CD19-Targeted CAR-T Cells in Refractory Systemic Autoimmune Diseases: A Monocentric Experience from the First Fifteen Patients
Authors: Mueller Fabian , Taubmann Jule , Voelkl Simon , Bucci Laura , Bergmann Christina , Aigner Michael , Wilhelm Artur , Rothe Tobias , Minopoulou Ioanna , Knitza Johannes , Kharboutli Soraya , Spoerl Silvia , Vasova Ingrid , Werner Dagmar , Reimann Hannah , Kretschmann Sascha , Mougiakakos Dimitrios , Krönke Gerhard , Schett Georg , Mackensen Andreas 
Published: December 2023

Background: CD19-targeting chimeric antigen receptor (CAR) T cells are highly efficient in B cell malignancies. However, CD19 CAR T cells also target autoreactive B cells that trigger autoimmune diseases (AID) including systemic lupus erythematosus (SLE), idiopahtic inflammatory myositis (IIM) and systemic sclerosis (SSc). Achieving long-term remission in AID with standard therapy remains challenging and usually necessitates long-term treatment.
Aim: To test whether CD19 CAR T cells achieve a deeper reset of B cells, eradicate autoimmunity, and achieve lasting drug-free remission in autoantibody-dependent AID.
Methods: Patients with treatment-refractory SLE, IIM and SSc were eligible if they had signs of active organ involvement, failure of multiple immunomodulatory therapies, and serious or immediately life-threatening disease. CAR T cell therapy was offered via an expanded access program. Autologous CD19 CAR T cells MB-CART19.1 were produced with the Miltenyi prodigy platform. After leukapheresis on day -13, manufacturing commenced in house and lymphodepletion was started with fludarabine 25 mg/m2/d intravenously (i.v.) on days -5 to -3 and cyclophosphamide 1000 mg/m2/d i.v. on day -3. On day 1, all patients received 1x106 CAR T cells / kg body weight.
Results: 15 patients (8 SLE, 4 SSc, and 3 IIM) were apheresed and were treated with a single infusion of CD19 CAR T cells. Median disease duration before CAR T was 3 years [1-20], median follow-up after CAR T was 12 months [2-28]. All patients failed on a median of 5 [2-14] previous treatments. Except for a maximum of 10 mg prednisolone daily, all immunomodulatory drugs were stopped prior to leukapheresis. After infusion, CAR T cells rapidly expanded till day 8.6 ± 0.8. CD19+ B cells were rapidly eliminated from peripheral blood after a mean of 5.9 ± 2.2 days. In 12/15 patients, B cells reoccurred at day 111±50. The last three patients with 77, 51 and 16 days follow-up are still B cell aplastic. All 8 SLE patient reached a complete remission after 3 months and maintain a SLE Disease Activity Index (SLEDAI) of 0 since. 3/3 IIM patients experienced major improvement and normalization of CK after 3 months which is ongoing. Of 4 SSc patients, 3 patients with &gt;3 months follow-up show a decreased disease activity by EULAR AI by -4.3 [-4.3; -3.6]. All 15 patients entirely stopped immunosuppressive drugs.
Overall safety of CAR T Cell therapy in AID was very favourable with cytokine-release syndrome (CRS) of grade 0 in 4, grade 1 in 10, and grade 2 in 1 patient. 6/15 patients received tocilizumab. One grade 1 immune-effector cell associated neurotoxicity syndrome (ICANS) presented as vertigo two weeks after CAR T infusion. No prolonged (&gt;28 days) bone marrow suppression occurred.
The Five SLE patients with a follow-up of 14-24 months stayed in remission despite reconstitution of B cells. In line, complement factor C3 stayed normal, proteinuria remained absent or at very low levels, and autoantibody seroconversion persisted. IgG responses to standard vaccines remained stable up to month 24 and were boosted by re-vaccination. Total B cell numbers gradually increased to a median of 230 cells/µl [183; 886] at month 12 and were mostly of a naïve phenotype. The early drop of CD19+CD27+ memory B cells increased again at month 12 indicating maturation of the B cells emerging after CAR T treatment.
Conclusion: CD19 CAR T cells induce persistent, drug-free remission in three distinct autoantibody dependent AID with very good tolerability. Though hypothetical cure appears possible, longer follow up is needed. This unprecedented drug-free remission is remarkable as B cells functionally reconstitute. An investigator-initiated trial is currently expanding our experience of efficacy and safety.