CAR T-cell therapy rescues adolescent with rapidly progressive lupus nephritis from haemodialysis

Systemic lupus erythematosus is a multisystem autoimmune disease with a heterogeneous clinical course that predominantly affects women. Systemic lupus erythematosus is characterised by immune complex-mediated organ damage. Kidney involvement in systemic lupus erythematosus, known as lupus nephritis, is one of the most common manifestations, occurring in 50–78% of patients with systemic lupus erythematosus. Lupus nephritis typically starts early, within the first 5 years after diagnosis, and is frequently among the initial manifestations of systemic lupus erythematosus.1Bertsias GK Tektonidou M Amoura Z et al.Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis.Ann Rheum Dis. 2012; 71: 1771-1782Crossref PubMed Scopus (811) Google Scholar For one in five patients, systemic lupus erythematosus first manifests during adolescence. The median age at diagnosis is 12·6 years for juvenile-onset systemic lupus erythematosus. Morbidity and mortality in juvenile-onset systemic lupus erythematosus are higher than adult-onset disease, and children with lupus nephritis have higher scores on the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).2Brunner HI Gladman DD Ibañez D Urowitz MD Silverman ED Difference in disease features between childhood-onset and adult-onset systemic lupus erythematosus.Arthritis Rheum. 2008; 58: 556-562Crossref PubMed Scopus (419) Google Scholar, 3Kamphuis S Silverman ED Prevalence and burden of pediatric-onset systemic lupus erythematosus.Nat Rev Rheumatol. 2010; 6: 538-546Crossref PubMed Scopus (234) Google Scholar End-stage renal disease and permanent haemodialysis are severe adverse events than can occur due to juvenile-onset and adult-onset systemic lupus erythematosus, with 15% of all patients with lupus nephritis developing end-stage renal disease.4Oni L Wright RD Marks S Beresford MW Tullus K Kidney outcomes for children with lupus nephritis.Pediatr Nephrol. 2021; 36: 1377-1385Crossref Scopus (48) Google Scholar The therapeutic goal of complete remission of lupus nephritis is only reached in 60% of patients by conventional therapies, including immunosuppressive drugs and B-cell-depleting antibodies,3Kamphuis S Silverman ED Prevalence and burden of pediatric-onset systemic lupus erythematosus.Nat Rev Rheumatol. 2010; 6: 538-546Crossref PubMed Scopus (234) Google Scholar and two-thirds of adults with juvenile-onset systemic lupus erythematosus develop organ damage and impaired health-related quality of life without reaching drug-free remission.5Groot N Shaikhani D Teng YKO et al.Long-term clinical outcomes in a cohort of adults with childhood-onset systemic lupus erythematosus.Arthritis Rheumatol. 2019; 71: 290-301Crossref PubMed Scopus (65) Google Scholar Due to their high B-cell depletion activity, CD19-targeted chimeric antigen receptor (CAR) T cells are a potentially powerful strategy to treat autoimmune diseases, such as systemic lupus erythematosus.6Mackensen A Müller F Mougiakakos D et al.Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus.Nat Med. 2022; 28: 2124-2132Crossref PubMed Scopus (222) Google Scholar, 7Schett G Mackensen A Mougiakakos D CAR T-cell therapy in autoimmune diseases.Lancet. 2023; 402: 2034-2044Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar In a small case series of eight patients aged 18–38 years with treatment-refractory systemic lupus erythematosus, adoptive transfer of CD19-targeted CAR T cells induced a deep reset of B cells leading to abrogation of autoreactive antibodies and durable remission, including abrogation of lupus nephritis with a follow-up time of 6–29 months.8Müller 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: 687-700Crossref PubMed Scopus (0) Google Scholar Herein, we report on a 15-year-old female patient with severe and rapidly progressive systemic lupus erythematosus. Despite escalating treatment regimens, including hydroxychloroquine, azathioprine, mycophenolate mofetil, and B-cell-targeting antibody belimumab, her kidney function deteriorated 6 months after disease onset. She developed severe nephritis with proteinuria (up to 10 717 mg/g creatinine in 24 h) and microscopic haematuria. Creatinine increased to 1·7 mg/dL within the next 4 weeks (normal range 0·41–0·81 mg/dL) accompanied by hyperphosphataemia and renal tubular acidosis. A kidney biopsy at that time showed diffuse intracapillary proliferating and focal extracapillary proliferating and necrotising glomerulonephritis corresponding to class 4 lupus nephritis with a modified national Institutes of Health (NIH) activity index of 15 (of a maximum of 24) and a modified NIH chronicity index of 1 (of a maximum of 12). Additional signs of systemic lupus erythematosus included rash, fever, and arthritis. Low levels of complement and presence of several autoantibodies including anti-nuclear-antibody anti-double-stranded DNA (anti-dsDNA; 4545 IU/mL [normal range is <100 IU/mL]), anti-nucleosome, and anti-histone antibodies were evident. Because renal function further rapidly worsened under therapy escalation with high-dose methylprednisolone and cyclophosphamide, plasma separation was initiated, leading to a reduction in autoantibody levels. However, treatment did not prevent renal failure and blood creatinine concentrations increased to 4·96 mg/dL at 8·5 months after disease onset and start of treatment. Eventually, the patient required haemodialysis and anti-hypertensive medication comprising four types of anti-hypertensives. Based on the clinical manifestations and laboratory values, the patient had a SLEDAI score of 23 (with scores of more than 20 being very rare), indicating very high systemic lupus erythematosus activity (figure C). At our site (University Hospital Erlangen, Erlangen, Germany), we initiated CD19-targeted CAR T-cell therapy in an expanded access programme for critically ill patients according to the German Arzneimittelgesetz, §21/2 and the Arzneimittel-Härtefall-Verordnung §2 following a mandatory case review by an independent interdisciplinary board. For the patient of interest, after informed consent, all immunosuppressive medication except prednisolone at 10 mg/day was discontinued before leukapheresis. The harvested T cells were transduced with a previously described lentiviral vector (Miltenyi Biotec, Bergisch Gladbach, Germany) encoding for a second-generation 4-1BB-based CD19 CAR using the CliniMACS Prodigy system (CliniMACS Prodigy, Bergisch Gladbach, Germany).6Mackensen A Müller F Mougiakakos D et al.Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus.Nat Med. 2022; 28: 2124-2132Crossref PubMed Scopus (222) Google Scholar The prednisolone dose was further tapered and eventually stopped 3 days before the planned CAR T-cell infusion. To account for severe renal insufficiency, the regimen for lymphodepletion was dose-adjusted and timed to coincide with ongoing haemodialysis sessions. Fludarabine 12·5 mg/m2 was administered on days –5, –4, and –3 and cyclophosphamide 500 mg/m2 was administered once on day –3. Meanwhile, haemodialysis was performed just before the start of lymphodepletion and then 18 h after the last chemotherapy infusion on days –3 and –2 as well as on day 0, the day of CAR T-cell infusion, when 1 x 106 fresh anti-CD19 CAR T cells per kg bodyweight were infused. Except for lymphodepletion-associated transient grade 4 granulocytopenia (minimum 0·4 per nL, on day 7), pre-existing anaemia (minimum haemoglobin concentration of 8·7 mg/dL, on day 1), and cytokine release syndrome grade 1 and malaise between days 3 and 7, the patient did not have any adverse events. Mild cytokine release syndrome was first treated with antipyretics and, due to incomplete resolution with a single infusion of tocilizumab (8 mg/kg) on day 6, 36 h after fever onset. The patient was discharged from the hospital on day 11. Neither prolonged bone marrow toxicity nor immune cell-associated neurotoxicity syndrome were observed. After administration, CAR T-cell concentrations were measured in peripheral blood samples at locally standardised timepoints by flow cytometry as previously reported.9Blumenberg V Busch G Baumann S et al.Early quantification of anti-CD19 CAR T cells by flow cytometry predicts response in R/R DLBCL.Blood Adv. 2023; 7: 6844-6849Crossref Scopus (0) Google Scholar Their number increased in the peripheral blood to a maximum of 6·6 cells per μL on day 10. Absolute peripheral B-cell aplasia was observed from day 7 and still persisted 6 months after administration of CAR T-cell therapy (figure). Despite a relatively low CAR T-cell peak in maximum cell expansion compared with an adult patient,8Müller 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: 687-700Crossref PubMed Scopus (0) Google Scholar the cells persisted at the last measurement at 6 months after infusion (figure), which was substantially longer than has been previously reported in adult patients, in whom CAR T cells are usually no longer detectable at 3 months after infusion.8Müller 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: 687-700Crossref PubMed Scopus (0) Google Scholar Systemic lupus erythematosus activity rapidly decreased after administration of CAR T cells. Symptoms of arthritis were resolved, complement factors C3 and C4 normalised within 6 weeks, and anti-nuclear-antibody anti-dsDNA (figure), and all other autoantibodies disappeared (data not shown). Renal function improved and haemodialysis intervals could be prolonged from 1 week after CAR T-cell infusion. The last haemodialysis session took place on day 17. Creatinine decreased to 1·2 mg/L within 3 months of CAR T-cell administration. The estimated glomerular filtration rate increased from a minimum of 8 mL/min per 1·73 m2 at the start of lymphodepletion to 42 mL/min per 1·73 m2 (stage 3b chronic kidney disease). Anti-hypertensive treatment was gradually tapered and only 20 mg of enalapril per day was retained as renoprotective medication. Proteinuria improved to 3400 mg per 24 h but remained elevated at the last follow-up visit 6 months after CAR T-cell administration, which suggests that some irreversible glomerular damage occurred. Despite the residual protein loss, the patient had normalised plasma albumin concentrations and no clinical signs of oedema. Urine analysis did not reveal signs of nephritis, with no haematuria and no erythrocyte casts. Overall, the patient's condition can be classified as dialysis-free, partial renal response, a favourable outcome given that the patient had already been on haemodialysis. One cannot exclude that lymphodepletion and plasmapheresis have initially contributed to the outcome but the sustained drug-free remission observed in this very severe case of systemic lupus erythematosus strongly suggests a causal effect of CAR T-cell treatment. Notably, the patient returned to school at month 4 after CAR T-cell therapy initiation and, at time of publication, is fully active in her daily life. In this paediatric patient with systemic lupus erythematosus, the first to our knowledge to be treated with anti-CD19 CAR T cells, therapy achieved sustained remission in a rapidly progressive and refractory lupus nephritis. By contrast with the previously reported results in adults with systemic lupus erythematosus receiving anti-CD19 CAR T-cell therapy, our patient had end-stage renal disease, requiring haemodialysis every 2–3 days. Despite kidney failure, CAR T-cell therapy was safe and well tolerated due to appropriate dose adjustment of lymphodepletion. As demonstrated here, anti-CD19 CAR T-cell therapy can rescue a patient with lupus nephritis from haemodialysis and long-term dependency on medications that might substantially reduce health-related sequelae and economic burden. Our patient, who had early onset and rapidly progressive lupus nephritis, illustrates that early intervention is crucial, in particular in juvenile-onset patients who frequently have an aggressive course of systemic lupus erythematosus and can develop disease-related organ damage within the first 2 years after.5Groot N Shaikhani D Teng YKO et al.Long-term clinical outcomes in a cohort of adults with childhood-onset systemic lupus erythematosus.Arthritis Rheumatol. 2019; 71: 290-301Crossref PubMed Scopus (65) Google Scholar The long-term efficacy and safety of CD19-targeted CAR T-cell therapy in paediatric patients with autoimmune diseases have yet to be confirmed and systematically evaluated in clinical studies. This case strongly advocates for the early access of this new therapeutic option in clinical trials for paediatric patients with systemic lupus erythematosus and a severe disease course. TK, NN-B, GS, MM, and FM contributed equally. TK, NN-B, AM, GS, MM, and FM designed the treatments and analyses. TK, NN-B, IV, AM, GS, MM, and FM monitored the patient. SKh, SS, IV, and JW collected clinical data. MA, SKr, and SV did molecular analyses. MA and SKr produced CAR T cells. SV performed immune monitoring. TK, NN-B, AM, GS, MM, and FM wrote the manuscript. TK, NN-B, AM, MM, and FM directly accessed and verified the study data. All authors had full access to the data in the study and had final responsibility for the decision to submit for publication. TK has received consulting fees from Novartis and Pfizer; speaker honoraria from Novartis, Pfizer, and Kiowa Kirin; and meeting support from Pfizer, Novartis, and AbbVie. MA has received grants from Miltenyi Biotec and Kyverna; consulting fees from Miltenyi Biotec; speaker honoraria from Miltenyi Biotec and Raumedic; payment for expert testimony from RUHR-IP; travel support from Miltenyi Biotec; and material from Miltenyi Biotec. SKh has received speaker honoraria from Bristol Myers Squibb (BMS) and Sobi; and meeting support from Janssen, BMS, Sobi, and Novartis. IV has received meeting support from Mallinckrodt. SV has received research support from the Interdisciplinary Center for Clinical Research (IZKF) at the University Hospital of the University of Erlangen-Nuremberg (grant No D43). JW has received speaker honoraria from Ascendis, Novo Nordisk, and Pfizer; and has participated on an advisory board for Roche, Biomarin, Hexal, Novo Nordisk, Pfizer, Hexal, and ICON. AM has received grants from Miltenyi Biomedicine and Kyverna; consulting fees from BMS/Celgene, Kite/Gilead, Novartis, BioNTech, Miltenyi Biomedicine, and Century Therapeutics; speaker honoraria from BMS/Celgene, Kite/Gilead, Novartis, and Miltenyi Biomedicine; and meeting support from AbbVie and Janssen. GS has received speaker honoraria from Novartis, BMS, Kyverna, and Cabaletta. MM has participated on an advisory board for Novartis. FM has received grants from Kite/Gilead; consulting fees from AbbVie, ArgoBio, AstraZeneca, BMS, Crispr Therapeutics, Janssen, Kite, and Novartis; speaker honoraria from AbbVie, ArgoBio, AstraZeneca, BMS, Crispr Therapeutics, Janssen, Kite, Kyverna, Miltenyi Biomedicine, Novartis, and Sobi; participated on an advisory board for BMS; and received research funding from Deutsche Krebshilfe (grant No 0113695). NN-B, SKr, and SS declare no competing interests. Patient data can only be shared in pseudonymised form. There are no other restrictions on access to the data. Readers can contact FM and MM by email ([email protected], [email protected]) to request access to these data. The study was supported by the Deutsche Forschungsgemeinschaft (TRR221).