytarabine) with the goal of targeting CARs within the CNS compartment and the CSF, while avoiding killing systemic CARs [ 98 ]. MNT has also been treated with both systemic and intrathecal chemotherapy with potential benefit and symptom improvements within days to weeks [ 21 , 28 , 30 , 92 ].

Treatments in development

There are multiple ongoing studies researching ways to prevent ICANS and other neurologic toxicities, with early studies suggesting prophylactic steroids and anakinra may cause lower rates of ICANS and CRS (please see Ref. [ 93 ] for a review on such studies). Additionally, newer CAR products are being developed with kill switches (including Rimiducid or AP1903) and adapter switches with the goal of a rapid, specific way to limit the activity of CARs [ 99 ]. As mentioned above, there is also work studying lymphodepleting chemotherapy before CAR-T, the addition of other immune activating agents like ICIs, and varying doses and dose schedules, among others, with the goal of improving efficacy and limiting toxicity. Furthermore, recent research has implicated myeloid cells and the tumor microenvironment as potential mediators of CAR efficacy and toxicity, promoting strategies to improve efficacy and decrease toxicity for cellular therapies by modulate the innate myeloid cells (please see Ref. [ 100 ] for a recent review on this important area of research).

Future directions

Overall, there have been exciting developments in CAR technologies over the last few years aiming at improving therapeutic efficacy and limiting toxicities and neurological complications. CAR-T therapies have become standard of care for many relapsed or refractory hematologic cancers. Ongoing work in laboratories around the world is researching how to make these therapies safer, more efficacious, and more accessible for more patients with both neoplastic and autoimmune diseases. For example, emerging therapies including CAR-NK have suggested clinical efficacy with minimal to no neurologic toxicity in preliminary studies. As CAR therapies are given to larger numbers of patients worldwide, close monitoring of acute and potentially delayed neurologic toxicity remains paramount.

Author contributions

Jorg Dietrich (JD) and Anna Hauswirth (AH) have both conceptualized the study, prepared the initial draft, edited the manuscript, and have read and agreed to the final version of the manuscript.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Jorg Dietrich reports a relationship with Johnson & Johnson that includes: consulting or advisory. Jorg Dietrich reports a relationship with Novartis that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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