DISEASE
In anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis (AAV), failure of the immune systems leads to the development of antibodies recognizing endogenous antigens, namely the enzymes proteinase 3 (PR3) and myeloperoxidase (MPO) [ 1–3 ]. As these antigens are expressed by both neutrophil granulocytes and monocytes and are mainly located in the cytoplasm, the autoantibodies are called anti-neutrophil cytoplasmic autoantibodies (ANCA). AAV is classified into granulomatosis with polyangiitis (GPA), microscopic polyangiitis and eosinophilic GPA. For the first two, clinical, epidemiologic, genetic and experimental evidence suggests that ANCA serotype (MPO-ANCA versus PR3-ANCA) may determine distinct but overlapping clinical and pathologic features of ANCA vasculitis: PR3-ANCA is associated with a higher prevalence of ophthalmologic, and ear, nose and throat symptoms, an increased risk of relapse and a better response to rituximab-based induction therapy. In contrast, MPO-ANCA is associated with an increased frequency of renal involvement, the development of chronic kidney disease and pulmonary fibrosis [ 4–10 ]. In addition, candidate gene approaches and large genome-wide association studies have revealed heterogeneous genetic backgrounds in which different regions of human leukocyte antigens with different polymorphisms were affected, as well as SERPINA1 and PRTN3 genes [ 11 , 12 ]. In vitro also, there are fundamental differences in the activation of myeloid cells by PR3-ANCA or MPO-ANCA, as well as differences in the cytokine pattern induced by stimulation with the respective ANCA subtype [ 13 , 14 ].
At the cellular level, the antigens are translocated to the membrane of the granulocytes and monocytes through a subliminal pre-activation, known as priming, and thus become accessible to the ANCA circulating in the blood. ANCA can bind to the exposed antigens and activate the affected cells via various signaling cascades. This neutrophil and monocyte activation leads to degranulation of toxic granula-proteins, generation of reactive oxygen species and formation of neutrophil extracellular traps (NETs) [ 15–18 ]. In addition to these cells of the innate immune system, antigen-specific B and T cells also play an essential role in the formation of ANCA. CD4 + T cells and MPO itself (released by activated neutrophils) were detected within lesions in glomeruli, so it is assumed that MPO-specific CD4 + T cells can support autoreactive B cells directly on site in the production of autoantibodies. Those further increase neutrophil activation resulting in enhanced tissue damage [ 19 , 20 ]. In addition to their role as ANCA producers, B cells act as antigen-presenting cells, secrete pro-inflammatory and immunoregulatory cytokines, and are involved in the formation of lymphatic structures in affected organs [ 21 , 22 ]. How important these further tasks of B cells are shows the efficacy of rituximab application in responsive patients despite persisting (although reduced) ANCA-levels [ 23 ]. Furthermore, activation of the complement system turned out to play a crucial role as well [ 24 ]. The final stage of the cascade is the destruction of the vascular system, which primarily affects the lungs and kidneys. This can lead to irreversible loss of organ function with life-threatening organ failure and the need for organ replacement therapy such as ventilation or dialysis.
The treatment of AAV is currently based on aggressive and rather non-specific immunosuppression. Treatment regimens consist of two phases, remission induction and remission maintenance. The aim of remission induction is to end disease activity as quickly as possible in the acute phase in order to restore organ function and prevent further loss of function and thus, for example, subsequent dialysis dependency. For this purpose, high doses of glucocorticoids are used in combination with either cytotoxic substances (cyclophosphamide) or B-cell depleting antibodies (rituximab). Repeated doses of either cyclophosphamide or rituximab are administered over several weeks. In particularly life-threatening cases, there is also the option of plasma exchange, however there is an ongoing debate regarding its role [ 25 , 26 ]. Once the disease activity has gone in remission, remission maintenance therapy is usually carried out for at least 2–3 years. Depending on the individual risk and initial therapy, patients receive either a different oral chemotherapeutic agent (azathioprine) or 6-monthly infusions of rituximab [ 27 ]. These regimens bring disease activity to a halt within 90 days in approximately 70%–90% of patients. Despite maintenance therapy, 8%–60% of patients develop a relapse of the disease within the first 2 years [ 28 ]. Mortality in the first year after diagnosis is approximately 12% and is about 2.6 times higher compared with healthy controls [ 29 ]. It should be noted that 48% of deaths in the first year in particular are due to infections, i.e. side effects of immunosuppressive therapy, and only 19% are due to the AAV itself [ 30 ]. Rituximab, although highly effective in depleting circulating B cells, is partly inefficient in induction therapy of AAV because it does not fully eliminate the pathogenic immune mechanisms driving acute inflammation. Long-lived plasma cells, which are resistant to CD20-targeted depletion, continue to produce ANCAs and sustain autoantibody-mediated neutrophil activation. In addition, tissue-resident B cells are only inefficiently depleted, further limiting its efficacy.
Novel CD20 antibodies such as obinutuzumab represent a promising extension of B cell–targeted therapy in AAV. Unlike rituximab, obinutuzumab is a type II glycoengineered CD20 antibody with enhanced antibody-dependent cellular cytotoxicity and reduced complement activation, leading to deeper and more sustained B-cell depletion. Early clinical reports suggest that obinutuzumab may achieve more complete depletion of pathogenic B cells, including in patients who are refractory to rituximab, and may provide longer remission intervals. Importantly, its distinct mechanism could offer advantages in reducing relapse risk and in patients who develop anti-rituximab antibodies [ 31 ]. ObiVas, a randomized, phase 2, double-blind, study comparing obinutuzumab versus rituximab, will test this hypothesis [ 32 ].
The complement system—once considered marginal in AAV—is now recognized as a key driver of the disease’s pathogenesis. Specifically, the alternative complement pathway is activated by ANCA-stimulated neutrophils, which release factors that lead to the generation of C5a, a potent chemoattractant and primer of neutrophils [ 33 ]. This C5a-driven feedback loop amplifies inflammation, promoting neutrophil recruitment and vascular injury [ 24 ]. Therapeutically, the C5a receptor antagonist avacopan targets this axis to mitigate neutrophil priming and inflammation, representing a novel and effective treatment modality in AAV [ 34 , 35 ].
Finally, T cell engagers are an emerging class of immunotherapies that redirect cytotoxic T cells toward specific immune targets through bispecific antibody formats, typically linking CD3 on T cells to a disease-driving antigen. In autoimmune diseases, this approach is being adapted to eliminate autoreactive B cells or plasma cells by targeting markers such as CD19, CD20 or BCMA, thereby reducing pathogenic autoantibody production [ 36 ]. Unlike conventional B cell–depleting agents, T-cell engagers may provide faster and more selective immune clearance, with the potential to reset dysregulated immune networks. However, their use in autoimmunity is still experimental.
Therefore, there is still a great need for more specific therapeutic approaches with fewer side effects. For these reasons, research into additional novel therapeutic strategies is essential. One promising approach for difficult-to-treat AAV patients has emerged recently—CD19-targeting chimeric antigen receptor (CAR)-T cells.
CD19 CAR-T CELLS
CAR-T cell
The CAR is an engineered hybrid antigen receptor that combines the ability of B cell–derived antibodies to bind unprocessed antigens and the feature of activated T cells to kill bound cells. The CAR redirects T cells toward cells or tissues expressing the antigen of interest and empowers the T cells to recognize surface antigens in an MHC-independent manner. The so-called first-generation CARs consist of an intracellular CD3ζ-derived signaling domain connected via a transmembrane and hinge domain to an extracellular antibody single chain fragment (scFv) recognizing the antigen of interest. Further development led to second generation CARs with an additional intracellular co-stimulatory domain which improves activation and proliferation of the T cell while reducing susceptibility to immunosuppression. This latter effect is caused by increased nuclear factor (NF)-κB activation from the more strongly activated T cells. NF-κB signaling counteracts inhibitory cytokine responses and regulatory T cell–induced proliferation-suppression. Widely used co-stimulatory domains derive from CD28, CD134 (OX40) or CD137 (4–1BB) [ 37–41 ]. Meanwhile, third-, fourth- and fifth-generation CARs exist with a wide variety of construct composition, e.g. different co-stimulatory domains, included chemokines or intracellular cytokine receptor domains as well as bispecific antigen binding domains or tandem CAR design [ 42–44 ].
Therapeutical applications of CAR-T cells
In order to administer autologous CAR-T cells to patients, sufficient T cells must first be collected from them using leukapheresis. This requires that immunosuppressive drugs be reduced or discontinued completely approximately 2 weeks beforehand, so that the T-cell population can recover sufficiently. The then-collected cells are activated in vitro , genetically modified to express the CAR construct, expanded and then administered to the patient. To ensure that the CAR-T cells have a niche in which to implant, the patient must first undergo lymphodepletion. In most cases, a combination of cyclophosphamide and fludarabine is used for this purpose.
Application in autoimmune diseases: systemic lupus erythematosus
In autoimmune diseases (AIDs) patients fail in proper differentiating of own and foreign. Therefore, B cells start to produce antibodies against autoantigens. Long-term elimination of the autoantibody-producing B cells or plasma cells would interrupt the pathologic cycle. Hence, usage of CD19 CAR-T cells seemed a promising approach. In preclinical studies using the NZB × NZW and MRL-lpr mouse models of the autoimmune lupus disease, CD19-targeting murine CAR-T cell–based therapies eliminated CD19-expressing B cells and attenuated the disease [ 45 ]. Furthermore, these CD19 CAR-T cells remained functional for months and removed transferred autologous CD19 + B cells without harming other B-cell populations.
For the first time in 2021, CD19 targeting human CAR-T cells have been successfully used to treat a patient with refractory systemic lupus erythematosus (SLE) [ 46 ]. The results were verified in five additional patients in 2022 [ 47 ]. Meanwhile, follow-up data of eight SLE patients have been published, showing still ongoing remission after 6–29 months post–CD19 CAR-T cell application [ 48 ]. In the same manuscript, positive effects of CD19-targeting CAR-T cells in idiopathic inflammatory myositis and systemic sclerosis were described lasting at least for 4–18 months. This underscores the applicability of CD19 CAR-T cells in a wide AID spectrum. Recently, a phase 1 clinical trial in 11 SLE patients with lupus nephritis analyzed the safety and efficacy of a BCMA-CD19 compound CAR (cCAR), that leads to the expression of both single CARs in a T cell. By that, B cells and plasma cells were addressed simultaneously, which expands the effect to multiple antibody-producing cell populations. All patients had reduced symptom severity including decreased SLE Disease Activity Index 2000 (SLEDAI-2K) score, less proteinuria and increased estimated glomerular filtration rates. The therapy was well tolerated, and only mild side effects (grade 1 cytokine release syndrome, mild fever) occurred [ 49 ]. The application has since been extended to pediatric patients. For example, in two 12-year-old females CD19 CAR-T cells lead to highly decreased disease activity [ 50 ]. Those mentioned above and other published studies [ 51 , 52 ] show that CD19 CAR-T cells could be a promising treatment option for patients who do not respond sufficiently to other treatment strategies.
Application in autoimmune diseases: wide range
CD19-targeting CAR-T cells were meanwhile used in a broad range of AIDs. Case reports of its successful application in multiple sclerosis [ 53 ], myasthenia gravis [ 54 ], Sjögren’s disease [ 55 ], idiopathic inflammatory myopathies [ 56 , 57 ], systemic sclerosis [ 58 , 59 ], rheumatoid arthritis [ 60 , 61 ] and antiphospholipid antibody syndrome [ 62 , 63 ] have been published. This list is certainly incomplete and is used to demonstrate the effectiveness of CD19 CAR-T cells in the autoimmune area. The application of the method has since been expanded to ANCA-associated vasculitis which is the main focus of this manuscript.
Application in autoimmune diseases: AAV
Experimental preclinical data
In a preclinical study of anti-MPO IgG-induced necrotizing crescentic glomerulonephritis (NCGN) CD19-targeting CAR-T cells were tested for their ability to reduce disease progression. In this disease model, MPO-knockout mice are immunized with MPO and subsequently produce antibodies against MPO. They are then irradiated, followed by injection of bone marrow cells from wild-type donor animals. The applied wild-type neutrophils and monocytes contain MPO and thus the antigen to which the anti-MPO antibodies of the recipient mice bind, thereby triggering the disease process. A CAR construct with a single chain fragment variable of an anti-CD19 antibody (clone 1D3), an IgG1 spacer, a CD4 transmembrane domain, an intracellular CD28 costimulatory domain and a CD3ζ activation domain was developed. Together with the wild-type bone marrow 2 × 10 6 CAR-T cells were applied and mice were analyzed 2, 5 and 8 weeks after cell transfer. CD19-targeting CAR-T cells and SP6 control CAR-T cells were detectable throughout the entire experimental period in lymphoid organs and the kidney. Mice that received CD19 CAR-T cells had near-complete B-cell depletion, a significantly reduced number of plasmablasts and were protected from development of NCGN [ 64 ]. These results were fundamental for the translation to the human application.
Application in human AAV
Since now there are three publications dealing with CD19 CAR-T cells in AAV patients. Minopoulou et al . presented treatment results of a 52-year-old male patient with severe therapy-refractory PR3-ANCA-positive GPA. Despite taking various medications including cyclophosphamide, rituximab, azathioprine, mycophenolate mofetil and methotrexate relapses could not be prevented and affected lungs, kidneys, joints, skin, sinonasal tract and eyes. Additionally, chronic damage occurred as optic atrophy, pulmonary fibrosis, elevated diastolic blood pressure, cutaneous ulcerations and peripheral neuropathy. The patient presented again with fever, weight loss, myalgia, arthralgia, exertional dyspnoea, productive cough, new granulomatous formation and elevated PR3-ANCA level. Rituximab infusion lead to improved exertional dyspnea and weight stabilization but myalgia, arthralgia and elevated ANCA levels remained unaffected. Therefore, administration of CD19-targeting CAR-T cells was decided. Therapy resulted in reduction of radiological findings (granuloma), fast decrease of PR3-ANCA level (undetectable at day 28 after CAR-T cell administration), no occurrence of arthralgia or myalgia, no new AAV-related symptoms up to the most recent follow-up (day 132), absence of CD19 + B cells or CD19low PCs in the bone marrow biopsy 48 days after anti-CD19 CAR-T cell infusion. Circulating CD19 + and CD20 + B cells stayed undetectable until the last day of follow-up. IgG levels were detected within normal limits, vaccination titers (anti-Rubella, -Tetanus, -Varicella) remained stable. The patient experienced cytokine release syndrome (CRS) grade 1 and neutropenia grade 3, which were appropriately managed with tocilizumab and filgrastim, respectively. No immune effector cell–associated neurotoxicity syndrome, infections or other therapy-related toxicities occurred [ 65 ].
Treatment effects of a second patient were described by Uhlmann et al . who applied CD19-targeting CAR-T cells to a 40-year-old male patient with GPA with persistent severe pulmonary inflammatory lesions despite rituximab, cyclophosphamide, cyclosporin A, avacopan and prednisolone administrations. Four months after CAR-T cell infusion almost complete resolution of inflammatory activity in the lung was reached. Prednisolone dosage could be reduced from 10 mg per day before CAR-T cells to 2 mg per day after CAR-T cells without significant increases in CRP or PR3-ANCA levels. The patient did not develop CRS or immune effector cell-associated neurotoxicity syndrome (ICANS). A temporary leukopenia occurred for 14 days without subsequent hematologic toxicity. Follow-up at publishing was 300 days, until then no B cell recovery had occurred [ 66 ].
Schultze-Florey et al . report on a 64-year-old Caucasian male with refractory MPO-positive AAV with kidney involvement. The patient received prednisolone, rituximab, cyclophosphamide, mycophenolic acid and avacopan. Nevertheless, MPO titer stayed elevated, crescentic glomerulonephritis was still active and Birmingham Vasculitis Activity Score (BVAS) was at 10. Application of CD19-targeting CAR-T cells was well-tolerated. The MPO titer decreased, kidney function was stabilized, proteinuria dropped by 87%, no signs of hematuria were detectable, and BVAS decreased to 0 during the 6-week follow-up. Leukocytes recovered 18 days and absolute lymphocyte counts 25 days after CAR-T cell-treatment; B-cell aplasia remained until end of follow-up [ 67 ].
All three publications show a positive effect of CD19 CAR-T cell treatment. For a better overview, the main facts are summarized in Table 1 .
Table 1:
Summary of publications regarding CD19 CAR-T cell-usage in AAV.
a BVAS version 2. CYC, cyclophosphamide; CsA, cyclosporin A; GN, glomerulonephritis; MMF, mycophenolate mofetil; RTX, rituximab; VDI, vasculitis damage index.
| Minopoulou et al . [ 65 ] | Uhlmann et al . [ 66 ] | Schultze-Florey et al . [ 67 ] | |
| Disease | Anti-PR3 ANCA GPA | Anti-PR3 ANCA GPA | Anti-MPO ANCA AAV |
| Patient | Male, 52 years | Male, 40 years | Male, 64 years |
| Affected organs | Lung, kidneys, joints, skin, sinonasal tract, eyes | Lung, none further mentioned | Kidneys, none further mentioned |
| Therapies before CAR-T cell therapy | CYC, RTX, azathioprine, MMF, methotrexate | CYC, RTX, CsA, avacopan, prednisolone | CYC, RTX, mycophenolic acid, avacopan, prednisolone |
| Disease activity before CAR-T cell therapy | Myalgia, arthralgia, BVAS 2, a elevated PR3-ANCA levels at 90 AU/mL, 0.00001/µL CD19 + B cells in peripheral blood | Lung: unresolved nodules, cavitary lesion in left lower lobe, heightened glucose metabolism, total lung capacity 76.0% Ref, forced vital capacity 60.2% | Elevated MPO titer, ongoing crescentic GN, BVAS 10 |
| Blood: normalized ANCA level, near-complete B-cell depletion | |||
| General: BVAS 8/33 | |||
| Lymphodepletion before CAR-T cell application | 300 mg/m² CYC + 30 mg/m² fludarabine daily on days –5, –4, –3 | 300 mg/m² CYC + 30 mg/m² fludarabine daily on days –5, –4, –3 | CYC + fludarabine (no further details) |
| CD19 CAR-T product | KYV-101, 1 × 10 8 CAR-T cells | KYV-101, 1 × 10 8 CAR-T cells/kg of body weight | Autologous, anti-CD19 CAR-T cells generated on site [Cellular Therapy Center GMP-Unit, CliniMACS Prodigy system (Miltenyi Biotec)] |
| Immunosuppression during CAR-T cell therapy | RTX ceased 24 days, avacopan 7 days before leukapheresis | Prednisolone 10 mg daily | Avacopan |
| Side effects | CRS grade 1, neutropenia grade 3 | Transient leukopenia | None mentioned |
| Follow-up time | 132 days | 300 days | 6 weeks |
| Outcome | Granulomas remained stable, BVAS 0, VDI score of 5, no new AAV-related symptoms, persisting B-cell aplasia, CAR-T cells detectable at low amount (peak at day 14) | Lung: almost no inflammatory activity, improvement in total lung capacity (85.6% Ref) and forced vital capacity (72.6%) | Decreased MPO titer, stable kidney function, reduced proteinuria (87%), reversal of hematuria, BVAS 0, persisting B-cell aplasia, CAR-T cells detectable at low amount (peak at day 10) |
| Blood: persisting B-cell aplasia | |||
| General: improvements in physical fitness and quality of life, BVAS 0/33 CAR-T cells still detectable (peak at day 9) | |||
| Follow-up therapy | Cessation of immunosuppressive treatment | Prednisolone tapered to 2 mg/day | Avacopan |
Usage of CD19 CAR-T cells in AAV is mentioned in an array of reviews concerning this therapeutic option in AIDs in general [ 39 , 68–73 ]. Data are so far only available in the above described publications but several studies have been registered on ClinicalTrials.gov that deal with the use of CD19 CAR-T cells in AAV (Table 2 ), so further data can be expected. It is noticeable that allogeneic cells are used in most studies. Some of their advantages and challenges are addressed below.
Table 2:
CD19 CAR-T applying studies in AAV registered on ClinicalTrials.gov by 25 August 2025.
APS, antiphospholipid syndrome; IIM, idiopathic inflammatory myopathies; IM, inflammatory myopathy; MG, myasthenia gravis; MS, multiple sclerosis; NMOSD, neuromyelitis optica spectrum disorder; SjS, Sjögren’s syndrome; SSc, systemic sclerosis.
| NCT number | Study status | Conditions | CAR-T cells | Cellular resource | Age (years) | Phase (interventional studies) | Start (dd.mm.year) | Country |
| NCT06941129 | Recruiting | AAV, SLE, SSc, IM | UCAR-T cell (universal anti-CD19/BCMA CAR-T cells) | Allogeneic | ≥18 | 1 | 11.02.2025 | China |
| NCT06508346 | Recruiting | AAV | Anti-CD19-CAR-T cells | Autologous | 5–25 | Observational study | 01.08.2024 | China |
| NCT06828042 | Recruiting | AAV, SLE, SSc, IM, SjS, APS | QH103 (universal anti-CD19-CAR-γδT cells) | Allogeneic | 18–80 | 1, 2 | 01.07.2025 | China |
| NCT07033299 | Not yet recruiting | AAV | CT1192 (universal CD19/20 CAR-T cells) | Allogeneic | 18–60 | 1 | 01.07.2025 | China |
| NCT06821659 | Not yet recruiting | AAV, SLE, SSc, IM, SjS | UWD-CD19 (universial anti-CD19-CAR-T cells) | Allogeneic | 18–80 | 1, 2 | 01.03.2025 | China |
| NCT06986018 | Not yet recruiting | AAV, IIM | RD06-04 (universial anti-CD19-CAR-T cells) | Allogeneic | 18–70 | Early 1 | 14.06.2025 | China |
| NCT06775912 | Recruiting | AAV, SLE, SSc, IIM, NMOSD, MS, MG | RD06-05 (anti-CD19/BCMA-CAR-T cells) | Not mentioned | 18–70 | Early 1 | 15.01.2025 | China |
| NCT06462144 | Recruiting | AAV, SLE, IIM | IMPT-514 (anti-CD19/CD20 CAR-T Cells) | Autologous | 18–75 | Early 1 | 13.06.2024 | China |
| NCT06308978 | Recruiting | AAV, SLE, SSc, IIM | FT819 (anti-CD19 CAR-T cells) | Allogeneic | 12–70 | 1 | 28.03.2024 | USA |
Side effects
The side effects are best described in B-cell malignancies, as CD19 CAR-T cell therapy has been approved and used for the longest time there. One common complication is the susceptibility to infections caused by immunosuppression. A systematic study by Hill et al . found that 23% of patients (133 patients were analyzed, 47 with acute lymphoblastic leukemia, 24 with chronic lymphocytic leukemia and 62 with non-Hodgkin lymphoma) suffered an infection within 4 weeks after CAR-T cell application, first infection was detected a median of 6 days (range 1–27 days) after CAR-T cell infusion; 80% of the first infections occurred within the first 10 days. For five patients it was life-threatening or fatal. The severity of CRS was associated with the occurrence of an infection in those patients. The median time to onset of CRS was 2 days before infection, and only three patients had infection preceding CRS. The median time to onset of CRS and first infection was 1.9 and 6 days, respectively [ 74 ].
CRS and immune effector cell–associated neurotoxicity syndrome (ICANS), as well as movement disorders, immune effector cell–associated hematotoxicity (ICAHT) and immune effector cell–associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) are meanwhile known as common side effects that should be considered [ 75 ]. CRS itself amplifies infection risk indirectly, mainly via immune dysregulation, mucosal barrier injury and immunosuppressive therapy used for CRS control.
Furthermore, acute kidney injury (AKI) was reported to appear in 34% of patients with hematologic diseases (acute lymphoblastic leukemia, diffuse large B-cell lymphoma, myeloma) after CD19 CAR-T cell therapy. Severity of CRS and elevated lactate dehydrogenase levels were associated with AKI occurrence [ 76 ]. A retrospective study by Gutgarts et al . reported a similar incidence (30% of any grade AKI) and subdivided into grade 1 AKI (incidence of 21.7%) and grade 2–3 AKI (incidence of 8.7%). No renal replacement was necessary [ 77 ]. Rousseau and Zafrani reviewed publications of diverse hematologic malignancies and reported AKI incidences between 2.3% and 46% which are associated with high-grade CRS, a prior autologous or allogeneic stem cell transplantation and admission to the intensive care unit [ 78 ].
In AIDs (SLE, idiopathic inflammatory myopathies, systemic sclerosis, Sjögren’s disease, rheumatoid arthritis, antiphospholipid antibody syndrome) (Table 3 ) data for the first patients suggest that CRS and ICANS appear quite often, but are mainly mild [ 79 , 80 ]. CRS severity was reported to correlate with tumor burden [ 81 ], therefore, it can be assumed that the appearance of lower-grade CRS is due to a lower number of B cells compared with B-cell malignancies that are lysed by CAR-T cells. Severe infections, hypogammaglobulinemia and cytopenia occurred in some patients. No case of cancer was reported so far [ 79 , 80 ]. It remains to be seen whether additional side effects will be detected with the treatment of more patients and whether further adverse events will occur after a longer observation period.
Table 3:
Side effects of CD19 CAR-T cell-therapy in autoimmune diseases. Exemplary list for various AIDs mentioned in this publication. For a better comparison, side effects in AAV patients already stated in Table 1 are listed again here.
APS, antiphospholipid syndrome; IIM, idiopathic inflammatory myopathies; MMF, mycophenolate mofetil; NR, not reported; RA, rheumatoid arthritis; RTX, rituximab; SSc, systemic sclerosis.
| Disease, number of patients | CRS Grade (number of patients) | Treatment | ICANS Grade (number of patients) | Treatment | Infections (Number of patients) | Additional side effects | Treatment |
| Kattamuri et al . [ 79 ] | |||||||
| SLE, 51 | 1 (43) | Tocilizumab (3 of 43) | None | None | Non-fatal (10) | NR | NR |
| SSc, 16 | Mild (9) | None | None | None | None | NR | NR |
| RA, 2 | Mild (2) | NR | None | None | None | NR | NR |
| IIM, 7 | 1 (5), 2 (1) | Tocilizumab (3 of 5, one not reported) | 1 (2) | Anakinra (1) | (1) | NR | NR |
| APS, 2 | 1 (2) | NR | NR (1) | Methylprednisolone (1) | NR | NR | NR |
| SjS, 1 | 2 (1) | Tocilizumab | NR (1) | Pulsed steroids | NR | Severe cytopentia (1) | Bone marrow stimulans |
| Scherlinger et al . [ 80 ] | |||||||
| AID (18): SLE (8), SSc (6), IIM (4) | 1 (13), >1 (1) | Tocilizumab (6), azathioprine + MMF (1) | 1 (1) | Glucocorticoid | Several (most upper respiratory tract), mostly mild, 3 to ≥12 months after treatment | Hypogammaglobulinemia (5; 2 of them previously existing because of RTX) | IgG substitution (2) |
| Lidar et al . [ 61 ] | |||||||
| RA (1) | 3 (1) | Tocilizumab | 4 (1) | Anakinra + high-dose corticosteroids (1) | NR | NR | NR |
| Zhang et al . [ 82 ] | |||||||
| MG (1) | None | None | None | None | Mild infections (conjunctivitis and upper respiratory tract) within 1 month after treatment Symptomatic treatment | NR | |
| Minopoulou et al . [ 65 ] | |||||||
| AAV (1) | 1 (1) | Tocilizumab | None | None | None | Neutropenia | Filgrastim |
| Uhlmann et al . [ 66 ] | |||||||
| AAV (1) | None | None | None | None | None | Leukocytopenia | NR |
| Schultze-Florey et al . [ 67 ] | |||||||
| AAV (1) | NR | NR | NR | NR | NR | NR | NR |
LIMITATIONS, POSSIBLE RESOLUTIONS, FUTURE DIRECTIONS
Despite already promising results from first CD19-targeting CAR-T cell therapies in AIDs and especially in AAV further research is invested in improving therapeutic strategies.
One issue is the absence of expression of CD19 on (auto)antibody-producing plasma cells which makes them unattackable by CD19-targeting CAR-T cells. First attempts were made using B-cell maturation antigen (BCMA) on the surface of long-lived plasma cells as a target. BCMA-CD19 compound CAR-T cells were applied in SLE patients to affect short- and long-lived antibody-producing cells at once to overcome that problem [ 49 , 52 , 83 ]. Others applied CD138-targeting CAR-T cells to affect plasma cells in multiple myeloma [ 84 ]. Its usage in AIDs could be an additional route. A combination of CD19 CAR-T cells and anti-CD38 antibodies is also conceivable as both were already reported to be effective alone [ 48 , 85 , 86 ] and could work synergistically in patients with insufficient therapy response.
Antigen escape should be considered as well. This phenomenon occurs when CAR-T cells are unable to bind to their target cells because the antigen is either absent or not recognized for various reasons, e.g. its epitopes are masked by other proteins, it has a mutated or alternatively spliced variant of the antigen or antigen processing is disrupted, to name just a few of the reasons that have been identified and discussed to date. These cells survive and can proliferate and antigen escape is already described as a cause of relapse of B-cell malignancies after treatment with CD19 CAR-T cells [ 87 ]. It might be countered by using two different CARs simultaneously or further compound CAR variants besides the already applied CD19 and BCMA compound. Another possibility was described by Choi et al . who designed a bicistronic construct that coded for a CAR and a secretable bispecific T-cell engager (BiTE) at once [ 88 ]. Their work aims to combat heterogeneous glioblastoma in which antigen escape occurs as well. The BiTE is a tandem single chain variable fragment (scFv) that binds with one scFv CD3 at T cells and with the other scFv an antigen at the target cell. By that, it recruits T cells and increases cytotoxicity as not only the target cells of the CAR are attacked (binds to the mutated glioblastoma-specific tumor antigen) but also the unmutated antigen-version that is expressed by a portion of the heterogenous tumor cells and by normal tissue.
T-cell engagers (TCE), including BiTEs, that bind B and T cells simultaneously via CD19 or CD20 and CD3, respectively, are already approved for B-cell malignancies. Successful application in AIDs seems highly probable, as, like CAR-T cells, they bring their target cells into contact with T cells, thereby inducing cytotoxic effects of the T cells [ 89 ]. Their advantages compared with CAR-T cells are faster applicability as they can be used immediately but autologous CAR-T cell production needs up to 6 weeks from leukapheresis to infusion, lower production costs as they can be produced in larger quantities and easier administration as they can be injected like other routine monoclonal antibodies. No preconditioning of the patient is necessary but, at least in cancer patients, pre-medication is used to avoid CRS [ 89 ]. To overcome the time delay caused by CAR-T cell production, intensive research is being conducted into the use of allogeneic CAR-T cell (Table 2 ). This approach eliminates the need for leukapheresis and enables the method to be used even in patients who, due to previous immunosuppressive treatments, have too few T cells for autologous CAR-T cell generation. Also, the faster start of treatment would reduce bridging medication and disease progression. Various options are being researched to circumvent graft-versus-host disease (GvHD) and host-versus-graft response (HvGR) which are possible side effects of allogenic cell application. For example genetic deletion of the T-cell receptor α chain to prevent donor T cells from attacking host cells or using γδ T cells which function independent of HLA proteins or natural killer T cells instead of the more frequently occurring and GvHD-inducing αβ T cells have been applied [ 90 , 91 ].
Finally, when it comes to the advantages of CAR therapy, the ability of CAR-T cells to migrate to lymphoid and target organs must be mentioned first and foremost. This enables profound depletion of B cells including organ-resident ones and is probably a reason for the effectiveness of the therapy in patients who have not responded or have responded inadequately to conventional therapy [ 47 , 53 , 92 ]. Second, a large proportion of publications dealing with CAR-T therapy in AIDs report long-term remission (as long-term data are already available), which makes it possible to discontinue or significantly reduce additional medication [ 47 , 48 , 56 , 57 , 59–61 , 63 , 92 , 93 ]. These remarkable results demonstrate the great potential of CAR-T cell therapy to prevent disease relapses and to significantly improve patients’ quality of life.
High costs are considered as a disadvantage of the therapy which limits its applicability. They are quoted at between US$350 000 [ 90 ] and US$500 000 [ 71 ], or £300 000 [ 89 ]. Including the additional costs for lymphodepletion, leukapheresis and treatment of side effects, it can rise to approximately US$800 000 [ 94 ]. Antibody-based therapies are significantly cheaper. TCE treatment, for example, is reported with $56 000 [ 89 ]. However, considering that this treatment option is intended for patients who are multiply refractory and have already undergone various courses of treatment and would continue to do so, or for whom there would otherwise be no other option, the costs are put into perspective by the fact that it is usually only administered once. Further cost reduction is expected through the use of allogeneic T cells, which were already mentioned above (Fig. 1 ).
ACKNOWLEDGEMENTS
The topic of this Review was also presented during the 62nd Congress of the European Renal Association in Vienna on 4–7 June 2025.
Contributor Information
Dörte Lodka, Experimental and Clinical Research Center, Charité – Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
Adrian Schreiber, Experimental and Clinical Research Center, Charité – Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of Nephrology and Medical Intensive Care, Charité – Universitätsmedizin Berlin, Berlin, Germany.
FUNDING
This paper is part of a Supplement that was financially supported by the ERA. The topic of this paper was also presented at the 62nd ERA Congress, Vienna & Virtual, June 4–7, 2025.
DATA AVAILABILITY STATEMENT
None declared.
CONFLICT OF INTEREST STATEMENT
None declared.
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Associated Data
Data Availability Statement
None declared.