The goal of this phase I/II clinical trial is to investigate anti-CD 19 chimeric antigen receptor T cell (CAR-T cell) therapy in patients with antineutrophil cytoplasmic antibodies (ANCA) immunoglobulin (IgG) positive ANCA associated vasculitis (AAV).

The main questions it aims to answer are:

• To assess the safety of anti-CD19 CAR-T cell therapy in subjects with active, treatment refractory, ANCA-IgG-positive AAV
• To assess the clinical efficacy of anti-CD19 CAR-T cell therapy in subjects with active, treatment refractory ANCA-IgG-positive AAV
• To assess the ANCA seroconversion rate in subjects with active, treatment refractory ANCA-IgG-positive AAV

Participants will receive a single dose of KYV-101 i.v., an autologous fully-human anti-CD19 CAR-T cell immunotherapy. Follow-up time is 52 weeks with regular visits at the site.

This study aims to investigate the use of KYV101 (a fully human anti-CD19 CAR T cell therapy) in ANCA-IgG-positive AAV patients who are refractory to previous treatments. This study is designed to determine (i) the safety of this B-cell targeted therapy, (ii) the clinical efficacy, (iii) the impact on the immunological status of the patient and in particular on ANCA positivity, and (iv) the 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).

Follow-up time is 52 weeks with regular visits at the site.

Inclusion Criteria:

• Understand and voluntarily sign an informed consent form

• Male or female, age ≥ 18 and ≤ 75 years at ti me of consent

• Able to adhere to the study visits and protocol

• Fulfilment of

• EITHER both of the following

  • 2022 ACR-EULAR classification criteria for granulomatosis with polyangiitis (GPA)
  • detectable anti-PR3 antibodies (≥ 20 AU/ml in CLIA) at screening

• OR both of the following

  • 2022 ACR/EULAR classification criteria for microscopic polyangiitis (MPA)
  • detectable anti-MPO antibodies (≥ 10 AU/ml in CLIA) at screening

• Active disease, defined as Clinical activity (BVAS ≥ 3) at screening

• Insufficient response or intolerance/contraindication to glucocorticoids and to at least one of the following treatments: rituximab, mycophenolate mofetil, azathioprine, methotrexate, cyclophosphamide, avacopan. Insufficient response is defined as having disease activity based on the definition explained in the previous bullet point

• Male subjects unless surgically sterile, must agree to use two acceptable 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

• Females of childbearing potential (FCBP) must have a negative urine pregnancy test at screening and must agree to use a highly effective contraceptive method (Pearl index less than 1) starting from the time of signing the ICF and for 12 months after dosing of the IMP

• Updated vaccination record according to the STIKO recommendations for immuno-compromised patients

Exclusion Criteria:

• ANC less than 500/µl, ALC less than 100/µl or hemoglobin less than 8g/dl, absolute CD3+T cell count less than 100/µl at screening
• Severely impaired renal (eGFR ≤ 30 ml/min/m2), liver (Child Pugh C), or heart or pulmonary (NYHA IV, blood oxygenation less than 92%) function
• Clinically relevant rapidly progressive glomerulonephritis or pulmonary alveolar hemorrhage
• Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study
• Prior treatment with anti-CD19 antibody therapy, adoptive T cell therapy or any prior gene therapy product (e.g. CAR T cell therapy)
• History of bone marrow/ hematopoietic stem cell or solid organ transplantation
• Any concomitant severe active infection, e.g. HIV, hepatitis B or C, SARS-CoV-2 (COVID-19), or active tuberculosis as defined by a positive Quantiferon TB-test. If presence of latent tuberculosis is established then treatment according to local guide-lines must have been initiated 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 adequately treated basal or squamous cell skin cancer)
• Requirement for immunization with live vaccine during the study period or within 14 days preceding leukapheresis,
• Subjects who are younger than 18 years or are incapable to understand the aim, importance and consequences of the study and to give legal informed consent (accord-ing to § 40 Abs. 4 and § 41 Abs. 2 and Abs. 3 AMG),
• Have a history of alcohol or substance abuse within the preceding 6 months that, in the opinion of the Investigator, may increase the risks associated with study participa-tion or study agent administration, or may interfere with interpretation of results,
• Subjects who possibly are dependent on the Sponsor, the Principal Investigator 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).

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results will be published anonymized and summarized