CD19-targeted CAR T cells in refractory antisynthetase syndrome

Idiopathic inflammatory myopathies are a group of rare, immune-mediated diseases that primarily affect the skeletal muscle but can also involve other organs such as the lungs, skin, and joints.1Lundberg IE Fujimoto M Vencovsky J et al.Idiopathic inflammatory myopathies.Nat Rev Dis Primers. 2021; 7: 86Crossref PubMed Scopus (95) Google Scholar Antisynthetase syndrome comprises a major cluster of such diseases and is characterised by the development of adaptive immune responses against various tRNA synthetases, including those for histidine (forming anti-Jo-1 antibodies), tyrosine (anti-PL7), alanine (anti-PL12), glycine (anti-EJ), isoleucine (anti-OJ), asparagine (anti-KS), phenylalanine (anti-Zo), and threonine (anti-HA).2Galindo-Feria AS Notarnicola A Lundberg IE Horuluoglu B Aminoacyl-tRNA synthetases: on anti-synthetase syndrome and beyond.Front Immunol. 2022; 13866087Crossref PubMed Scopus (11) Google Scholar Histopathology studies of patients with antisynthetase syndrome have shown the presence of B cells and plasmablasts located adjacent to T cells in the affected muscles,3Preuße C Paesler B Nelke C et al.Skeletal muscle provides the immunological micro-milieu for specific plasma cells in anti-synthetase syndrome-associated myositis.Acta Neuropathol. 2022; 144: 353-372Crossref PubMed Scopus (5) Google Scholar and the condition is also associated with changes in the profile of peripheral B cells.3Preuße C Paesler B Nelke C et al.Skeletal muscle provides the immunological micro-milieu for specific plasma cells in anti-synthetase syndrome-associated myositis.Acta Neuropathol. 2022; 144: 353-372Crossref PubMed Scopus (5) Google Scholar In accordance with these findings, B-cell-depleting therapy with rituximab was efficacious in a subset of patients with antisynthetase syndrome, supporting the pathogenic role of autoreactive B cells.4Oddis C Reed AM Aggarwal R et al.Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial.Arthritis Rheum. 2013; 65: 314-324Crossref PubMed Scopus (443) Google Scholar Antisynthetase syndrome can be refractory despite several treatment options—including glucocorticoids, intravenous immunoglobulins, T-cell-targeting drugs, and B-cell-targeting drugs—and is therefore associated with increased mortality.5Cavagna L Trallero-Araguás E Meloni F et al.Influence of antisynthetase antibodies specificities on anti-synthetase syndrome clinical spectrum time course.J Clin Med. 2019; 82013Crossref Scopus (109) Google Scholar Considering the pathophysiology of antisynthetase syndrome, treatment with chimeric antigen receptor (CAR) T cells that recognise CD19⁺ B cells might be useful in refractory forms of the disease. In the past 2 years, CAR T cells have been successful in the treatment of autoimmune diseases such as refractory systemic lupus erythematosus.6Mougiakakos D Krönke G Völkl S et al.CD19-targeted CAR T cells in refractory systemic lupus erythematosus.N Engl J Med. 2021; 385: 567-569Crossref PubMed Scopus (91) Google Scholar, 7Mackensen 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 (70) Google Scholar Here we report the case of a patient with an idiopathic inflammatory myopathy who was successfully treated with CD19 CAR T cells. A 41-year-old man presented with refractory antisynthetase syndrome, showing increased creatinine kinase concentrations, muscle inflammation by MRI, interstitial lung disease, Raynaud's syndrome, periorbital oedema, and anti-Jo-1 autoantibodies. Muscle biopsies showed signs of antisynthetase syndrome with perifascicular muscle atrophy and necrotic muscle fibres (figure A). MHC-1 expression was ubiquitous on the muscle fibres with predominance at the perifascicular borders. Perimysial fragmentation, sarcolemmal decoration of muscle fibres with C5b9, and T-cell infiltrates invading the endomysial compartments were also found in the neuropathology examination. During the previous 18 months the patient had continuously active myositis with creatinine kinase concentrations always greater than 1000 U/L. Treatment with oral glucocorticoids (10–250 mg prednisolone per day for most of the 18-month disease course) was unsuccessful, whereas intravenous rituximab (2 × 1 g) initially led to a transient improvement (figure B). However, the following course of intravenous rituximab (1 × 1 g) was unsuccessful. Treatment with intravenous immunoglobulins (2 mg/kg) followed by oral tacrolimus (10 mg/day for 4 months) led to a second transient improvement of the disease, but it relapsed quickly. Remission could not be reached thereafter, even after a third course of intravenous rituximab (2 × 1 g) and intravenous cyclophosphamide (1 g/m2). The patient presented in overall poor condition with severe muscle weakness, pain, and shortness of breath requiring up to 50 L/min nasal oxygen. Viral or bacterial infections, including SARS-CoV-2, were ruled out. A chest CT scan showed signs of alveolitis and interstitial lung disease, which are frequently observed with Jo-1-associated antisynthetase syndrome. The patient had increased concentrations of creatinine kinase (9305 U/L; normal <190 U/L), myoglobin (2148 μg/L; normal <70 μg/L), and C-reactive protein (21·7 mg/L; normal <5 mg/L). CAR T-cell treatment was initiated after the discussion of treatment options. Glucocorticoids were tapered to reach 10 mg/day at the time of leukapheresis (13 days before CAR T-cell administration). No other immunosuppressive treatment or treatment specific to antisynthetase syndrome was given in the 4 weeks before leukapheresis. CAR T-cell manufacture with a CD19 CAR lentiviral vector (Miltenyi Biotech; Bergisch Gladbach, Germany), conditioning, and CAR T-cell administration were done as described previously.6Mougiakakos D Krönke G Völkl S et al.CD19-targeted CAR T cells in refractory systemic lupus erythematosus.N Engl J Med. 2021; 385: 567-569Crossref PubMed Scopus (91) Google Scholar, 7Mackensen 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 (70) Google Scholar After the transfer of 1 × 106 CAR T cells per kg bodyweight, the number of CAR T cells greatly (>600 times) increased in vivo (day 2, 0·1 cells per μL; day 8, 60·3 cells per μL), followed by a fast decline (figure C, D). Circulating B cells were completely depleted for a period of 100 days and were reconstituted thereafter (figure E). White blood cell count, monocytes, neutrophils, CD4+ T cells, and CD8+ T cells rapidly recovered after conditioning chemotherapy (appendix p 1). After CAR T-cell treatment, the patient unexpectedly had a spurious increase in myalgia and an increase in creatinine kinase concentration to 13 600 U/L. This effect could result from the killing of B cells and CAR T-cell activation in vivo leading to spurious local inflammation in the muscle. Increased creatinine kinase concentrations and myalgia have been reported as part of cytokine release syndrome.8Brudno JN Kochenderfer JN Toxicities of chimeric antigen receptor T cells: recognition and management.Blood. 2016; 127: 3321-3330Crossref PubMed Scopus (837) Google Scholar After this short worsening, the patient markedly improved in physical function according to all International Myositis Assessment and Clinical Studies Group core set measures (figure F, appendix p 1). He regained muscle strength, with a manual muscle test score of 115/150 at baseline and 149/150 (nearly full muscle strength) at day 180 after CAR T-cell administration. This improvement was paralleled by regained muscle endurance: the patient held a filled 700 mL glass water bottle (weighing 1·3 kg) with one outstretched arm for a mean of 5 s at baseline and 33 s at day 180. Further improvements were seen in the 30 s sit-to-stand test (zero repetitions at baseline and seven repetitions at day 180) and in maximum walking distance (10 m at baseline and >5 km at day 180). Concentrations of creatinine kinase decreased from 13 600 U/L to 102 U/L and myoglobin from 2148 μg/L to 70 μg/L (figure G, appendix p 1); alanine aminotransferase also returned to normal concentrations (appendix p 1). The high concentration of anti-Jo-1 antibodies (331 U/L) completely disappeared after CAR T-cell treatment (5 U/L; cutoff 25 U/L, Orgentec ELISA, Mainz, Germany; figure G). Extramuscular disease activity markedly decreased (figure H) and a major improvement in the patient's antisynthetase syndrome (according to the 2016 American College of Rheumatology/European League Against Rheumatism total improvement score [TIS]) was observed at day 46 (TIS 87·5) and day 180 (TIS 98; figure I). MRI of the patient's thighs showed complete resolution of lesions suggestive of myositis, such as muscle and fascial inflammatory changes in the quadriceps and the hamstrings (figure J). The patient's respiratory symptoms improved, with no need for oxygen supplementation, and a chest CT scan showed full regression of alveolitis (figure K). Regarding safety, the patient developed a fever (38–39°C, with no effect on blood pressure) 1–3 days after CAR T-cell treatment, which was treated with paracetamol and 3 × 720 mg tocilizumab. This mild (grade 1) cytokine release syndrome resolved within 3 days. The patient's immunoglobulin concentrations were already low before CAR T-cell therapy (IgG 4·57 g/L) and further decreased slightly after therapy, leading to intravenous substitution of IgG (10 g/month). No other toxicities related to CAR T-cell therapy were observed. Taken together, this case shows the feasibility, tolerability, and efficacy of CAR T-cell therapy for the treatment of idiopathic inflammatory myopathies. We observed a complete resolution of antisynthetase syndrome in this patient despite the cessation of all immunosuppressive drugs, and this resolution was sustained even after the reconstitution of B cells. Although short-term effects cannot be completely ruled out, the fast and complete recovery of all haematopoietic lineages within 1 week, the lack of response to previous cyclophosphamide treatment, and the deep and sustained response even after B-cell recovery suggest that conditioning therapy might not have substantially contributed to the treatment response. Tocilizumab, which was used to treat cytokine release syndrome, seems unlikely to have influenced remission as the drug was found to be ineffective in the treatment of antisynthetase syndrome.9Oddis CV Rockette HE Zhu L et al.Randomized trial of tocilizumab in the treatment of refractory adult polymyositis and dermatomyositis.ACR Open Rheumatol. 2022; 11: 983-990Crossref Scopus (7) Google Scholar Long-term follow-up will be needed to assess whether CAR T-cell treatment might have permanently resolved antisynthetase syndrome in this patient. We declare no competing interests. FM, SB, and JK contributed equally. This work was supported by the Deutsche Forschungsgemeinschaft through the Collaborative Research Center 1181 and 221. Download .pdf (1.86 MB) Help with pdf files Supplementary appendix