¹University Hospital Heidelberg, Heidelberg
²Universitätmedizin Mainz, Mainz

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Introduction: Standard therapy of systemic sclerosis (SSc)- or rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) at best decelerates progression. Second generation (2ndGen) CD19.CAR-T cells showed positive effects in patients with autoimmune disease entities like systemic lupus erythematosus (SLE) or SSc.

Methods: Since 2022, we administered in a compassionate use program, for the first time in non-cancer patients, third-generation (3rdGen) CD19.CAR-T cells to three treatment-refractory patients with rapidly progressive ILD and fatal prognosis suffering from SSc-ILD or RA-ILD. Patients received i.v. a dose of 200 million CAR-T cells/sqm body surface after standard lymphodepletion with fludarabine and cyclophosphamide. All patient were on nintendanib and mycophenolate (MMF) directly before CAR-T administration; both agents were re-started after CAR-T infusion in all three patients.

Results: Manufacturing of 3rdGen CD19.CAR-T cells was successful in all three patients. No neurotoxicity (ICANS) and only mild cytokine release syndrome (CRS °1–°2) were observed. Hematopoietic recovery was observed.

The first patient (female, 38 y/o) suffered from speech dyspnea (NYHA III). 3rdGen CD19.CAR-T cells persisted over >24 months, as reported [1], [2]. Serological remission and significant improvement of ILD were achieved (FVC +38%; reduction of the area of pulmonary fibrosis in 68Ga-FAPI-PET/CT by > -50%). Dyspnea improved to NYHA I-II.

The second patient (SSc, female, 62 y/o) received 3rdGen CD19.CAR-T cells in June 2024 after progress of SSc-ILD. Lung fibrosis stabilized. 3rdGen CD19.CAR-T cells were still detectable after 5 months.

The third patient (RA, male, 42 y/o) developed polyarthritis and ILD after a corona virus infection; he was positive for rheumatoid factor and Ro52 antibodies. After several lines of therapies, he received 3rdGen CD19.CAR-T cells in August 2024. Lung fibrosis was stabilized. 3rdGen CD19.CAR-T cells were still detectable 3 months from administration.

Conclusion: In contrast to all other known patients with autoimmune diseases treated with 2ndGen CD19.CAR-T cells, the 3rdGen CD19.CAR-T cells persisted in our patients, for up to two years now. The first patient responded well, the two other patients were stabilized over the so far short post follow-up. The cases demonstrate power and caveats of CAR-T cells in autoimmune fibrotic ILD.

References

[1] Merkt W, Freitag M, Claus M, Kolb P, Falcone V, Röhrich M, Rodon L, Deicher F, Andreeva I, Tretter T, Tykocinski LO, Blank N, Watzl C, Schmitt A, Sauer T, Müller-Tidow C, Polke M, Heußel CP, Dreger P, Lorenz HM, Schmitt M. Third-generation CD19.CAR-T cell-containing combination therapy in Scl70+ systemic sclerosis. Ann Rheum Dis. 2024 Mar 12;83(4):543-6. DOI: 10.1136/ard-2023-225174
[2] Merkt W, Lorenz HM, Schmitt M. CAR T-Cell Therapy in Autoimmune Disease. N Engl J Med. 2024 May 2;390(17):1628-9. DOI: 10.1056/NEJMc2403705
[3] Merkt W, Röhrich M, Mavriopoulou E, Stütz AN, Distler JHW, Schmitt A, Polke M, Heußel CP, Schmitt M, Lorenz HM. 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 Jul;13(7):651-4. DOI: 10.1016/S2213-2600(25)00159-6