The goal of this phase I/II clinical trial is to compare B-cell depletion by rituximab and anti-CD 19 CAR-T therapy in patients with rheumatoid arthritis. The main questions it aims to answer are:

• To assess the safety of anti-CD19 CAR T cell therapy in subjects with active, ACPA positive and treatment refractory RA (Phase-I)
• To assess the safety of anti-CD19 CAR T cell therapy and of rituximab in subjects with active, ACPA positive and treatment refractory RA (Phase-II)
• To assess ACPA seroconversion after anti-CD19 CAR T cell or rituximab therapy in subjects with active, ACPA positive and treatment refractory RA (Phase-II)

Participants in the test-arm will receive a single dose of KYV-101 i.v., an autologous fully-human anti-CD19 CAR T-cell immunotherapy. In the comparator group patients will receive 2x1 g Rituximab i.v.

Follow-up time (both arms) is 52 weeks with regular visits at the site.

This study aims to investigate the use of either rituximab as an established therapy or KYV101 (a fully human anti-CD19 CAR T cell therapy) in ACPA-positive RA patients who are refractory to previous treatments. This study is designed to determine and compare (i) the safety of these two B-cell targeted therapies, (ii) their clinical efficacy, (iii) their impact on the immunological status of the patient and in particular on ACPA positivity, and (iv) their ability to induce long-term (deep) clinical and molecular remission and drug-free survival.

The investigational product (IMP), KYV-101, is an autologous fully-human anti-CD19 CAR T-cell immunotherapy. . Before IMP infusion, patients will receive a premedication of 4 mg Dimetindenmaleat iv or equivalent antihistamine and 1000 mg oral acetaminophene. Prophylactic doses of acyclovir of 400mg 2x daily as well as cotrimoxazole 960mg 3x weekly will be administered orally following CAR T cell infusion until week 24. Tocilizumab 8mg/kg will be administered intravenously when required for treatment of IMP-related cytokine release syndrome. Dexamethasone as needed will be administered intravenously when required for treatment of neurological adverse event (ICANS).

In the control arm in phase II, rituximab will be administered. Rituximab, a chimeric monoclonal antibody targeting CD20, induces B cell depletion and is authorized for treatment of RA. A dose of 1000 mg will be administered intravenously at baseline and at day 14 as per summary of product characteristics. The need for further courses will be evaluated 24 weeks after baseline where retreatment of 1000 mg rituximab may be initiated if residual disease activity remains.

Follow-up time (both arms) is 52 weeks with regular visits at the site.

Main Inclusion Criteria:

• Understand and voluntarily sign an informed consent form
• Male or female, age ≥ 18 and ≤ 80 years at time of consent
• Able to adhere to the study visits and protocol
• Fulfilment of the 2010 ACR-EULAR RA classification criteria
• ACPA positivity (cut off 20 mU/ml) at screening
• Disease Activity Score DAS28-ESR>3.2 at screening
• Failure (defined as inadequate response after at least 3 months of therapy) of at least one conventional DMARD and at least two tsDMARD/bDMARDs
• At least one swollen joint with Power Doppler activity of at least grade 1 or B-mode activity of at least grade 2 at screening
• Willingness to participate in a synovial puncture and biopsy
• Male subjects unless surgically sterile, must agree to use two accepta-ble methods for contraception (e.g. spermicide and condom) during the trial and refrain from fathering a child starting from the time of signing the Informed Consent Form (ICF) until 12 months after dosing of the IMP or rituximab
• Females of childbearing potential (FCBP) must have a negative serum pregnancy test at screening and must agree to use a highly effective contraceptive method (Pearl index <1) starting from the time of signing the ICF and for 12 months after dosing of the IMP or rituximab
• Updated vaccination record according to the STIKO recommendations for immunocompromised patients

Main Exclusion Criteria:

• ANC < 1.000/mm3, ALC < 500/mm3 or hemoglobin < 8g/dl, absolute CD3+T cell count < 100/µl
• Severely impaired renal (eGFR ≤ 30 ml/min/m2), liver (Child Pugh B or C), or heart andor pulmonary (NYHA III or IV, blood oxygenation <92%) function
• Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to partici-pate in the study or confounds the ability to interpret data from the study
• Prior treatment with anti-CD19 antibody therapy, adoptive T cell thera-py or any prior gene therapy product (e.g. CAR T cell therapy)
• Only in phase II: Prior treatment of rituximab < 7 months before base-line OR ≥ 7 months before baseline and B cell level < 0.1/nl
• History of bone marrow/ hematopoietic stem cell or solid organ trans-plantation
• csDMARD other than MTX at baseline
• Any concomitant severe active infection, e.g. HIV, hepatitis B or C, SARS-CoV-2 (COVID-19), or active tuberculosis as defined by a posi-tive Quantiferon TB-test. If presence of latent tuberculosis is estab-lished then treatment according to local guidelines must have been ini-tiated prior to enrollment
• Pregnant or lactating females
• Females who are intending to conceive during the study
• Known hypersensitivity to any drug components
• Malignancy in the last 5 years before screening (except basal or squamous cell skin cancer)
• Requirement for immunization with live vaccine during the study peri-od or within 14 days preceding leukapheresis,
• Subjects who are younger than 18 years or are incapable to under-stand the aim, importance and consequences of the study and to give legal informed consent (according to § 40 Abs. 4 and § 41 Abs. 2 and Abs. 3 AMG),
• Subject who Hhave a history of alcohol or substance abuse within the preceding 6 months that, in the opinion of the Investigator, may in-crease the risks associated with study participation or study agent ad-ministration, or may interfere with interpretation of results,
• Subjects who possibly are dependent on the Sponsor, the Principal In-vestigator or Investigator (e.g. family members).
• Subjects who are institutionalized by order of court or public authority
• Subjects participating in another clinical trial with an investigational medicinal product or medical device (3 months before this trial)

results will be published anonymized and summarized