CAR T-клеточная терапия для неврологических расстройств: научное обоснование и механистические исследования.

Introduction

The introduction of biosynthetically engineered chimeric antigen receptor (CAR) T-cells in the treatment of hemato-oncological disorders has had a transformative impact. 1 Difficult to treat patients with relapsed or refractory (r/r) aggressive B-cell lymphoma achieved deep and long-lasting remissions highlighting the curative potential of this therapy. 2 One of the very first clinical trials in r/r diffuse large B-cell lymphoma (i.e., ZUMA-1) 3 increased the patients’ 2-year overall survival to 50% as compared to 17% in historical controls. 4 Consequently, every year new commercial CAR T-cell products gain regulatory approval for new indications and CAR T-cells already in use are approved for being used at earlier lines. At the same time, significant progress is being made both in the design of next-generation CAR constructs and in the use of alternative cell types, such as NK-cells or macrophages, instead of T-cells. The next major breakthrough is expected with the introduction of allogeneic cell products, which aim to improve accessibility to the still highly expensive CAR T-cell therapies. Moreover, the results in solid tumors remain insufficient, and extensive research and development efforts are focused on overcoming the barriers imposed by the tumor microenvironment (TME). Approaches include genetically modifying CAR cells to secrete cytokines such as interleukin-12 (IL-12) or using mRNA-based vaccines for repetitive restimulation of CAR T cells. 5 , 6 Overall, this presents a promising outlook for bench-to-bedside pharmaceutical optimization and signals a productive dialog among multidisciplinary teams. Due to their unique ability to achieve deep depletion of target cells even within inflammatory niches, CAR T cells are currently being repurposed for use in autoimmune diseases (AIDs). What started with a few case reports has rapidly evolved, and by 2025, more than a hundred active clinical trials will be underway—further highlighting the potentially transformative impact of this approach. Although AIDs are not always acutely life-threatening, they significantly impair quality of life, lead to irreversible organ damage, necessitate lifelong use of often potent immunosuppressive medications, and impose a substantial socioeconomic burden. 7 In this review, we will explore the evolution of cellular therapies leading to CAR T-cells and explain why CAR T-cell therapy might hold great promise for AIDs, including those within the neurological spectrum.

Literature search

A literature search was performed in the PubMed database. There were no language or publication date restrictions. Only studies in humans that used CAR therapy in any of its forms in patients with autoimmune neurological disorders (including multiple sclerosis (MS), neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein antibody-associated disease, myasthenia gravis (MG), Lambert–Eaton myasthenic syndrome, stiff-person syndrome, autoimmune peripheral neuropathies, and autoimmune encephalitis) were included. The last search date was August 11, 2025. In total, 2686 publications were screened, which provided individual data on cumulatively 63 patients with a neurological AID within the scope of this review. The identified published studies with the patient data are depicted in Table 1 . 8 – 24

Basic principles of T cell-based adoptive cell therapy

The most successful and widely used immunotherapy to date is allogeneic hematopoietic stem cell transplantation (allo-HSCT). Following myeloablative chemo- and/or radiotherapy, the patient’s immune system reconstitutes from the donor’s stem cells and ideally eliminates residual malignant cells, while balancing between the so-called “graft-versus-host (GvH) and graft-versus-tumor (GvT) effect.” 25 Notably, allo-HSCT is also used in AIDs, where the goal is less about GvT effects and more about eliminating a pathogenic immune system. However, due to its substantial treatment-related mortality, largely driven by graft-versus-host disease (GvHD), it is certainly not considered a standard therapy. Owing to that, conventional immunotherapy in AIDs mainly targets nonspecifically the effector B-cell compartment in a time-limited manner via monoclonal antibodies, mechanistically blocking the propagation of the immune dysregulation but not necessarily achieving an “immunological reset,” as will later be discussed. This approach echoes the difference of treatment goals in each patient group, with respect to terminality of disease and preservation of living standards, and is one of the major discussion points underpinning CAR T-cell therapy in nonmalignant diseases.

It is now widely accepted that the transplanted and reconstituted donor T cells are the key mediators of the GvT effect. 26 A logical refinement, therefore, would be to artificially redirect the action of the infused T-cells against highly specific and well-characterized disease-associated antigens, enabling targeted activity while minimizing side effects such as GvHD. This approach has been exemplified in studies exploring the application of T-cell receptor (TCR)-engineered T-cells that target tumor-specific or tumor-associated antigens. 27 These biomedical advances are driven by a deep understanding of T-cell function at the molecular level.

The structural and functional basis of T-cell antigen recognition is facilitated by the membrane-bound TCR complex and its co-receptors. 28 In brief, the TCR is closely associated with invariant CD3 proteins, particularly CD3ζ, which plays a crucial role in intracellular signal transduction upon antigen binding. This occurs through immunoreceptor tyrosine-based activation motifs that initiate a cascade of protein phosphorylation. 29 Similar to immunoglobulin (Ig) molecules, the TCR repertoire recognizes antigens through gene rearrangements; however, unlike Ig, it does not undergo somatic hypermutation to refine antigen affinity over time. As another key distinction from the Ig on the surface of B-cells, which can bind free-floating antigens in their native form, T cells rely on their TCR to recognize antigens only when they are processed into peptide fragments and presented by major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs) or their target cells (i.e., infected, malignant, or foreign cells). Furthermore, following successful antigen binding, the ensuing T-cell immune response depends on so-called “co-stimulatory molecules.” Both, suboptimal and persistent co-stimulation can lead to functional inertness and exhaustion. 30 A hallmark example of effective co-stimulation enabling T-cell activation and proliferation is the interaction between CD28 on T-cells and CD80 or CD86 on APCs. 31 In summary, successful T-cell activation hinges on the formation of the immunologic synapse, which depends on the spatiotemporal dynamics of the involved molecules. The goal is to enhance the efficacy of adoptively transferred T cells, especially in overcoming the barriers imposed by the TME.

The core principle of the CAR concept is the integration and optimization of these insights ( Figure 1(a) ). 1 Unlike conventional TCR-mediated T-cell activation, which relies on three separate components—antigen recognition, activation signaling, and co-stimulation—CARs combine all three functions within a single molecule at fixed ratios. Moreover, antigen recognition occurs in an MHC-independent manner, and the construct is highly modifiable, allowing for extensive optimization. In addition to T cells, other innate immune cells, such as NK-cells or macrophages, 32 , 33 can serve as cellular carriers. This highlights the versatility of the approach, though it is not discussed in detail in this review.

CAR T-cell designs and approved therapies

CARs are engineered type I transmembrane proteins composed of three main domains: an amino-terminal extracellular domain, a transmembrane domain, and a carboxy-terminal intracellular domain. The molecule can be divided into five distinct regions, with the antigen-binding domain being the most critical. This domain is typically a single-chain variable fragment (scFv), which is formed by linking the variable regions of an antibody’s heavy (VH) and light (VL) chains via a flexible peptide linker. Variable regions of heavy-chain-only antibodies (VHHs or nanobodies) represent an interesting alternative offering the advantage of simpler molecular reconfiguration and of accessing an extended array of epitopes. 34 VHHs are camelid-derived, whereas scFvs can be murine, humanized, or fully human. Among scFvs, fully human variants are preferred as they minimize immunogenicity, enhance persistence, and reduce the risk of antidrug antibody (ADA) responses. 35 The clinical efficacy of the VHH-based design was proven with the approval of ciltacabtagen-autoleucel (cilta-cel) for r/r multiple myeloma (MM). 36 Cilta-cel comprises two llama-based VHH regions that bind two different B-cell maturation antigen (BCMA) epitopes. The choice of target antigen for each CAR is based on the disease’s pathophysiology. For currently approved CAR constructs, CD19 was selected due to its uniform expression on B-cell lineage, making it a key target in B-cell lymphomas and acute lymphoblastic leukemia (ALL). Similarly, BCMA was chosen for its specificity to plasma cells in MM. 37 However, targeting alternative antigens may offer additional therapeutic benefits depending on the clinical context, 38 or in a potential relapse via antigen escape, as may be the case for GPRC5D-targeting in MM. 39

The hinge region flexibly connects the antigen-binding domain to the stable transmembrane domain. Collectively, these regions influence CAR T-cell signaling, primarily by determining the receptor’s overall molecular and mechanical properties. 40 The choice and number of intracellular co-stimulatory domains have been the key determinants in defining CAR T-cell generations. The prototypic first-generation CAR construct engineered by Zelig Eshhar and colleagues included only CD3ζ signaling as its intracellular activation domain ( Figure 1(b) ). 41 It enabled in vitro cytotoxicity but failed to sustain T-cell expansion in vivo, limiting its therapeutic efficacy. 42 Subsequent studies highlighted the critical role of incorporating co-stimulatory domains—such as CD28, 4-1BB, ICOS, and OX40—to achieve full T-cell activation, cytotoxicity, expansion, and persistence. 43 Clinical and preclinical evidence suggests that the choice of co-stimulatory molecule influences key differences between CAR constructs, including kinetics, metabolic characteristics, toxicity, and efficacy, though no single molecule has been definitively proven superior. 44 , 45 CD28-based CARs are associated with faster and more intense signaling, not only driving effector memory differentiation but also increasing the risk of T-cell exhaustion. In contrast, 4-1BB-based CARs promote central memory differentiation through slower, more sustained signaling, enhancing long-term persistence. 46 Emerging research is also exploring how spatiotemporal dynamics of CAR activation may differ from the physiological TCR-immunological synapse, potentially influencing T-cell subset selection and function. 47 – 49 All CAR T-cell therapies approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) currently belong to the second generation and are approved exclusively for hematologic malignancies. 50 – 56 Their characteristics are summarized in Table 2 .

The introduction of a second co-stimulatory domain to the now established second-generation CAR backbone led to the development of third-generation CARs. However, this modification did not result in a breakthrough comparable to the transition from first- to second-generation CARs. 63 The more experimental fourth- and fifth-generation CAR T-cells, though lacking a formal definition, have moved away from previous structural improvements and focus instead on integrating constitutive cytokine secretion and optimizing intracellular signaling at the genetic level. 5 , 64 , 65 Despite their potential, none of these advanced CAR designs have been systematically tested in large-scale clinical studies yet. Particularly in neurological AIDs, most studies employ established second-generation CAR constructs incorporating either CD28 or 4-1BB co-stimulatory domains, while dual-CAR designs are increasingly being explored to improve efficacy.

Therefore, CAR design provides numerous opportunities to modify each domain, allowing for tumor-specific adaptation and precise customization of CAR function. How this modification translates to clinical benefit is a more nuanced subject, though. The roles of CAR construct design, costimulatory domains, and the optimal target antigen remain unresolved and may depend on both disease characteristics and individual patient factors.

Theoretically, and especially for AIDs, fully human CARs should offer advantages in terms of better tolerability and a reduced risk of developing ADAs, which are more common in patients with AIDs. 66 Up until the point of writing though, all of the above strategies for extracellular domain-construction (i.e., murine, 9 , 17 humanized, 16 and fully human CARs) 8 , 13 have been used, so the question which ones are indeed comparatively preferable in AIDs remains open.

Regarding the CAR target molecule, CD19 remains the most equivocal target for B-cell-mediated AIDs. Efficacy data from anti-BCMA-directed CAR T-cell approaches in anti-signal recognition particle (SRP) necrotizing myopathy and MG, though, the latter with a bispecific approach, have also been promising. 16 , 67 Other targeted approaches are also being explored, such as in MuSK-positive MG, where chimeric autoantibody receptor T-cells selectively eliminate the B-cell population producing the well-defined pathogenic autoantibody. 68 However, given that the pathogenic role of B-cells extends beyond autoantibody production, it remains an open question how these approaches will holistically impact B-cell populations and ergo disease pathology. While humoral immunity may not be impaired, a major safety goal, it will be particularly interesting to assess the effectiveness of these treatments. Partly accounting for this, there have been efforts in utilizing fourth-generation CAR T-cells. Three patients with refractory rheumatoid arthritis were recently successfully treated with anti-CD19 CAR T-cells also secreting antibodies against IL-6 and TNFα, which are central to the disease pathophysiology—as well as intricately involved with “cytokine release syndrome” (CRS). 69 A concurrent engagement of both the pathogenic antibodies and the underlying immune effectors, with a theoretically reduced incidence of CRS complications, is a very appealing structure.

As to the inherent CAR characteristics, one emerging insight is that CAR T-cell persistence does not necessarily appear to be a prerequisite for therapeutic success in AIDs, in contrast to malignant diseases. 70 Interestingly, even though CAR T-cells in AID patients often persist for only a short period and show signs of diminished functional activity, clinical responses tend to be sustained, suggesting that long-term persistence may not be required for therapeutic efficacy in this setting. This phenomenon may reflect disease-specific dynamics rather than intrinsic T-cell dysfunction. One plausible explanation is that the regenerating hematopoietic compartment, less affected by cytotoxic preconditioning in AIDs than in malignancies, could competitively displace CAR T cells. Additionally, the typically low antigen burden in AIDs may limit antigen-driven expansion and persistence. If confirmed, these factors would suggest that long-term CAR T-cell persistence is not required for therapeutic efficacy in AIDs, thereby shifting construct priorities toward transient but potent immune modulation, such as that achieved with mRNA-based CAR T-cell therapies. Third-generation CAR constructs have indeed shown persistence of up to 2 years in a single AID patient in remission. 71

Further opportunities along the manufacturing process, including allogeneic and RNA-engineered CARs, will be discussed in subsequent paragraphs ( Figure 2 ).

CAR T-cell-associated toxicities

Since their introduction in clinical trials, CAR T-cell therapies have been linked to a distinct set of complications, many of which have been extensively analyzed in relevant reviews. 72 – 75 CAR T-cell therapies are associated with two major toxicities: CRS and immune effector cell-associated neurotoxicity syndrome (ICANS), both of which occur in a significant proportion of treated patients ( Table 3 ). 76 CRS results from CAR T-cell activation, triggering the release of proinflammatory cytokines such as IL-6, IL-1, and interferon-gamma, which further stimulate myeloid cells to amplify cytokine production, leading to a systemic hyperinflammatory response. The severity of CRS correlates with tumor antigen burden, as a higher number of target antigens drives stronger CAR T-cell activation and more intense cytokine release. While the pathophysiology of CRS is well characterized, ICANS remains less clearly understood. Excessive influx of pro-inflammatory cytokines into the central nervous system (CNS), facilitated by increased blood-brain barrier (BBB) permeability and resulting in microglia activation, has been proposed as key mechanisms, with IL-1 and localized inflammatory axes such CXCL16/CXCR6 and CCR5 overexpression in CD4+ T-cells playing a potential role. 77 – 80 In anti-CD19 CAR T-cell therapies, additional on-target, off-tumor effects on CD19-expressing mural cells in the brain may further exacerbate neurotoxicity. 81 Both CRS and ICANS develop against a backdrop of endothelial inflammation, which may be influenced by disease-specific or genetic predisposition, and prognostic models for risk stratification are currently being validated. 82 , 83 Clinical and real-world data suggest that CD28-based co-stimulation is associated with a higher incidence of ICANS in ALL, likely due to faster CAR T-cell expansion postinfusion. 84 Additional factors implicated in increased CRS and ICANS risk include high tumor burden, which leads to heightened cytokine release, as well as baseline inflammatory status, preexisting neurological conditions, older age, and the intensity of the lymphodepleting regimen. 85 – 87 Strategies to mitigate these toxicities are under investigation, including fine-tuning second-generation CAR constructs to optimize intracellular signaling, as well as implementing a fixed CD4 + to CD8 + T-cell ratio, which may promote a more balanced immune response. 88 , 89 Additionally, predictive models are being developed to anticipate adverse events and account for product-specific heterogeneity. 90 Ongoing research aims to further refine CAR designs and identify biomarkers that can predict toxicity, ultimately enhancing the safety of CAR T-cell therapies without compromising efficacy.

Clinically, the presentation of CRS and ICANS can vary significantly, ranging from mild, flu-like symptoms and neuropsychological disturbances to severe cases requiring intensive care unit (ICU) admission. 91 Notably, laboratory markers and cytokine levels do not directly determine CRS grading, although radiological findings—such as leptomeningeal enhancement, brainstem involvement, or cerebral edema affecting the thalami—may suggest ICANS development in the appropriate clinical context. 92 , 93 The typical onset of CRS occurs within the first 1–14 days postinfusion, peaking within the first week depending on the CAR T-cell product used. In contrast, ICANS tends to present slightly later, typically between days 3 and 6, peaking on days 7–8, and resolving within 2–3 weeks. Treatment strategies primarily involve blocking implicated cytokine receptors or signaling cascades, particularly IL-6 and IL-1, with agents such as tocilizumab and anakinra. 94 – 96 However, tocilizumab has demonstrated efficacy in managing ICANS primarily when accompanied by CRS. Due to its presumed limited penetration into the cerebrospinal fluid, which may paradoxically result in elevated IL-6 levels within the CNS, some experts recommend avoiding its use in cases of isolated ICANS or when CRS is limited to grade 1. 73 , 97 Further clarification of these clinical nuances, as well as the refinement of current treatment strategies, would require evidence from prospective randomized controlled trials. 98

While ICANS is generally considered to be reversible, 99 it is still not well known whether there are any long-term effects of CAR T-cell therapy on patient cognition. In a study by Ruark et al., 100 37.5% of patients reported cognitive difficulties in a patient-reported outcome measure-format 1 year after administration of CAR T-cells; this study though, lacked a relevant pre-administration baseline value. Moreover, perceived impaired cognition and objectively measurable cognitive impairment are only weakly correlated, 101 and yet there is a paucity on studies combining the two. Some of the available studies indicate no significant burden in cognitive outcomes, but owing to small sample sizes and heterogeneous results, more evidence is required for formal conclusions. 99 , 102 , 103

Regarding corticosteroid use, initial concerns about impairing CAR T-cell expansion have been addressed by recent studies, which indicate that early corticosteroid administration can mitigate the initial inflammatory cascade without significantly compromising long-term disease control or survival outcomes. 104 Nevertheless, any acute intervention for CAR-T-related toxicities may influence the infused CAR T-cell dynamics, potentially affecting the patient’s long-term therapeutic benefit. CRS and ICANS must also be distinguished from immune effector cell-associated hemophagocytic syndrome (IEC-HS), a rare but distinct manifestation of secondary macrophage activation syndrome or hemophagocytic lymphohistiocytosis, that has been primarily observed with T-cell engager (TCE) therapy. IEC-HS typically occurs later in the clinical course and is, by definition, associated with cytopenias, coagulopathy, and/or transaminitis. 105 In contrast, the much more common phenomenon of isolated cytopenias, collectively termed immune effector cell-associated hematotoxicity (IACHT), is considered to be multifactorial, resulting from both the lymphodepleting conditioning regimen and the immune effector cell therapy itself. The CAR-HEMATOTOX scoring system, which incorporates baseline cytopenia and inflammatory markers, has been validated across all currently approved CAR T-cell indications and serves as a practical tool for identifying patients at risk for prolonged (i.e., >90 days) hematotoxicity. 106 , 107 Management of IACHT includes supportive care, such as growth factor administration, evaluation of infection prophylaxis duration, and determination of optimal vaccination timepoints. 108 – 111 However, severe or persistent cases may necessitate an autologous stem cell boost if available and even rescue HSCT. 112 A recently published study comparing hematotoxicity in some of the first patients with systemic lupus erythematosus (SLE) treated with CAR T-cell therapy to established data from B-cell lymphoma patients shows that the neutrophil lineage is primarily affected in both groups; however, the duration of hematotoxicity in SLE patients appears to be several months shorter than in those with malignancies. 113

The on-target, off-tumor effect refers to the unintended lysis of normal cells that physiologically express the targeted surface antigen. 114 In CD19- and BCMA-targeted therapies, B cells are partially and often long-term depleted, leading to impairment of humoral immunity. 115 In cases of severe hypogammaglobulinemia and/or recurrent infections, immunoglobulin substitution is administered. 110 However, it is important to note that infections represent the most significant contributor to nonrelapse-related mortality (NRM) in CAR T-cell therapy, 116 whereby the role of CMV-reactivation is also currently under investigation. 117

The toxicity profile of CAR T-cell therapy will inevitably vary depending on the target antigen and the affected cell type. For instance, particularly for BCMA-directed CAR T-cell therapies, and depending on the product, delayed neurotoxicity has been reported, reaching cumulatively up to 10%, and mainly include cranial nerve palsies, parkinsonism, and polyneuropathies. 118 – 120 Additionally, the underlying disease itself will influence the nature and severity of treatment-related side effects. So far, most clinical experience has been gathered from B-cell-depleting CAR T-cell therapies in B-cell malignancies, and whether these findings can be directly extrapolated to other diseases remains uncertain. 75

Another potential risk that warrants further investigation is the development of secondary, particularly myeloid, malignancies. The NRM bestowed by secondary malignancies may range from 5.8% to 7.8% in recent meta-analyses, 116 , 121 up to 33% in a different large cohort, 122 depending on observation time and on how the primary competing NRM risk, namely infections, are accounted for. Reports from FDA support the prospective emergence of secondary neoplasms at a nonnegligible rate post-CAR T-cell treatment. 123 These findings however, require careful extrapolation to AIDs, since their mechanism may not only be accounted for by the singular chemotherapy conditioning and the product infusion alone. One possible underlying mechanism is clonal hematopoiesis induced by prior treatment modalities and lymphodepleting regimens, 124 which would not necessarily be indicative of the population at hand. Even though there is growing evidence that clonal hematopoiesis of indeterminate significance may indeed be more prevalent in AID-patients compared to the general population, this need not necessarily be true compared to cancer patients. 125 , 126 The increased preexisting genomic hits and germline mutations in this patient group may further confound the extrapolation. 127 Conversely, the integration of genetic sequences into the host genome—even when restricted to T cells and despite advances in vector safety—carries the potential risk of insertional mutagenesis, which may drive malignant transformation. Compared with eventual secondary myeloid malignancies, their incidence appears to be much smaller, but a more profound causality may be inferred. 128 , 129 Recent reports have documented such cases in a small number of patients receiving both anti-CD19 and anti-BCMA CAR T-cell therapies. Nevertheless, there is an a priori increased incidence of secondary T-cell malignancies in B-cell neoplasm patients, and vice versa, somewhat obscuring the aforementioned causality. 130 Cumulatively, this highlights the need for a deeper understanding of the contributing factors and the development of improved monitoring and early detection strategies. 131 More recently, an apparent AID-specific side-effect of CAR T-therapy has been described and termed “Local immune effector cell-associated toxicity syndrome” (LICATS). 132 In one pool of 39 patients receiving CAR T-cell therapy, 30 of them showed evidence of an organ-specific inflammatory reaction exclusively in one or more of the initially involved disease sites (e.g., kidney, skin, joints, muscles), that was irrespective of any underlying CRS-diagnosis. All of the events occurred during the B-cell aplasia period (80% of them within the first month postinfusion) and resolved either in a self-limiting manner or with a short treatment course of corticosteroids. More specifically, 20 patients necessitated no corticosteroid usage (being termed as LICATS Grade 1), and all others necessitated less than 67 mg of prednisolone dose (maximum cumulative dose of 244 mg) for complete symptom resolution. The occurrence of the events in a per se still immunocompromised organism, as well as their way of resolution speak against an AID-flare; nevertheless, histological correlates are reported in only four patients, as the work-up consisted mainly on clinical evidence, and laboratory and/or imaging studies. The formal description of LICATS in organ-specific AIDs draws parallels with the nonspecific inflammatory changes observed in the lymph nodes of some lymphoma patients, which indeed do not signify disease progression. Moreover, similar findings were also observed in two different refractory SEL patient cohorts, where 4 out of 19 patients had documented reactions consistent with LICATS, strengthening its introduction. Of note though, is the description of two events (diarrhea and arthritis) occurring in nonpreviously affected regions. 133 Attempting to ascertain the exact scope of LICATS, as well as studying any overarching pathophysiology of nonCRS-related postinfusion immune reactions in AIDs remains an active focus of research.

As CAR T-cell therapy continues to evolve, with expanding indications and the development of next-generation products, it is highly likely that risk assessment strategies will need to be adapted to account for new toxicities and patient-specific factors.

Manufacturing, optimization, and clinical implementation of CAR T-cell therapy: Lessons from hematological malignancies

The process of CAR T-cell therapy, whether in a commercial or academic setting, involves several critical and highly coordinated steps, all of which must adhere to good manufacturing practices. 139 – 141 It begins with the collection and transportation of donor material, followed by a rapid and precise manufacturing process, transportation to the treating facility, administration to the patient, and continuous postinfusion care with the FDA suggesting a life-long follow-up ( Figure 2 ). Since CAR T-cell therapies are administered on an individual-patient basis, their production differs fundamentally from conventional bulk pharmaceutical manufacturing. A key aspect of this process is traceability, ensuring that each product follows a stand-alone chain of identity for the patient and a chain of custody for the product. The process involves a multidisciplinary team of laboratory, logistics, and clinical personnel, highlighting opportunities for optimization across these fields. 142 Lessons from CAR T-cell therapy in hematologic malignancies have provided valuable insights.

Clinical experience suggests that patients with lower baseline tumor burden achieve deeper and more durable responses. This underscores the importance of early patient referral to accredited institutions and the expansion of clinical trials to explore broader indications and earlier lines of therapy. Whether this also holds true for AIDs is under investigation.

Although patient selection is primarily guided by the eligibility criteria of pivotal trials leading to product approval, CAR T-cell therapy remains highly individualized, with no absolute fitness exclusion criteria. 143 Notably, patients with AIDs coexisting with malignancies were typically excluded in clinical trials—due to concerns about disease flares, impaired T-cell function under chronic immunosuppression, and the risk of confounding adverse events. Moreover, concurrent immunosuppressive therapy may interfere with CAR T-cell expansion and persistence, complicating the assessment of safety and efficacy endpoints. However, early real-world data from retrospective analyses suggest that CAR T-cell therapy is well tolerated in patients with concurrent AIDs, showing comparable toxicity profiles and antitumor efficacy to those without such comorbidities. Notably, some reports have indicated biochemical or clinical improvements in AID activity post-CAR T-cell infusion. 144

Instead, cell quality—including the number, ratio, and transduction efficiency of isolated T-cells—is prioritized to proceed with the therapy, as these factors directly impact therapeutic efficacy. Additionally, both the type of prior therapy and the underlying disease can influence these parameters. 145 , 146 In patients with malignancies, adherence to predefined treatment washout, both prior to leukapheresis and CAR T-cell infusion, is typically feasible. In contrast, patients with AIDs are often maintained on continuous immunosuppression, which presents unique challenges for CAR T-cell manufacturing and therapeutic efficacy. Immunosuppressive agents such as mycophenolate mofetil, cyclosporine, or high-dose corticosteroids can impair T-cell function and expansion, potentially compromising both the CAR T-cell product and its in vivo performance.

In clinical practice, tapering or temporarily discontinuing T-cell-modulating agents, when disease control allows, is generally recommended. For corticosteroids, a reduction to ⩽5–10 mg/day of prednisolone equivalent is often feasible and may serve as a bridging strategy. Alternatively, treatment-free intervals of at least 3–7 days, depending on the elimination half-life of the respective agents, are encouraged prior to leukapheresis or infusion where clinically feasible. However, such modifications carry a risk of disease flares, and tapering should therefore be performed cautiously and individually adapted.

Similar considerations apply to the postinfusion phase: immunosuppressive agents administered to control flares may also interfere with CAR T-cell persistence and activity. These aspects are particularly relevant not only for autologous CAR T-cell therapies but also for allogeneic and in vivo gene-engineering approaches.

The manufacturing process consists of distinct steps that have been largely streamlined, and in part automated. These include cell sorting (particularly for specific T-cell subpopulations), 147 polyclonal T-cell activation (usually via antibody-coated microbeads), gene transduction, and subsequent expansion, 148 all of which have the potential to actively influence the CAR T-cell characteristics in vivo. 139 Beginning with leukapheresis, it is typically aimed to collect a minimum of 0.6 × 10 9 /L cells, though the required lymphocyte threshold may vary by manufacturer. Recent European Society for Blood and Marrow Transplantation/European Haematology Association guidelines provide further recommendations on this aspect. 111 Leukapheresis products enriched with less-differentiated T-cells—such as naïve ( T n ), stem cell like memory ( T SCM ), or CD8 + CD45RO neg CD27 + T-cells displaying both effector and memory cell characteristics—have been associated with superior antitumor control and improved clinical outcomes in MM and chronic lymphocytic leukemia. 149 – 151 CAR T-cell persistence is a major determinant of long-term therapeutic responses, at least in hematologic malignancies. 152 To reduce immunotoxicity and improve outcomes, separate processing of purified CD4 + and CD8 + T-cells with fixed 1:1 CD4 + to CD8 + CAR T-cell ratio is already implemented for certain approved products. 153 , 154 This approach is based on the observation that CD4 + CAR T-cells not only serve as key effector cells but are also the primary drivers of toxicities such as the CRS. 154

A key challenge in CAR T-cell manufacturing is designing and generating the vector for CAR transgene integration. All currently approved CAR T-cell products rely on viral vectors (either lentiviral or retroviral), as neither method has demonstrated a decisive advantage, 155 and with the caveat of high cost and potential risk of insertional mutagenesis. CRISPR/Cas9 technology offers more precise and multiplexed gene editing, potentially allowing for the fine-tuning of next-generation CAR constructs via targeted knock-in and/or knock-out 156 ; this would allow for allogeneic products for AIDs.

Shorter vein-to-vein times have been correlated with improved clinical outcomes. 157 , 158 However, major logistical and regulatory hurdles remain, spanning transport, approval processes, manufacturing, and prerelease quality control testing. 159 , 160 The introduction of “off-the-shelf” allogeneic CAR T-cell products could revolutionize the field, although previous efforts were limited by issues such as poor persistence and T-cell exhaustion due to concurrent TCR and CAR engagement. Ongoing trials are exploring ways to overcome these limitations, 161 , 162 with successful steps also in the AID-domain, as will later be discussed.

One of the major causes of CAR T-cell failure in malignancies is disease progression during the approval and manufacturing period. In many cases, patients receive bridging therapy to control disease before undergoing lymphodepleting chemotherapy prior to CAR T-cell infusion. 163 While bridging therapy may further immunosuppress patients and impair T-cell regeneration, lymphodepletion serves an opposite role by creating a niche for CAR T-cell engraftment and rapid expansion, a process termed homeostatic proliferation. 164 The most commonly used lymphodepleting agents are fludarabine and cyclophosphamide, although these regimens are not universally optimal. 165 One of the most commonly used alternatives is bendamustine, which has a favorable toxicity profile. 166 All FDA- and EMA-approved CAR T-cell therapies require preconditioning regimens. Extrapolating from the debated corticosteroid thresholds used in the treatment and prophylaxis of CRS and ICANS, a similar rationale applies to AID-patients receiving immunosuppressive therapy: tapering is often required to avoid compromising CAR T-cell expansion and persistence.

Following infusion, patients undergo distinct follow-up phases to monitor acute, mid-, and long-term complications. The first phase spans the initial 28 days, primarily focusing on monitoring for CRS, ICANS, and infections, necessitating access to an ICU. Up to day 100, the main concerns shift to immune recovery and reconstitution, which influence susceptibility to opportunistic infections, viral reactivation, and CAR-T cell persistence. Beyond this period, the emphasis transitions to long-term disease control, prolonged cytopenia, and organ function assessment, with patient visits occurring at progressively longer intervals. 73 Comprehensive safety monitoring and optimized follow-up protocols are essential for improving real-world patient outcomes.

Even with an optimal CAR T-cell product, treatment failure may occur due to several factors: postinfusion CAR T-cell dysfunction, which may arise from cell-intrinsic or TME-related factors, severe toxicities leading to nondisease-related mortality, a hostile TME preventing infiltration (especially in solid tumors), 167 and tumor-intrinsic factors such as antigen loss and multilineage heterogeneity. Implemented strategies would aim to enhance CAR T-cell persistence, counteract immunosuppressive signals, and improve tumor infiltration, ultimately increasing therapeutic efficacy. Combination strategies involving CAR T-cells with other immunotherapies—such as checkpoint inhibitors or bispecific antibodies—are also under evaluation. 168 – 170 These strategies are particularly relevant as CAR T-cell therapies are being moved earlier within the treatment algorithms. Ongoing trials and post hoc analyses will be essential in shaping optimal decision-making strategies for integrating CAR T-cell therapy into clinical practice.

Summarizing, from a neurologist’s perspective, key considerations center on the individualized nature of CAR T-cell manufacturing. The patient’s “journey” typically begins with inclusion in a clinical trial or treatment under exempt approval. Prior therapies may affect T-cell quality at collection, while concurrent immunosuppression can influence in vivo CAR T-cell expansion and persistence. Manufacturing processes are largely standardized, drawing from hematologic experience (e.g., use of less-differentiated T cells, fixed CD4:CD8 ratios). Efforts toward allogeneic CAR platforms aim to reduce vein-to-vein time and ensure consistent product quality—an approach increasingly relevant for autoimmune indications. Close and long-term follow-up remains essential to manage both known and emerging complications.

Early clinical experience with B-cell-depleting CAR T-cell therapy in AIDs

Early experience with the repurposing of CAR T-cell therapy beyond oncology has already revolutionized the therapeutic outlook in AIDs and generated significant scientific discourse. The unique characteristics of CAR T cells, particularly their ability to achieve deep and sustained depletion of target cells, make them a promising candidate for the treatment of B-cell-mediated AIDs ( Figure 3 ). Conventional therapeutic approaches for controlling pathological B-cell responses include the use of monoclonal antibodies, such as the anti-CD20 antibody rituximab, to eliminate B-cells through antibody-dependent cytotoxicity, antibody-dependent phagocytosis, and complement-mediated cytotoxicity. 171 , 172 Additional strategies involve blocking B-cell activation with agents such as anti-BAFF antibodies, direct antibody removal via apheresis, or the administration of nonspecific immunosuppressants, including corticosteroids. 173 – 175 More recently, noncell based attempts to engage the T-cell compartment have included the use of TCEs in MG. However, these approaches require long-term administration and may not be sufficient to target tissue-resident B-cells. 176 , 177 CAR T-cell therapy has the potential to overcome these limitations by engaging multiple immune compartments, infiltrating tissues, and acting autonomously. Indeed, CD-20 mAbs and CD-19/CD-3 TCEs in patients with AIDs, despite their promising major clinical utility, 178 have achieved full depletion of B-cells or disruption of the follicular architecture in excised lymph nodes—effects that have been seen with CAR T-cell therapy. 179

The first report came from a case study of a young patient with SLE who was successfully treated with anti-CD19 CAR T-cells and remained therapy- and disease-free 3 years posttreatment. 180 This was followed by a case series in five SLE patients, demonstrating a rapid (within 3 months) and sustained remission. 181 Notably, B-cell regeneration occurred within 3–4 months without disease recurrence, while the circulating CAR T-cell population contracted relatively quickly. This case series was later expanded to include patients with systemic sclerosis (SSc) and idiopathic inflammatory myopathies (IIM), where the observed positive effects were maintained even with longer follow-up periods. 70 A growing body of research now demonstrates that CAR T-cell-mediated B-cell depletion is a promising therapeutic approach for AIDs within the rheumatologic spectrum. Consequently, a large number of studies have been initiated, particularly considering that the incidence of AIDs—and thus the number of potential patients—is significantly higher than that of malignant diseases. 182 The observation that B-cell reconstitution did not lead to disease relapse led to the concept of an “immunological reset.” The exact mechanisms by which CAR T-cells mediate this reset in AIDs remains to be elucidated, but early data provide important insights. 183 , 184 B-cell reconstitution occurs significantly earlier in AID patients treated with CAR T-cells compared to those with hematologic malignancies. Interestingly, the disease does not relapse alongside B-cell reconstitution, in contrast to what is often observed after treatment with monoclonal anti-CD20 antibodies. 185 This early regeneration may be related to the faster contraction of CAR T-cells, which, in turn, is likely due to the rapid elimination of the target antigen. Additionally, the reconstituting immune system following lymphodepletion appears to be more competitive in AID patients than in heavily pretreated individuals with malignant diseases. The regenerated B-cells are predominantly naïve, while pathologic autoantibodies are often, but not always, completely depleted. Importantly, the extent of antibody depletion varies by underlying disease—for instance, in SLE, autoantibody levels are typically fully depleted, whereas in other conditions, residual pathogenic antibodies may persist. 11 , 181 Nonetheless, clinical remission can still be achieved even in cases where autoantibodies are not entirely eliminated, further supporting the notion that the pathological role of B-cells extends beyond autoantibody production. In addition to generating autoantibodies, B-cells contribute to pro-inflammatory cytokine production, immune homeostasis, and antigen presentation, all of which play a role in AID pathogenesis. 171 Interestingly, the impact on humoral immunity is less profound than initially expected. This can be attributed, in part, to the relatively short duration of B-cell aplasia and, in the case of anti-CD19-directed CAR T-cell therapies, to the fact that CD19-negative long-lived plasma cells are not eradicated. As a result, protective vaccine titers are largely preserved in most patients. These observations also provide valuable insights into the pathogenic role of different B-cell populations, particularly regarding the contribution of long-lived plasma cells to the maintenance of AIDs. 115 , 186 Interestingly, anti-BCMA CAR T-cell therapies, which target BCMA-expressing plasma cells, including long-lived plasma cells, have also shown encouraging clinical outcomes, further supporting the role of (possibly short-lived) plasma cell depletion in AID treatment.

Regarding their use in neuroimmunological B-cell-mediated AIDs, experience from CNS lymphomas has clearly demonstrated that CAR T-cells can cross the BBB. Importantly, CNS involvement does not appear to be associated with a significantly increased toxicity profile, suggesting that CAR T-cell therapy may be a viable approach for neurological AIDs without an unacceptable risk of neurotoxicity. 187 Initial experiences with CAR T-cell therapy in neuroimmune disorders have now been reported, including in peripheral nervous system diseases such as MG and Lambert–Eaton syndrome, as well as CNS diseases like MS and stiff person syndrome. 10 , 13 , 15 In treatment-refractory cases, B-cell- and plasma cell-depleting CAR T-cell therapies have already been administered, with promising early results. 144 , 188 In a relapsing case of concurrent MS and autoimmune arthritis following CAR T-cell therapy, the patient safely underwent rescue autologous stem cell transplantation, which led to a transient decline in the T-cell compartment but no measurable impact on B-cells. 22 However, these findings require further validation in the numerous ongoing clinical trials. 189

The use of CAR T-cells in AIDs presents significant safety considerations, particularly because morbidity and mortality in AIDs differ from those in neoplastic diseases. Preliminary data regarding acute toxicities such as CRS and ICANS are highly promising, likely due to the lower antigen burden compared to neoplasms. However, longer follow-up is required, particularly with respect to secondary neoplasms. Two emerging strategies—mRNA-based and allogeneic (allo-)CAR T-cell therapies—have shown promise in enhancing safety for patients with AIDs, particularly in early-stage studies.

Rather than using DNA vectors for stable CAR expression, Granit et al. 9 engineered CD8+ T cells via mRNA, enabling controlled ex vivo proliferation. This approach allows for predictable cell kinetics, temporally limited effector function, and transient CAR expression—advantages that reduce the risk of acute toxicities and eliminate concerns related to genomic integration. Notably, it also circumvents the need for lymphodepletion, thereby sparing patients from the toxic effects of chemotherapy. However, the transient nature of expression raises questions about long-term efficacy, and repeated dosing would likely drive-up manufacturing costs, underscoring the need for optimized production platforms.

Interestingly enough, a recent preclinical study aims to transition the CAR T-cell engineering from ex vivo to in vivo. 190 Building on this concept, CD8-targeted lipid nanoparticles have been developed to deliver CD19-CAR mRNA in vivo, offering the potential for similarly specific cytotoxic activity through repeated, temporally controlled dosing.

Moreover, a key concern regarding the use of autologous CAR T-cell products in AIDs is the genetic modification of potentially autoreactive T-cells. One potential strategy to mitigate this risk and improve accessibility is the use of allo-CAR T-cells. These “off-the-shelf” products could be generated from a single healthy donor to treat multiple patients, offering not only cost advantages but also improvements in scalability, logistics, and manufacturing efficiency. Collectively, these features could substantially increase global accessibility to CAR T-cell therapies. To mitigate the risk of GvHD and enhance persistence, allogeneic T-cells can be genetically modified using CRISPR/Cas9-based editing, for example, by knocking out the TCR to eliminate GvHD potential, and MHC molecules to reduce host-mediated rejection. Data from case series using anti-CD19 allo-CAR T cells in SSc and IIM with this approach have been promising in terms of both efficacy and tolerability. 191

In an effort to leverage the low immunogenicity of NK-cells, an alternative strategy employed human-induced pluripotent stem cells to generate CAR NK-cells with enhanced safety and specificity. 192 To prevent recognition by host T cells, MHC molecules were knocked out. Cytotoxic activity was restricted exclusively to the CAR-mediated pathway, and activation was further enhanced via IL-2 receptor signaling. A safety switch targeting EGFR was also integrated, allowing depletion of the CAR NK cells if needed. The resulting bispecific anti-BCMA/CD19 CAR NK cells induced a favorable therapeutic response lasting over 6 months in a patient with poly-refractory SSc. 192

Taken together, leveraging deep and sustained B-cell depletion appears to be a promising and viable therapeutic strategy for AIDs—particularly in severe neurological manifestations—offering a potential alternative to conventional immunosuppressive approaches. Robust clinical studies will be essential to define the safety and efficacy profiles of these emerging therapies, while translational efforts will be key to addressing both anticipated and unforeseen challenges. This remains a rapidly evolving field, with ongoing research expected to shape future clinical practice.

This study is a narrative review of the literature, which inherently limits its scope compared to a systematic review. Due to the currently limited availability of individual patient data, which are mainly derived from case reports and series, and the fact that most major clinical trials are still ongoing, with only sparse interim results published, a precise estimation of adverse event type and incidence, such as that provided by a meta-analysis, is not yet feasible. Likewise, meaningful extrapolation of treatment effects is constrained, given the heterogeneous nature, pathophysiology, and natural history of the neurological AIDs at hand—much less if exact parallels were to be drawn with rheumatological or hematological AIDs.

Conclusion

Adoptive cellular therapies, particularly CAR-based approaches, are increasingly recognized as powerful tools for modulating the immune system across a broad spectrum of diseases beyond oncology. In the context of treatment-refractory AIDs, preliminary data suggest both safety and efficacy. However, the complexity of immunological disorders, their incomplete pathophysiological understanding, and their heterogeneous manifestations present challenges for clinical research. Ongoing studies may be constrained by these nuances, as well as by initially small patient populations. Well-designed future clinical trials will be essential to validate the curative potential of CAR T-cell therapy in AIDs, refine patient selection criteria, and assess long-term safety and durability of responses.

The extensive experience gained from treating hematologic malignancies—where tens of thousands of patients have received CAR T-cell therapy—provides valuable insights that can help guide the scientific community in this emerging field. While current studies in AIDs are still in their early stages, they hold the potential to transform the therapeutic landscape. By leveraging lessons from hemato-oncology, we can continue advancing our understanding and application of CAR T-cell therapy in AIDs, fostering cautious but well-founded optimism about its future clinical impact.

The images were generated with biorender.com.

ORCID iDs: Dimitrios E. Katsaros https://orcid.org/0000-0002-4886-4540

Dimitrios Mougiakakos https://orcid.org/0000-0002-2817-6660

Declarations

Ethics approval and consent to participate: Not applicable.

Consent for publication: Not applicable.

Author contributions: Dimitrios E. Katsaros: Conceptualization; Visualization; Writing – original draft; Writing – review & editing.

Dimitrios Mougiakakos: Conceptualization; Supervision; Writing – original draft; Writing – review & editing.

Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: D.M. is supported by the European Regional Development Fund (project ZELL-THEMA and KS-MED).

D.M. has received speaker honoraria and consulting fees from AbbVie, AstraZeneca, AvenCell, BMS, Beigene, Galapagos, Gilead, Janssen, Kyverna Therapeutics, Miltenyi, and Novartis.

Availability of data and materials: Not applicable.

References

1 Sterner RC Sterner RM. CAR-T cell therapy: current limitations and potential strategies . Blood Cancer J 2021 ; 11 ( 4 ): 69 . 33824268 10.1038/s41408-021-00459-7 PMC8024391

2 Jacobson CA Munoz J Sun F , et al . Real-world outcomes with chimeric antigen receptor T cell therapies in large B cell lymphoma: a systematic review and meta-analysis . Transplant Cell Ther 2024 ; 30 ( 1 ): 77.e1–77.e15. 10.1016/j.jtct.2023.10.017 37890589

3 Neelapu SS Locke FL Bartlett NL , et al . Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma . N Engl J Med 2017 ; 377 ( 26 ): 2531 – 2544 . 29226797 10.1056/NEJMoa1707447 PMC5882485

4 Crump M Neelapu SS Farooq U , et al . Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study . Blood 2017 ; 130 ( 16 ): 1800 – 1808 . 28774879 10.1182/blood-2017-03-769620 PMC5649550

5 Labanieh L Mackall CL. CAR immune cells: design principles, resistance and the next generation . Nature 2023 ; 614 ( 7949 ): 635 – 648 . 36813894 10.1038/s41586-023-05707-3

6 Ma L Hostetler A Morgan DM , et al . Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity . Cell 2023 ; 186 ( 15 ): 3148–3165.e20. 10.1016/j.cell.2023.06.002 PMC10372881 37413990

7 Mougiakakos D Meyer E Schett G. CAR T-cells in autoimmunity: game changer or stepping stone? Blood J 2025 ; 145 ( 17 ): 1841 – 1849 . 10.1182/blood.2024025413 39700499

8 Qin C Tian DS Zhou LQ , et al . Anti-BCMA CAR T-cell therapy CT103A in relapsed or refractory AQP4-IgG seropositive neuromyelitis optica spectrum disorders: phase 1 trial interim results . Signal Transduct Target Ther 2023 ; 8 ( 1 ): 5 . 36596762 10.1038/s41392-022-01278-3 PMC9810610

9 Granit V Benatar M Kurtoglu M , et al . Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia gravis (MG-001): a prospective, multicentre, open-label, non-randomised phase 1b/2a study . Lancet Neurol 2023 ; 22 ( 7 ): 578 – 590 . 37353278 10.1016/S1474-4422(23)00194-1 PMC10416207

10 Haghikia A Hegelmaier T Wolleschak D , et al . Anti-CD19 CAR T cells for refractory myasthenia gravis . Lancet Neurol 2023 ; 22 ( 12 ): 1104 – 1105 . 37977704 10.1016/S1474-4422(23)00375-7

11 Tian DS Qin C Dong MH , et al . B cell lineage reconstitution underlies CAR-T cell therapeutic efficacy in patients with refractory myasthenia gravis . EMBO Mol Med 2024 ; 16 ( 4 ): 966 – 987 . 38409527 10.1038/s44321-024-00043-z PMC11018773

12 Zhang W Liu D Zhang T , et al . BCMA-CD19 bispecific CAR-T therapy in refractory chronic inflammatory demyelinating polyneuropathy . hLife 2024 ; 2 ( 8 ): 434 – 438 .

13 Fischbach F Richter J Pfeffer LK , et al . CD19-targeted chimeric antigen receptor T cell therapy in two patients with multiple sclerosis . Med 2024 ; 5 ( 6 ): 550–558.e2. 10.1016/j.medj.2024.03.002 38554710

14 Motte J Sgodzai M Schneider-Gold C , et al . Treatment of concomitant myasthenia gravis and Lambert-Eaton myasthenic syndrome with autologous CD19-targeted CAR T cells . Neuron 2024 ; 112 ( 11 ): 1757–1763.e2. 10.1016/j.neuron.2024.04.014 38697115

15 Faissner S Motte J Sgodzai M , et al . Successful use of anti-CD19 CAR T cells in severe treatment-refractory stiff-person syndrome . Proc Natl Acad Sci U S A . 2024 ; 121 ( 26 ): e2403227121. 10.1073/pnas.2403227121 PMC11214089 38885382

16 Zhang Y Liu D Zhang Z , et al . Bispecific BCMA/CD19 targeted CAR-T cell therapy forces sustained disappearance of symptoms and anti-acetylcholine receptor antibodies in refractory myasthenia gravis: a case report . J Neurol 2024 ; 271 ( 7 ): 4655 – 4659 . 38602546 10.1007/s00415-024-12367-4

17 Cabrera-Maqueda JM Sepulveda M García RR , et al . CD19-directed CAR T-cells in a patient with refractory MOGAD: clinical and immunologic follow-up for 1 year . Neurol Neuroimmunol Neuroinflamm 2024 ; 11 ( 5 ): e200292. 10.1212/NXI.0000000000200292 PMC11309560 39106426

18 Wickel J Schnetzke U Sayer-Klink A , et al . Anti-CD19 CAR-T cells are effective in severe idiopathic Lambert-Eaton myasthenic syndrome . Cell Rep Med 2024 ; 5 ( 11 ): 101794 . 39447569 10.1016/j.xcrm.2024.101794 PMC11604532

19 Haghikia A Hegelmaier T Wolleschak D , et al . Clinical efficacy and autoantibody seroconversion with CD19-CAR T cell therapy in a patient with rheumatoid arthritis and coexisting myasthenia gravis . Ann Rheum Dis 2024 ; 83 ( 11 ): 1597 – 1598 . 38937071 10.1136/ard-2024-226017

20 Vu T Tekce HD Rivner M , et al . Efficacy and safety of autologous BCMA-directed mRNA CAR T-cell therapy in generalized myasthenia gravis: results from a phase 2b randomized placebo-controlled trial (S34.002) . Neurology 2025 ; 104 ( 7_Supplement_1 ): 5230 .

21 Dong M-H Mei Z-C Zhou L-Q , et al . Anti-BCMA CAR-T cell therapy in relapsed/refractory chronic inflammatory demyelinating polyneuropathy . Med 2025 ; 100704 . 40425008 10.1016/j.medj.2025.100704

22 Pecher AC Hensen L Schairer-Marquardt R , et al . Relapse after anti-CD19 CAR T-cell therapy in a patient with severe rheumatoid arthritis and multiple sclerosis effectively treated by autologous stem cell transplantation . Ann Rheum Dis 2025 ; 84 ( 7 ): 1284 – 1286 . 40312206 10.1016/j.ard.2025.03.018

23 Motte J Klimas R Sgodzai M , et al . CD19-targeted CAR T-cell therapy for treatment-refractory autoimmune neuropathies . Lancet Neurol 2025 ; 24 ( 7 ): 564 – 566 . 40541202 10.1016/S1474-4422(25)00199-1

24 Hegelmaier T Wolleschak D Pappa V , et al . Chimeric antigen receptor T cells in treatment-refractory DAGLA antibody-associated encephalitis . Med 2025 ; 6 ( 9 ): 100776 . 40706586 10.1016/j.medj.2025.100776

25 Weiden PL Flournoy N Thomas ED , et al . Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts . N Engl J Med 1979 ; 300 ( 19 ): 1068 – 1073 . 34792 10.1056/NEJM197905103001902

26 Biernacki MA Sheth VS Bleakley M. T cell optimization for graft-versus-leukemia responses . JCI Insight 2020 ; 5 ( 9 ): e134939. 10.1172/jci.insight.134939 PMC7253012 32376800

27 Tsimberidou AM Van Morris K Vo HH , et al . T-cell receptor-based therapy: an innovative therapeutic approach for solid tumors . J Hematol Oncol 2021 ; 14 ( 1 ): 102 . 34193217 10.1186/s13045-021-01115-0 PMC8243554

28 Alcover A Alarcón B Di Bartolo V. Cell biology of T cell receptor expression and regulation . Annu Rev Immunol 2018 ; 36 ( 1 ): 103 – 125 . 29261409 10.1146/annurev-immunol-042617-053429

29 Fernández-Aguilar LM Vico-Barranco I Arbulo-Echevarria MM , et al . A story of kinases and adaptors: the role of Lck, ZAP-70 and LAT in switch panel governing T-cell development and activation . Biology 2023 ; 12 ( 9 ): 1163 . 37759563 10.3390/biology12091163 PMC10525366

30 Shakiba M Zumbo P Espinosa-Carrasco G , et al . TCR signal strength defines distinct mechanisms of T cell dysfunction and cancer evasion . J Exp Med 2022 ; 219 ( 2 ): e20201966. 10.1084/jem.20201966 PMC8704919 34935874

31 Lumsden JM Williams JA Hodes RJ. Differential requirements for expression of CD80/86 and CD40 on B cells for T-dependent antibody responses in vivo . J Immunol 2003 ; 170 ( 2 ): 781 – 787 . 12517941 10.4049/jimmunol.170.2.781

32 Li Y-R Zhou Y Yu J , et al . Generation of allogeneic CAR-NKT cells from hematopoietic stem and progenitor cells using a clinically guided culture method . Nat Biotechnol 2025 ; 43 ( 3 ): 329 – 344 . 38744947 10.1038/s41587-024-02226-y PMC11919731

33 Lei A Yu H Lu S , et al . A second-generation M1-polarized CAR macrophage with antitumor efficacy . Nat Immunol 2024 ; 25 ( 1 ): 102 – 116 . 38012418 10.1038/s41590-023-01687-8

34 Safarzadeh Kozani P Naseri A Mirarefin SMJ , et al . Nanobody-based CAR-T cells for cancer immunotherapy . Biomark Res 2022 ; 10 ( 1 ): 24 . 35468841 10.1186/s40364-022-00371-7 PMC9036779

35 Khan AN Chowdhury A Karulkar A , et al . Immunogenicity of CAR-T cell therapeutics: evidence, mechanism and mitigation . Front Immunol 2022 ; 13 : 886546 . 35677038 10.3389/fimmu.2022.886546 PMC9169153

36 San-Miguel J Dhakal B Yong K , et al . Cilta-cel or standard care in lenalidomide-refractory multiple myeloma . N Engl J Med 2023 ; 389 ( 4 ): 335 – 347 . 37272512 10.1056/NEJMoa2303379

37 Horna P Nowakowski G Endell J , et al . Comparative assessment of surface CD19 and CD20 expression on B-cell lymphomas from clinical biopsies: implications for targeted therapies . Blood 2019 ; 134 ( Suppl_1 ): 5345 – 5345 .

38 Frigault MJ Graham CE Berger TR , et al . Phase 1 study of CAR-37 T cells in patients with relapsed or refractory CD37+ lymphoid malignancies . Blood 2024 ; 144 ( 11 ): 1153 – 1167 . 38781564 10.1182/blood.2024024104 PMC11830985

39 Bal S Htut M Berdeja JG , et al . BMS-986393, a G protein-coupled receptor class C group 5 member D (GPRC5D)-targeted CAR T cell therapy, in patients (pts) with relapsed/refractory (RR) multiple myeloma (MM) and 1–3 prior regimens: updated phase 1 safety and efficacy results . Blood 2024 ; 144 ( Suppl. 1 ): 2069 .39541105

40 Fujiwara K Tsunei A Kusabuka H , et al . Hinge and transmembrane domains of chimeric antigen receptor regulate receptor expression and signaling threshold . Cells 2020 ; 9 ( 5 ): 1182 . 32397414 10.3390/cells9051182 PMC7291079

41 Gross G Waks T Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity . Proc Natl Acad Sci U S A 1989 ; 86 ( 24 ): 10024 – 10028 . 2513569 10.1073/pnas.86.24.10024 PMC298636

42 Jensen MC Popplewell L Cooper LJ , et al . Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans . Biol Blood Marrow Transplant 2010 ; 16 ( 9 ): 1245 – 1256 . 20304086 10.1016/j.bbmt.2010.03.014 PMC3383803

43 Van Der Stegen SJC Hamieh M Sadelain M. The pharmacology of second-generation chimeric antigen receptors . Nat Rev Drug Discov 2015 ; 14 ( 7 ): 499 – 509 . 26129802 10.1038/nrd4597 PMC6410718

44 Anagnostou T Riaz IB Hashmi SK , et al . Anti-CD19 chimeric antigen receptor T-cell therapy in acute lymphocytic leukaemia: a systematic review and meta-analysis . Lancet Haematol 2020 ; 7 ( 11 ): e816–e826. 10.1016/S2352-3026(20)30277-5 33091355

45 Smith R Shen R. Complexities in comparing the impact of costimulatory domains on approved CD19 CAR functionality . J Transl Med 2023 ; 21 ( 1 ): 515 . 37518011 10.1186/s12967-023-04372-4 PMC10387212

46 Kawalekar OU O’Connor RS Fraietta JA , et al . Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells . Immunity 2016 ; 44 ( 2 ): 380 – 390 . 26885860 10.1016/j.immuni.2016.01.021 PMC13498396

47 Salter AI Ivey RG Kennedy JJ , et al . Phosphoproteomic analysis of chimeric antigen receptor signaling reveals kinetic and quantitative differences that affect cell function . Sci Signal 2018 ; 11 ( 544 ): eaat6753. 10.1126/scisignal.aat6753 PMC6186424 30131370

48 Frigault MJ Lee J Basil MC , et al . Identification of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells . Cancer Immunol Res 2015 ; 3 ( 4 ): 356 – 367 . 25600436 10.1158/2326-6066.CIR-14-0186 PMC4390458

49 Ying Z He T Wang X , et al . Parallel comparison of 4-1BB or CD28 co-stimulated CD19-targeted CAR-T cells for B cell non-Hodgkin’s lymphoma . Mol Ther Oncolytics 2019 ; 15 : 60 – 68 . 31650026 10.1016/j.omto.2019.08.002 PMC6804784

50 Havert M. Summary basis for regulatory action: axicabtagene ciloleucel . U.S. Food & Drug Administration , https://www.fda.gov/files/vaccines%2C%20blood%20%26%20biologics/published/October-18–2017-Summary-Basis-for-Regulatory-Action—YESCARTA.pdf ( 2017 , accessed 11 August 2025 ).

51 Liu XV. Summary basis for regulatory action: tisagenlecleucel . U.S. Food & Drug Administration , https://www.fda.gov/files/vaccines%2C%20blood%20%26%20biologics/published/August-3 ( 2017 , accessed 11 August 2025).

52 Price G. Summary basis for regulatory action: brexucabtagene autoleucel . U.S. Food & Drug Administration , https://www.fda.gov/media/141093/download ( 2020 , accessed 11 August 2025).

53 Kwilas A. Summary basis for regulatory action: idecabtagene vicleucel , https://fda.report/media/147627/Summary+Basis+for+Regulatory+Action+-+ABECMA.pdf . ( 2021 , accessed 11 August 2025 ).

54 Schultz KLW. Summary basis for regulatory action: lisocabtagene maraleucel , https://fda.report/media/146242/Summary+Basis+for+Regulatory+Action+-+BREYANZI.pdf ( 2021 , accessed 11 August 2025 ).

55 Ye Z. Summary basis for regulatory action: ciltacabtagene autoleucel . U.S. Food & Drug Administration , https://www.fda.gov/media/156999/download ( 2022 , accessed 11 August 2025).

56 Timmons A. Summary basis for regulatory action—AUCATZYL (obecabtagene autoleucel) . U.S. Food and Drug Administration , https://www.fda.gov/media/183887/download ( 2024 , accessed 11 August 2025).

57 Wang M Munoz J Goy A , et al . KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma . N Engl J Med 2020 ; 382 ( 14 ): 1331 – 1342 . 32242358 10.1056/NEJMoa1914347 PMC7731441

58 Berdeja JG Madduri D Usmani SZ , et al . Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study . Lancet 2021 ; 398 ( 10297 ): 314 – 324 . 34175021 10.1016/S0140-6736(21)00933-8

59 Munshi NC Anderson LD Shah N , et al . Idecabtagene vicleucel in relapsed and refractory multiple myeloma . N Engl J Med 2021 ; 384 ( 8 ): 705 – 716 . 33626253 10.1056/NEJMoa2024850

60 Abramson JS Palomba ML Gordon LI , et al . Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study . Lancet 2020 ; 396 ( 10254 ): 839 – 852 . 32888407 10.1016/S0140-6736(20)31366-0

61 Roddie C Sandhu KS Tholouli E , et al . Obecabtagene autoleucel in adults with B-cell acute lymphoblastic leukemia . N Engl J Med 2024 ; 391 ( 23 ): 2219 – 2230 . 39602653 10.1056/NEJMoa2406526 PMC12818175

62 Maude SL Laetsch TW Buechner J , et al . Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia . N Engl J Med 2018 ; 378 ( 5 ): 439 – 448 . 29385370 10.1056/NEJMoa1709866 PMC5996391

63 Derigs P Schubert ML Dreger P , et al . Third-generation anti-CD19 CAR T cells for relapsed/refractory chronic lymphocytic leukemia: a phase 1/2 study . Leukemia 2024 ; 38 ( 11 ): 2419 – 2428 . 39192036 10.1038/s41375-024-02392-7 PMC11519001

64 Mitsuno K Suematsu M Naito Y , et al . Selective JAK2 pathway inhibition enhances anti-leukemic functionality in CD19 CAR-T cells . Cancer Immunol Immunother 2025 ; 74 ( 3 ): 79 . 39891728 10.1007/s00262-024-03927-8 PMC11787079

65 Tousley AM Rotiroti MC Labanieh L , et al . Co-opting signalling molecules enables logic-gated control of CAR T cells . Nature 2023 ; 615 ( 7952 ): 507 – 516 . 36890224 10.1038/s41586-023-05778-2 PMC10564584

66 Vaisman-Mentesh A Gutierrez-Gonzalez M DeKosky BJ , et al . The molecular mechanisms that underlie the immune biology of anti-drug antibody formation following treatment with monoclonal antibodies . Front Immunol 2020 ; 11 : 1951 . 33013848 10.3389/fimmu.2020.01951 PMC7461797

67 Qin C Dong MH Zhou LQ , et al . Single-cell analysis of refractory anti-SRP necrotizing myopathy treated with anti-BCMA CAR-T cell therapy . Proc Natl Acad Sci U S A 2024 ; 121 ( 6 ): e2315990121. 10.1073/pnas.2315990121 PMC10861907 38289960

68 Oh S Mao X Manfredo-Vieira S , et al . Author correction: precision targeting of autoantigen-specific B cells in muscle-specific tyrosine kinase myasthenia gravis with chimeric autoantibody receptor T cells . Nat Biotechnol 2024 ; 42 ( 12 ): 1923 . 39543316 10.1038/s41587-024-02502-x PMC11631755

69 Li Y Li S Zhao X , et al . Fourth-generation chimeric antigen receptor T-cell therapy is tolerable and efficacious in treatment-resistant rheumatoid arthritis . Cell Res 2025 ; 35 ( 3 ): 220 – 223 . 39779933 10.1038/s41422-024-01068-2 PMC11909189

70 Müller F Taubmann J Bucci L , et al . CD19 CAR T-cell therapy in autoimmune disease—a case series with follow-up . N Engl J Med 2024 ; 390 ( 8 ): 687 – 700 . 38381673 10.1056/NEJMoa2308917

71 Merkt W Röhrich M Mavriopoulou E , et al . Persisting CD19.CAR-T cells in combination with nintedanib: clinical response in a patient with systemic sclerosis-associated pulmonary fibrosis after 2 years . Lancet Respir Med 2025 ; 13 ( 7 ): 651 – 654 . 40449514 10.1016/S2213-2600(25)00159-6

72 Brudno JN Kochenderfer JN. Current understanding and management of CAR T cell-associated toxicities . Nat Rev Clin Oncol 2024 ; 21 ( 7 ): 501 – 521 . 38769449 10.1038/s41571-024-00903-0 PMC11529341

73 Hayden PJ Roddie C Bader P , et al . Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA) . Ann Oncol 2022 ; 33 ( 3 ): 259 – 275 . 34923107 10.1016/j.annonc.2021.12.003

74 Goldman A Maor E Bomze D , et al . Adverse cardiovascular and pulmonary events associated with chimeric antigen receptor T-cell therapy . J Am Coll Cardiol 2021 ; 78 ( 18 ): 1800 – 1813 . 34711339 10.1016/j.jacc.2021.08.044 PMC8562317

75 Cappell KM Kochenderfer JN. Long-term outcomes following CAR T cell therapy: what we know so far . Nat Rev Clin Oncol 2023 ; 20 ( 6 ): 359 – 371 . 37055515 10.1038/s41571-023-00754-1 PMC10100620

76 Hay KA Hanafi LA Li D , et al . Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy . Blood 2017 ; 130 ( 21 ): 2295 – 2306 . 28924019 10.1182/blood-2017-06-793141 PMC5701525

77 Pinto SN Krenciute G. The mechanisms of altered blood–brain barrier permeability in CD19 CAR T-cell recipients . Int J Mol Sci 2024 ; 25 ( 1 ): 644 . 38203814 10.3390/ijms25010644 PMC10779697

78 Giavridis T Van Der Stegen SJC Eyquem J , et al . CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade . Nat Med 2018 ; 24 ( 6 ): 731 – 738 . 29808005 10.1038/s41591-018-0041-7 PMC6410714

79 Lu IN Müller-Miny L Krekeler C , et al . The CXCL16/CXCR6 axis is linked to immune effector cell-associated neurotoxicity in chimeric antigen receptor (CAR) T cell therapy . Genome Med 2025 ; 17 ( 1 ): 71 . 40588764 10.1186/s13073-025-01498-6 PMC12210444

80 Rozenberg A Shelly S Winer R , et al . CCR5 predicts neurotoxicity in CAR -T-cell therapy . Br J Haematol 2025 ; 207 ( 3 ): 1133 – 1137 . 40572013 10.1111/bjh.20228 PMC12436234

81 Parker KR Migliorini D Perkey E , et al . Single-cell analyses identify brain mural cells expressing CD19 as potential off-tumor targets for CAR-T immunotherapies . Cell 2020 ; 183 ( 1 ): 126–142.e17. 10.1016/j.cell.2020.08.022 PMC7640763 32961131

82 Evangelidis P Evangelidis N Kalmoukos P , et al . Genetic susceptibility in endothelial injury syndromes after hematopoietic cell transplantation and other cellular therapies: climbing a steep hill . Curr Issues Mol Biol 2024 ; 46 ( 5 ): 4787 – 4802 . 38785556 10.3390/cimb46050288 PMC11119915

83 Pennisi M Sanchez-Escamilla M Flynn JR , et al . Modified EASIX predicts severe cytokine release syndrome and neurotoxicity after chimeric antigen receptor T cells . Blood Adv 2021 ; 5 ( 17 ): 3397 – 3406 . 34432870 10.1182/bloodadvances.2020003885 PMC8525234

84 Han MW Jeong SY Suh CH , et al . Incidence of immune effector cell-associated neurotoxicity among patients treated with CAR T-cell therapy for hematologic malignancies: systematic review and meta-analysis . Front Neurol 2024 ; 15 : 1392831 . 39474369 10.3389/fneur.2024.1392831 PMC11518750

85 Grant SJ Grimshaw AA Silberstein J , et al . Clinical presentation, risk factors, and outcomes of immune effector cell-associated neurotoxicity syndrome following chimeric antigen receptor T cell therapy: a systematic review . Transplant Cell Ther 2022 ; 28 ( 6 ): 294 – 302 . 35288347 10.1016/j.jtct.2022.03.006 PMC9197870

86 Locke FL Rossi JM Neelapu SS , et al . Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma . Blood Adv 2020 ; 4 ( 19 ): 4898 – 4911 . 33035333 10.1182/bloodadvances.2020002394 PMC7556133

87 Neelapu SS Jacobson CA Oluwole OO , et al . Outcomes of older patients in ZUMA-1, a pivotal study of axicabtagene ciloleucel in refractory large B-cell lymphoma . Blood 2020 ; 135 ( 23 ): 2106 – 2109 . 32181801 10.1182/blood.2019004162 PMC7273828

88 Brudno JN Lam N Vanasse D , et al . Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma . Nat Med 2020 ; 26 ( 2 ): 270 – 280 . 31959992 10.1038/s41591-019-0737-3 PMC7781235

89 Gardner RA Finney O Annesley C , et al . Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults . Blood 2017 ; 129 ( 25 ): 3322 – 3331 . 28408462 10.1182/blood-2017-02-769208 PMC5482103

90 Alb M Reiche K Rade M , et al . Novel strategies to assess cytokine release mediated by chimeric antigen receptor T cells based on the adverse outcome pathway concept . J Immunotoxicol 2024 ; 21 ( Sup1 ): S13–S28. 10.1080/1547691X.2024.2345158 39655500

91 Pensato U Amore G D’Angelo R , et al . Frontal predominant encephalopathy with early paligraphia as a distinctive signature of CAR T-cell therapy-related neurotoxicity . J Neurol 2022 ; 269 ( 2 ): 609 – 615 . 34424399 10.1007/s00415-021-10766-5 PMC8381707

92 Pennisi M Jain T Santomasso BD , et al . Comparing CAR T-cell toxicity grading systems: application of the ASTCT grading system and implications for management . Blood Adv 2020 ; 4 ( 4 ): 676 – 686 . 32084260 10.1182/bloodadvances.2019000952 PMC7042979

93 Yoon JG Smith DA Tirumani SH , et al . CAR T-cell therapy: an update for radiologists . Am J Roentgenol 2021 ; 217 ( 6 ): 1461 – 1474 . 34191544 10.2214/AJR.21.26091

94 Le RQ Li L Yuan W , et al . FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome . Oncologist 2018 ; 23 ( 8 ): 943 – 947 . 29622697 10.1634/theoncologist.2018-0028 PMC6156173

95 De Philippis C Mannina D Giordano L , et al . Impact of preemptive use of tocilizumab on chimeric antigen receptor T cell outcomes in non-Hodgkin lymphoma . Transplant Cell Ther 2023 ; 29 ( 7 ): 429.e1–429.e6. 10.1016/j.jtct.2023.03.019 36966874

96 Park JH Nath K Devlin SM , et al . CD19 CAR T-cell therapy and prophylactic anakinra in relapsed or refractory lymphoma: phase 2 trial interim results . Nat Med 2023 ; 29 ( 7 ): 1710 – 1717 . 37400640 10.1038/s41591-023-02404-6 PMC11462637

97 Nellan A McCully CML Cruz Garcia R , et al . Improved CNS exposure to tocilizumab after cerebrospinal fluid compared to intravenous administration in rhesus macaques . Blood 2018 ; 132 ( 6 ): 662 – 666 . 29954750 10.1182/blood-2018-05-846428 PMC6086204

98 Santomasso BD Gust J Perna F. How I treat unique and difficult to manage cases of CAR T-cell therapy associated neurotoxicity . Blood 2023 ; 141 ( 20 ): 2443 – 2451 . 36877916 10.1182/blood.2022017604 PMC10329188

99 Ursu R Maillet D Belin C , et al . Long-term neurologic safety in patients with B-cell lymphoma treated with anti-CD19 chimeric antigen receptor T-cell therapy . Neurology 2022 ; 99 ( 12 ): 511 – 515 . 35851255 10.1212/WNL.0000000000201083

100 Ruark J Mullane E Cleary N , et al . Patient-reported neuropsychiatric outcomes of long-term survivors after chimeric antigen receptor T cell therapy . Biol Blood Marrow Transplant 2020 ; 26 ( 1 ): 34 – 43 . 31605820 10.1016/j.bbmt.2019.09.037 PMC6951812

101 Costa DSJ Fardell JE . Why are objective and perceived cognitive function weakly correlated in patients with cancer? J Clin Oncol 2019 ; 37 ( 14 ): 1154 – 1158 . 30920881 10.1200/JCO.18.02363

102 Hoogland AI Li X Modi K , et al . Real-world patient-reported and neurocognitive outcomes in the year after axicabtagene ciloleucel . Transplant Cell Ther 2025 ; 31 ( 3 ): 157.e1–157.e13. 10.1016/j.jtct.2024.12.020 PMC12153818 39733840

103 Ho M-H Cheung DST Wang T , et al . Cancer-related cognitive impairment in patients with hematologic malignancies after CAR T cell therapy: a systematic review and meta-analysis of prevalence . Support Care Cancer 2025 ; 33 ( 4 ): 312 . 40119970 10.1007/s00520-025-09356-2 PMC11929693

104 Lakomy T Akhoundova D Nilius H , et al . Early use of corticosteroids following CAR T-cell therapy correlates with reduced risk of high-grade CRS without negative impact on neurotoxicity or treatment outcome . Biomolecules 2023 ; 13 ( 2 ): 382 . 36830750 10.3390/biom13020382 PMC9953517

105 Hines MR Knight TE McNerney KO , et al . Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome . Transplant Cell Ther 2023 ; 29 ( 7 ): 438.e1–438.e16. 10.1016/j.jtct.2023.03.006 PMC10330221 36906275

106 Rejeski K Perez A Sesques P , et al . CAR-HEMATOTOX: a model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma . Blood 2021 ; 138 ( 24 ): 2499 – 2513 . 34166502 10.1182/blood.2020010543 PMC8893508

107 Rejeski K Hansen DK Bansal R , et al . The CAR-HEMATOTOX score as a prognostic model of toxicity and response in patients receiving BCMA-directed CAR-T for relapsed/refractory multiple myeloma . J Hematol Oncol 2023 ; 16 ( 1 ): 88 . 37525244 10.1186/s13045-023-01465-x PMC10391746

108 Liévin R Di Blasi R Morin F , et al . Effect of early granulocyte-colony-stimulating factor administration in the prevention of febrile neutropenia and impact on toxicity and efficacy of anti-CD19 CAR-T in patients with relapsed/refractory B-cell lymphoma . Bone Marrow Transplant 2022 ; 57 ( 3 ): 431 – 439 . 35094012 10.1038/s41409-021-01526-0 PMC8907072

109 Drillet G Lhomme F De Guibert S , et al . Prolonged thrombocytopenia after CAR T-cell therapy: the role of thrombopoietin receptor agonists . Blood Adv 2023 ; 7 ( 4 ): 537 – 540 . 35930692 10.1182/bloodadvances.2022008066 PMC9979763

110 Wat J Barmettler S. Hypogammaglobulinemia after chimeric antigen receptor (CAR) T-cell therapy: characteristics, management, and future directions . J Allergy Clin Immunol Pract 2022 ; 10 ( 2 ): 460 – 466 . 34757064 10.1016/j.jaip.2021.10.037 PMC8837681

111 Reynolds G Hall VG Teh BW. Vaccine schedule recommendations and updates for patients with hematologic malignancy post-hematopoietic cell transplant or CAR T-cell therapy . Transpl Infect Dis 2023 ; 25 ( Suppl. 1 ): e14109. 10.1111/tid.14109 PMC10909447 37515788

112 Cordeiro A Bezerra ED Hirayama AV , et al . Late events after treatment with CD19-targeted chimeric antigen receptor modified T cells . Biol Blood Marrow Transplant 2020 ; 26 ( 1 ): 26 – 33 . 31419568 10.1016/j.bbmt.2019.08.003 PMC6953906

113 Müller F Schwingen NR Hagen M , et al . Comparison of the safety profiles of CD19-targeting CAR T-cell therapy in patients with SLE and B-cell lymphoma . Blood J 2025 ; 146 ( 9 ): 1088 – 1095 . 10.1182/blood.2025028375 40504989

114 Zhang Y Li Y Cao W , et al . Single-cell analysis of target antigens of CAR-T reveals a potential landscape of “on-target, off-tumor toxicity” . Front Immunol 2021 ; 12 : 799206 . 34975912 10.3389/fimmu.2021.799206 PMC8716389

115 Bhoj VG Arhontoulis D Wertheim G , et al . Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy . Blood 2016 ; 128 ( 3 ): 360 – 370 . 27166358 10.1182/blood-2016-01-694356 PMC4957161

116 Cordas Dos Santos DM Tix T Shouval R , et al . A systematic review and meta-analysis of nonrelapse mortality after CAR T cell therapy . Nat Med 2024 ; 30 ( 9 ): 2667 – 2678 . 38977912 10.1038/s41591-024-03084-6 PMC11765209

117 Kampouri E Flaherty P Xie H , et al . The impact of CMV reactivation on mortality after chimeric antigen receptor T-cell therapy . Blood Adv 2025 ; 9 ( 12 ): 2997 – 3001 . 40203190 10.1182/bloodadvances.2024015164 PMC12205581

118 Ellithi M Elsallab M Lunning MA , et al . Neurotoxicity and rare adverse events in BCMA-directed CAR T cell therapy: a comprehensive analysis of real-world FAERS data . Transplant Cell Ther 2025 ; 31 ( 2 ): 71.e1–71.e14. 10.1016/j.jtct.2024.12.002 39672542

119 Sidana S Patel KK Peres LC , et al . Safety and efficacy of standard-of-care ciltacabtagene autoleucel for relapsed/refractory multiple myeloma . Blood 2025 ; 145 ( 1 ): 85 – 97 . 39365257 10.1182/blood.2024025945 PMC11952008

120 Van Oekelen O Aleman A Upadhyaya B , et al . Neurocognitive and hypokinetic movement disorder with features of parkinsonism after BCMA-targeting CAR-T cell therapy . Nat Med 2021 ; 27 ( 12 ): 2099 – 2103 . 34893771 10.1038/s41591-021-01564-7 PMC8678323

121 Tix T Alhomoud M Shouval R , et al . Second primary malignancies after CAR T-cell therapy: a systematic review and meta-analysis of 5,517 lymphoma and myeloma patients . Clin Cancer Res 2024 ; 30 ( 20 ): 4690 – 4700 . 39256908 10.1158/1078-0432.CCR-24-1798 PMC11546643

122 Gazeau N Beauvais D Tilmont R , et al . Myeloid neoplasms after CD19-directed CAR T cells therapy in long-term B-cell lymphoma responders, a rising risk over time? Leukemia 2025 ; 39 ( 7 ): 1714 – 1722 . 40275069 10.1038/s41375-025-02605-7 PMC12208870

123 Elsallab M Ellithi M Lunning MA , et al . Second primary malignancies after commercial CAR T-cell therapy: analysis of the FDA Adverse Events Reporting System . Blood 2024 ; 143 ( 20 ): 2099 – 2105 . 38483155 10.1182/blood.2024024166

124 Miller PG Sperling AS Brea EJ , et al . Clonal hematopoiesis in patients receiving chimeric antigen receptor T-cell therapy . Blood Adv 2021 ; 5 ( 15 ): 2982 – 2986 . 34342642 10.1182/bloodadvances.2021004554 PMC8361461

125 Bekele DI Patnaik MM. Autoimmunity, clonal hematopoiesis, and myeloid neoplasms . Rheum Dis Clin N Am 2020 ; 46 ( 3 ): 429 – 444 . 10.1016/j.rdc.2020.03.001 32631598

126 Pérez González A Pellín Jou C Palomo L , et al . Prevalence, dynamics and clinical significance of clonal hematopoiesis of indeterminate potential (CHIP) in newly diagnosed cancer patients . Blood 2023 ; 142 ( Suppl. 1 ): 5593 .

127 Yap TA Ashok A Stoll J , et al . Prevalence of germline findings among tumors from cancer types lacking hereditary testing guidelines . JAMA Netw Open 2022 ; 5 ( 5 ): e2213070. 10.1001/jamanetworkopen.2022.13070 PMC9123503 35594047

128 Harrison SJ Touzeau C Kint N , et al . CAR+ T-cell lymphoma after Cilta-cel therapy for relapsed or refractory myeloma . N Engl J Med 2025 ; 392 ( 7 ): 677 – 685 . 39938094 10.1056/NEJMoa2309728

129 Dulery R Guiraud V Choquet S , et al . T cell malignancies after CAR T cell therapy in the DESCAR-T registry . Nat Med 2025 ; 31 ( 4 ): 1130 – 1133 . 39779930 10.1038/s41591-024-03458-w

130 Dores GM Morton LM. T-cell neoplasms after B-cell neoplasms—the pre–CAR T-cell era . N Engl J Med 2024 ; 391 ( 7 ): 662 – 664 . 39141862 10.1056/NEJMc2408029 PMC11328961

131 Berg P Ruppert-Seipp G Müller S , et al . CAR T-cell-associated secondary malignancies challenge current pharmacovigilance concepts . EMBO Mol Med 2025 ; 17 ( 2 ): 211 – 218 . 39762651 10.1038/s44321-024-00183-2 PMC11822130

132 Hagen M Müller F Wirsching A , et al . Local immune effector cell-associated toxicity syndrome in CAR T-cell treated patients with autoimmune disease: an observational study . Lancet Rheumatol 2025 ; 7 ( 6 ): e424–e433. 10.1016/S2665-9913(25)00091-8 40318690

133 Wu C Wang R Ye Y , et al . Local immune effector cell-associated toxicity syndrome in CAR T-cell treated patients with refractory systemic lupus erythematosus . Lancet Rheumatol 2025 ; 7 ( 10 ): e667–e669. 10.1016/S2665-9913(25)00221-8 40816305

134 Neelapu SS Jacobson CA Ghobadi A , et al . 5-Year follow-up supports curative potential of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1) . Blood 2023 ; 141 ( 19 ): 2307 – 2315 . 36821768 10.1182/blood.2022018893 PMC10646788

135 O’Reilly MA Wilson W Burns D , et al . Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in the United Kingdom: a real-world intention-to-treat analysis . Hemasphere 2024 ; 8 ( 6 ): e87. 10.1002/hem3.87 PMC11170269 38873532

136 Merz M Albici A Von Tresckow B , et al . Idecabtagene vicleucel or ciltacabtagene autoleucel for relapsed or refractory multiple myeloma: an international multicenter study . Hemasphere 2025 ; 9 ( 1 ): e70070. 10.1002/hem3.70070 PMC11735948 39822585

137 Looka A Qualls DA Matthews D , et al . A real-world comparison of commercial-use axicabtagene ciloleucel and lisocabtagene maraleucel in large B-cell lymphoma . Blood Adv 2025 ; 9 ( 3 ): 455 – 462 . 39546746 10.1182/bloodadvances.2024012992 PMC11808612

138 Schuster SJ Tam CS Borchmann P , et al . Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study . Lancet Oncol 2021 ; 22 ( 10 ): 1403 – 1415 . 34516954 10.1016/S1470-2045(21)00375-2

139 Abou-el-Enein M Elsallab M Feldman SA , et al . Scalable manufacturing of CAR T cells for cancer immunotherapy . Blood Cancer Discov 2021 ; 2 ( 5 ): 408 – 422 . 34568831 10.1158/2643-3230.BCD-21-0084 PMC8462122

140 European Medicines Agency . EudraLex—Volume 4: good manufacturing practice (GMP) guidelines . European Commission , https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en ( 2023 , accessed 8 February 2025 ).

141 U.S. Food and Drug Administration . Current good manufacturing practice in manufacturing, processing, packing, or holding of drugs . Electronic Code of Federal Regulations , https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-210 ( 2025 , accessed 8 February 2025 ).

142 Greco R Alexander T Del Papa N , et al . Innovative cellular therapies for autoimmune diseases: expert-based position statement and clinical practice recommendations from the EBMT practice harmonization and guidelines committee . EClinicalMedicine 2024 ; 69 : 102476 . 38361991 10.1016/j.eclinm.2024.102476 PMC10867419

143 Jaggers JL Giri S Klepin HD , et al . Characterizing inclusion and exclusion criteria in clinical trials for chimeric antigen receptor (CAR) T-cell therapy among adults with hematologic malignancies . J Geriatr Oncol 2021 ; 12 ( 2 ): 235 – 238 . 32855108 10.1016/j.jgo.2020.08.004 PMC11892239

144 Wang J Alkrekshi A Dasari S , et al . CD19-targeted chimeric antigen receptor T-cell therapy in patients with concurrent B-cell non-Hodgkin lymphoma and rheumatic autoimmune diseases: a propensity score matching study . Bone Marrow Transplant 2023 ; 58 ( 11 ): 1223 – 1228 . 37604871 10.1038/s41409-023-02086-1

145 Das RK Vernau L Grupp SA , et al . Naïve T-cell deficits at diagnosis and after chemotherapy impair cell therapy potential in pediatric cancers . Cancer Discov 2019 ; 9 ( 4 ): 492 – 499 . 30630850 10.1158/2159-8290.CD-18-1314 PMC6676489

146 Farina M Chiarini M Almici C , et al . Timely leukapheresis may interfere with the “fitness” of lymphocytes collected for CAR-T treatment in high risk DLBCL patients . Cancers 2022 ; 14 ( 21 ): 5276 . 36358694 10.3390/cancers14215276 PMC9655620

147 Matsumoto M Tashiro S Ito T , et al . Fully closed cell sorter for immune cell therapy manufacturing . Mol Ther Methods Clin Dev 2023 ; 30 : 367 – 376 . 37637381 10.1016/j.omtm.2023.07.012 PMC10457513

148 Zhou J Jin L Wang F , et al . Chimeric antigen receptor T (CAR-T) cells expanded with IL-7/IL-15 mediate superior antitumor effects . Protein Cell 2019 ; 10 ( 10 ): 764 – 769 . 31250350 10.1007/s13238-019-0643-y PMC6776495

149 Garfall AL Dancy EK Cohen AD , et al . T-cell phenotypes associated with effective CAR T-cell therapy in postinduction vs relapsed multiple myeloma . Blood Adv 2019 ; 3 ( 19 ): 2812 – 2815 . 31575532 10.1182/bloodadvances.2019000600 PMC6784521

150 Fraietta JA Lacey SF Orlando EJ , et al . Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia . Nat Med 2018 ; 24 ( 5 ): 563 – 571 . 29713085 10.1038/s41591-018-0010-1 PMC6117613

151 Chen GM Chen C Das RK , et al . Integrative bulk and single-cell profiling of premanufacture T-cell populations reveals factors mediating long-term persistence of CAR T-cell therapy . Cancer Discov 2021 ; 11 ( 9 ): 2186 – 2199 . 33820778 10.1158/2159-8290.CD-20-1677 PMC8419030

152 Melenhorst JJ Chen GM Wang M , et al . Decade-long leukaemia remissions with persistence of CD4+ CAR T cells . Nature 2022 ; 602 ( 7897 ): 503 – 509 . 35110735 10.1038/s41586-021-04390-6 PMC9166916

153 Sommermeyer D Hudecek M Kosasih PL , et al . Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo . Leukemia 2016 ; 30 ( 2 ): 492 – 500 . 10.1038/leu.2015.247 PMC4746098 26369987

154 Boulch M Cazaux M Cuffel A , et al . A major role for CD4+ T cells in driving cytokine release syndrome during CAR T cell therapy . Cell Rep Med 2023 ; 4 ( 9 ): 101161 . 37595589 10.1016/j.xcrm.2023.101161 PMC10518592

155 Marcucci KT Jadlowsky JK Hwang WT , et al . Retroviral and lentiviral safety analysis of gene-modified T cell products and infused HIV and oncology patients . Mol Ther 2018 ; 26 ( 1 ): 269 – 279 . 29203150 10.1016/j.ymthe.2017.10.012 PMC5763152

156 Dimitri A Herbst F Fraietta JA. Engineering the next-generation of CAR T-cells with CRISPR-Cas9 gene editing . Mol Cancer 2022 ; 21 ( 1 ): 78 . 35303871 10.1186/s12943-022-01559-z PMC8932053

157 Locke FL Siddiqi T Jacobson CA , et al . Impact of vein-to-vein time in patients with R/R LBCL treated with axicabtagene ciloleucel . Blood Adv 2025 ; 9 ( 11 ): 2663 – 2676 . 39883946 10.1182/bloodadvances.2024013656 PMC12155625

158 Chen AJ Zhang J Agarwal A , et al . Value of reducing wait times for chimeric antigen receptor T-cell treatment: evidence from randomized controlled trial data on tisagenlecleucel for diffuse large B-cell lymphoma . Value Health 2022 ; 25 ( 8 ): 1344 – 1351 . 35341689 10.1016/j.jval.2022.02.007

159 Hu B Vaidya R Ahmed F , et al . Real-world analysis of barriers to timely administration of chimeric antigen receptor T cell (CAR T) therapy in diffuse large B-cell lymphoma . Transplant Cell Ther 2024 ; 30 ( 11 ): 1082 .e1–1082.e10. 10.1016/j.jtct.2024.09.007 39270935

160 Chong EA Levine BL Grupp SA , et al . CAR T cell viability release testing and clinical outcomes: is there a lower limit? Blood 2019 ; 134 ( 21 ): 1873 – 1875 . 31554634 10.1182/blood.2019002258 PMC6872962

161 Depil S Duchateau P Grupp SA , et al . “Off-the-shelf” allogeneic CAR T cells: development and challenges . Nat Rev Drug Discov 2020 ; 19 ( 3 ): 185 – 199 . 31900462 10.1038/s41573-019-0051-2

162 Benjamin R Jain N Maus MV , et al . UCART19, a first-in-class allogeneic anti-CD19 chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia (CALM): a phase 1, dose-escalation trial . Lancet Haematol 2022 ; 9 ( 11 ): e833–e843. 10.1016/S2352-3026(22)00245-9 PMC11575699 36228643

163 Bhaskar ST Dholaria B Savani BN , et al . The evolving role of bridging therapy during CAR-T therapy . Clin Hematol Int 2024 ; 6 ( 3 ): 9 – 16 . 39027142 10.46989/001c.116261 PMC11257384

164 Neelapu SS. CAR-T efficacy: is conditioning the key? Blood 2019 ; 133 ( 17 ): 1799–800. 10.1182/blood-2019-03-900928 31023743

165 Fabrizio VA Boelens JJ Mauguen A , et al . Optimal fludarabine lymphodepletion is associated with improved outcomes after CAR T-cell therapy . Blood Adv 2022 ; 6 ( 7 ): 1961 – 1968 . 34788386 10.1182/bloodadvances.2021006418 PMC9006295

166 Lickefett B Chu L Ortiz-Maldonado V , et al . Lymphodepletion—an essential but undervalued part of the chimeric antigen receptor T-cell therapy cycle . Front Immunol 2023 ; 14 : 1303935 . 38187393 10.3389/fimmu.2023.1303935 PMC10770848

167 Albelda SM. CAR T cell therapy for patients with solid tumours: key lessons to learn and unlearn . Nat Rev Clin Oncol 2024 ; 21 ( 1 ): 47 – 66 . 37904019 10.1038/s41571-023-00832-4

168 Philipp N Kazerani M Nicholls A , et al . T-cell exhaustion induced by continuous bispecific molecule exposure is ameliorated by treatment-free intervals . Blood 2022 ; 140 ( 10 ): 1104 – 1118 . 35878001 10.1182/blood.2022015956 PMC10652962

169 Friedrich MJ Neri P Kehl N , et al . The pre-existing T cell landscape determines the response to bispecific T cell engagers in multiple myeloma patients . Cancer Cell 2023 ; 41 ( 4 ): 711–725.e6. 10.1016/j.ccell.2023.02.008 36898378

170 Cohen AD Mateos MV Cohen YC , et al . Efficacy and safety of cilta-cel in patients with progressive multiple myeloma after exposure to other BCMA-targeting agents . Blood 2023 ; 141 ( 3 ): 219 – 230 . 36095849 10.1182/blood.2022015526 PMC10562529

171 Edwards JCW Cambridge G . B-cell targeting in rheumatoid arthritis and other autoimmune diseases . Nat Rev Immunol 2006 ; 6 ( 5 ): 394 – 403 . 16622478 10.1038/nri1838

172 Maurer MA Rakocevic G Leung CS , et al . Rituximab induces sustained reduction of pathogenic B cells in patients with peripheral nervous system autoimmunity . J Clin Invest 2012 ; 122 ( 4 ): 1393 – 1402 . 22426210 10.1172/JCI58743 PMC3314454

173 Furie R Petri M Zamani O , et al . A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus . Arthritis Rheum 2011 ; 63 ( 12 ): 3918 – 3930 . 22127708 10.1002/art.30613 PMC5007058

174 Jacob S Mazibrada G Irani SR , et al . The role of plasma exchange in the treatment of refractory autoimmune neurological diseases: a narrative review . J Neuroimmune Pharmacol 2021 ; 16 ( 4 ): 806 – 817 . 34599742 10.1007/s11481-021-10004-9 PMC8714620

175 Dalakas MC. Update on intravenous immunoglobulin in neurology: modulating neuro-autoimmunity, evolving factors on efficacy and dosing and challenges on stopping chronic IVIg therapy . Neurotherapeutics 2021 ; 18 ( 4 ): 2397 – 2418 . 34766257 10.1007/s13311-021-01108-4 PMC8585501

176 Smith RM Jones RB Specks U , et al . Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis . Ann Rheum Dis 2020 ; 79 ( 9 ): 1243 – 1249 . 32581088 10.1136/annrheumdis-2019-216863 PMC7456549

177 Schreiber S Al-Dubai M Vielhaber S , et al . Effective use of BCMA-targeting bispecific T cell-engaging antibody in treatment-refractory LRP4+ myasthenia gravis . Mol Ther 2025 ; 33 ( 9 ): 4130 – 4134 . 40534130 10.1016/j.ymthe.2025.06.029 PMC12432888

178 Ruck T Huntemann N Öztürk M , et al . CD19xCD3 T cell engager blinatumomab effective in refractory generalized myasthenic syndromes . Mol Ther 2025 ; 33 ( 9 ): 4135 – 4142 . 40583272 10.1016/j.ymthe.2025.06.042 PMC12432851

179 Tur C Eckstein M Bucci L , et al . Effects of different B-cell-depleting strategies on the lymphatic tissue . Ann Rheum Dis . Epub ahead of print July 2025. DOI: 10.1016/j.ard.2025.06.2120 . 40651933

180 Mougiakakos D Krönke G Völkl S , et al . CD19-targeted CAR T cells in refractory systemic lupus erythematosus . N Engl J Med 2021 ; 385 ( 6 ): 567 – 569 . 34347960 10.1056/NEJMc2107725

181 Mackensen A Müller F Mougiakakos D , et al . Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus . Nat Med 2022 ; 28 ( 10 ): 2124 – 2132 . 36109639 10.1038/s41591-022-02017-5

182 Schett G Mackensen A Mougiakakos D. CAR T-cell therapy in autoimmune diseases . Lancet 2023 ; 402 ( 10416 ): 2034 – 2044 . 37748491 10.1016/S0140-6736(23)01126-1

183 Kattamuri L Mohan Lal B Vojjala N , et al . Safety and efficacy of CAR-T cell therapy in patients with autoimmune diseases: a systematic review . Rheumatol Int 2025 ; 45 ( 1 ): 18 . 39754644 10.1007/s00296-024-05772-5

184 Ismail FS Gallus M Meuth SG , et al . Current and future roles of chimeric antigen receptor T-cell therapy in neurology: a review . JAMA Neurol 2025 ; 82 ( 1 ): 93 . 39585688 10.1001/jamaneurol.2024.3818

185 Ehrenstein MR Wing C. The BAFFling effects of rituximab in lupus: danger ahead? Nat Rev Rheumatol 2016 ; 12 ( 6 ): 367 – 372 . 26888554 10.1038/nrrheum.2016.18

186 Khodadadi L Cheng Q Radbruch A , et al . The maintenance of memory plasma cells . Front Immunol 2019 ; 10 : 721 . 31024553 10.3389/fimmu.2019.00721 PMC6464033

187 Cook MR Dorris CS Makambi KH , et al . Toxicity and efficacy of CAR T-cell therapy in primary and secondary CNS lymphoma: a meta-analysis of 128 patients . Blood Adv 2023 ; 7 ( 1 ): 32 – 39 . 36260735 10.1182/bloodadvances.2022008525 PMC9813524

188 Schmelz JL Navsaria L Goswamy R , et al . Chimeric antigen receptor T-cell therapy’s role in antiphospholipid syndrome: a case report . Br J Haematol 2020 ; 188 ( 3 ): e5–e8. 10.1111/bjh.16266 31721157

189 Alexander T Arnold R . HSCT for systemic autoimmune diseases with neurologic involvement . Handb Clin Neurol 2024 ; 202 : 259 – 264 . 39111912 10.1016/B978-0-323-90242-7.00014-6

190 Hunter TL Bao Y Zhang Y , et al . In vivo CAR T cell generation to treat cancer and autoimmune disease . Science 2025 ; 388 ( 6753 ): 1311 – 1317 . 40536974 10.1126/science.ads8473

191 Wang X Wu X Tan B , et al . Allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis . Cell 2024 ; 187 ( 18 ): 4890–4904.e9. 10.1016/j.cell.2024.06.027 39013470

192 Wang X Zhang Y Jin Y , et al . An iPSC-derived CD19/BCMA CAR-NK therapy in a patient with systemic sclerosis . Cell 2025 ; 188 ( 16 ): 4225–4238.e12. 10.1016/j.cell.2025.05.038 40562027