Universal CAR-T Cell Injection Targeting CD19/BCMA in Patients With Inflammatory Bowel Disease

Inclusion Criteria

• •The subject voluntarily participates in this trial and signs the informed consent form.
• •Aged ≥ 18 years and ≤ 70 years, regardless of gender.
• •Organ function and laboratory tests:
• •1. Liver function: Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 2 × Upper Limit of Normal (ULN); Total Bilirubin (TBIL) ≤ 2 × ULN (except for Gilbert's syndrome).
• •2. Renal function: Creatinine ≤ 1.5 × ULN or Creatinine Clearance ≥ 40 ml/min.
• •3. Complete blood count: Neutrophil count ≥ 1 × 10⁹/L; Hemoglobin ≥ 60 g/L; Platelet count ≥ 20 × 10⁹/L; Lymphocyte count \> 0.3 × 10⁹/L.
• •4. Coagulation function: International Normalized Ratio (INR) ≤ 1.5 × ULN, or Prothrombin Time (PT) ≤ 1.5 × ULN.
• •5. Oxygen saturation (SpO₂) ≥ 92% in room air at rest.
• •6. Echocardiography shows Left Ventricular Ejection Fraction (LVEF) ≥ 50%.
• •Female subjects of childbearing potential must have a negative result in serum or urine pregnancy test at screening.
• •Female subjects of childbearing potential must agree to use highly effective contraceptive methods from at least 28 days before the start of lymphodepletion until 12 months after RD06-05 infusion. Male subjects of childbearing potential must agree to use effective barrier contraceptive methods from the start of lymphodepletion until 12 months after RD06-05 infusion, and must not donate semen or sperm during the entire trial period.
• •Diagnosis of ulcerative colitis confirmed by clinical and endoscopic evidence at least 3 months before screening, and verified by histopathological report. If no pathological report is available, additional biopsies may be performed during the screening period to obtain specimens, which will be sent to a local pathological laboratory for diagnostic confirmation.
• •Moderate to severe active ulcerative colitis, defined as a Mayo score between 6 and 12 points with an endoscopic subscore ≥ 2 points (endoscopic examination performed within 14 days before screening).
• •Confirmed that the extent of ulcerative colitis lesions involves above the rectosigmoid junction (approximately ≥ 15 cm from the anal verge).
• •Patients with extensive colitis or pancolitis with a disease duration of more than 8 years, or left-sided colitis with a disease duration of more than 12 years, must have written evidence of having undergone a colonoscopy within 12 months before the first screening visit (may be performed during the screening period or within 14 days before screening).
• •Subjects with a family history of colorectal cancer, personal history of high risk for colorectal cancer, age \> 50 years, or other known risk factors must have completed colorectal cancer-related screening (including but not limited to colonoscopic biopsy, imaging, biomarkers, etc., which may be performed during the screening period).
• •Previous proven inadequate response, loss of response, or intolerance to at least one of the following drugs:
• •Glucocorticoids:
• •After at least one cycle of induction therapy (equivalent to oral prednisone 30 mg daily for 2 weeks or intravenous administration for 1 week), signs and symptoms of persistent active disease still exist; OR Previous failure of at least two attempts to reduce glucocorticoid dosage to below oral prednisone 10 mg/day or equivalent dose; OR Previous history of glucocorticoid intolerance (including but not limited to: Cushing's syndrome, osteopenia or osteoporosis, hyperglycemia, insomnia, infection, etc.).
• •Immunomodulators:
• •After previous treatment with oral azathioprine (≥ 1.5 mg/kg) or 6-mercaptopurine (≥ 0.75 mg/kg) for at least 8 weeks, signs and symptoms of persistent active disease still exist; OR Previous history of intolerance to at least one immunomodulator (including but not limited to: nausea, vomiting, abdominal pain, pancreatitis, abnormal liver function tests, lymphopenia, TPMT gene mutation, infection, etc.).
• •Patients with previous inadequate response, loss of efficacy, or intolerance to at least two drugs of different mechanism classes among biological therapy (such as anti-TNF antibodies, anti-IL antibodies, or anti-integrin antibodies) or Janus kinase (JAK) inhibitor therapy (such as upadacitinib) for ulcerative colitis. The aforementioned drugs must be domestically approved for the treatment of ulcerative colitis. Investigators must be able to provide relevant records of sufficient clinical treatment with the drug. Patients must meet any of the following criteria:
• •Inadequate efficacy: Despite induction therapy with the approved induction dose as specified in the drug instruction manual, the patient still shows signs and symptoms of persistent active disease; OR Loss of efficacy: On the basis of previous benefit, recurrence of signs and symptoms of active disease occurs during treatment with the approved maintenance dose as specified in the drug instruction manual (even if the drug is discontinued voluntarily after obtaining clinical benefit, it is not considered as biological therapy failure or intolerance to ulcerative colitis treatment); OR Intolerance: Previous history of intolerance to biological agents or JAK inhibitors approved for ulcerative colitis, including but not limited to infliximab, adalimumab, golimumab, ustekinumab, vedolizumab, upadacitinib, or others (including but not limited to infusion-related events, demyelination, congestive heart failure, or any drug-related adverse event leading to dose reduction or discontinuation).
• •The following drugs are allowed to be used in the study under stable dosage:
• •Oral 5-aminosalicylic acid (5-ASA) treatment: The prescribed dosage has been used stably for at least 2 weeks before the screening colonoscopy; Oral glucocorticoid treatment (prednisone ≤ 20 mg/day or equivalent dose, or extended-release budesonide tablets 9 mg/day): The prescribed dosage has been used stably for at least 2 weeks before the screening colonoscopy.
• •Having the condition to discontinue other therapeutic drugs for UC (except the above-mentioned allowed concomitant drugs) before pretreatment. For specific drugs, please refer to the "Section 7.14 Prohibited Concomitant Treatments" in the protocol and the corresponding drug washout period regulations.
• •Willing and able to complete the scheduled study assessments, including but not limited to endoscopic examinations.
• •The subject must be diagnosed with Crohn's disease at least 3 months before enrollment, and the diagnosis must be confirmed by clinical, endoscopic, and histopathological criteria. If no pathological report is available, the investigator may obtain specimens through additional biopsies during the screening period and send them to a local pathological laboratory for diagnostic confirmation.
• •The subject must be a patient with moderate to severe active Crohn's disease, defined as a Crohn's Disease Activity Index (CDAI) score ≥ 220 points during the screening period, and meet any of the following conditions:
• •Elevated C-reactive protein (CRP) level during the screening period (based on the upper limit of the reference range of the laboratory of each study center); OR Colonoscopy within 4 months before screening shows at least 3 non-anastomotic ulcers (each with a diameter \> 0.5 cm) or at least 10 aphthous ulcers (involving a continuous intestinal segment ≥ 10 cm), consistent with the characteristics of Crohn's disease; OR Computed Tomography Enterography (CTE), Magnetic Resonance Enterography (MRE), Contrast-Enhanced Small Bowel Radiography, or Capsule Endoscopy within 4 months before screening shows Crohn's disease-related ulcers (patients with only aphthous ulcers, fixed strictures, or small bowel strictures with pre-stenotic dilatation should not be enrolled).
• •Subjects with a family history of colorectal cancer, personal history of high risk for colorectal cancer, age \> 50 years, or other known high-risk factors must complete the latest colorectal cancer monitoring (including but not limited to colonoscopy and endoscopic biopsy, imaging, tumor biomarkers, etc.).
• •The subject has inadequate efficacy, loss of efficacy, or poor tolerance to at least one of the following drugs:
• •Glucocorticoids:
• •Glucocorticoid-refractory disease: Refers to subjects who still have signs and/or symptoms of active Crohn's disease after receiving oral prednisone (or equivalent drug) at a daily dose of ≥ 30 mg or budesonide at a daily dose of ≥ 9 mg for at least 4 weeks; OR Glucocorticoid-dependent disease: Refers to (1) inability to reduce the dose to prednisone equivalent dose \< 10 mg/day or budesonide \< 3 mg/day within 3 months after starting glucocorticoid use; or (2) recurrence within 3 months after completing a course of glucocorticoid treatment; OR Glucocorticoid intolerance: Refers to adverse reactions that lead to drug discontinuation when the subject uses glucocorticoids, including but not limited to Cushing's syndrome, osteopenia/osteoporosis, hyperglycemia, neuropsychiatric adverse reactions, etc.
• •Immunomodulators:
• •Persistent signs and/or symptoms of active disease still exist after using any of the following drugs for at least 3 months:
• •1. Oral azathioprine (AZA) at a daily dose of ≥ 1.5 mg/kg, or 6-mercaptopurine (6-MP) at a daily dose of ≥ 0.75 mg/kg, or methotrexate (MTX) at 25 mg per week (intramuscular injection or subcutaneous injection); OR
• •2. Oral AZA or 6-MP within the therapeutic range determined by thiopurine metabolite detection; OR
• •3. Combined use of thiopurine and allopurinol, and within the therapeutic range determined by thiopurine metabolite detection; OR Intolerance to at least one immunomodulator: Adverse reactions leading to drug discontinuation when using any immunomodulator, including but not limited to nausea/vomiting, abdominal pain, pancreatitis, abnormal liver function, lymphopenia.
• •* Subject with biological therapy failure: Refers to subjects with inadequate efficacy, loss of efficacy, or poor tolerance to at least two biological agents of different mechanisms that have been approved for the treatment of Crohn's disease (such as anti-TNF antibodies, anti-IL antibodies, or anti-integrin antibodies). Investigators must be able to provide sufficient medication history records during the induction period and/or maintenance period. The subject must meet one of the following criteria:
• •Inadequate efficacy: Refers to persistent signs and/or symptoms of active disease after induction therapy with the induction dose specified in the product instruction manual; OR Loss of efficacy: Refers to the recurrence of signs and/or symptoms of active disease after obtaining clinical improvement during treatment with the approved maintenance dose; OR Poor tolerance: Refers to adverse reactions that lead to dose reduction or discontinuation when the subject uses domestically or approved biological agents (including but not limited to infusion-related events, demyelination, congestive heart failure, etc.).
• •Subjects are allowed to use the following drugs concomitantly at a stable dose during the study:
• •Oral 5-aminosalicylic acid (5-ASA) treatment: The dose has been stable for at least 2 weeks before the screening colonoscopy; Oral glucocorticoid treatment (prednisone ≤ 20 mg/day or equivalent dose, or budesonide ≤ 9 mg/day): The dose has been stable for at least 2 weeks before the screening colonoscopy; Antibiotics specifically used for the treatment of Crohn's disease: If used continuously, the dose has been stable for at least 2 weeks before the screening colonoscopy; Probiotics: Such as Saccharomyces boulardii, etc., with a stable dose for at least 2 weeks before the screening colonoscopy; Antidiarrheals: Such as loperamide, compound diphenoxylate with atropine, etc., used to control chronic diarrhea.
• •Having the condition to discontinue other therapeutic drugs for CD (except the above-mentioned allowed concomitant drugs) before pretreatment. For specific drugs, please refer to the "Section 7.14 Prohibited Concomitant Treatments" in the protocol and the corresponding drug washout period regulations.
• •Willing and able to complete the planned study assessments, including endoscopic examinations and daily diary records.