A Clinical Study Evaluating the Safety and Efficacy of GT719 Universal Cell Injection in the Treatment of Immune-mediated Kidney Diseases
This study is a single-arm, open-label, dose-escalation and dose-expansion clinical trial, divided into two phases: the first phase is the dose-escalation phase, and the second phase is the dose-expansion phase. In the dose-escalation phase, approximately 9-18 adult participants with immune-mediated kidney diseases are planned to be enrolled and treated with GT719 universal cell injection. The objectives of this phase are to evaluate the safety and tolerability of the product, determine the recommended dose (RD) for subsequent studies, conduct a preliminary assessment of its clinical efficacy, and investigate the pharmacokinetic and pharmacodynamic characteristics. Upon completion of the dose-escalation phase, after evaluation by investigators and collaborators, an appropriate dose will be selected for the dose-expansion phase. An additional 12 participants will be enrolled to fully assess the safety and efficacy of the product.
• 1\. The participant or their legal representative voluntarily signs a written informed consent form, and is willing and able to comply with the procedures of this study.
• 2\. Aged 18 to 75 years (inclusive) at the time of signing the informed consent, regardless of gender.
• 3\. Positive expression of CD19 on B cells in peripheral blood is confirmed by flow cytometry.
• 4\. Participants with IgA nephropathy (IgAN) at high risk of progression:
• ① A definite pathological diagnosis of IgAN confirmed by renal biopsy (renal biopsy must be performed within 2 years prior to screening or during the screening period).
⁃ Meet at least one of the following requirements:
⁃ Prior treatment with glucocorticoids, budesonide enteric-coated capsules, immunosuppressants (including mycophenolate mofetil, cyclophosphamide, cyclosporine, tacrolimus, Tripterygium wilfordii, leflunomide, azathioprine), or biological agents (including but not limited to anti-CD20 monoclonal antibodies, telitacicept, daratumumab) for a cumulative duration of at least 3 months, with persistent 24-hour urinary protein ≥ 0.75 g or UPCR ≥ 0.75 g/g.
• The predicted probability of a 50% decline in eGFR or end-stage renal disease (ESRD) within 5 years calculated by the international IgAN prediction tool is ≥ 20%.
• A ≥ 20% decline in eGFR within 3 months.
• Renal biopsy performed within 6 months indicating Oxford classification C2 lesion.
• Patients who are intolerant to conventional treatment and for whom the investigator determines that the benefits outweigh the risks, with adequate informed consent obtained, may be considered for inclusion.
• 5\. Participants with ANCA-associated vasculitis (AAV)/ANCA-associated glomerulonephritis (AAGN) must meet the following criteria:
• ① Diagnosis of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) according to the 2022 ACR/EULAR classification criteria for ANCA-associated vasculitis.
• ② Positive anti-myeloperoxidase (MPO-ANCA) antibody or anti-proteinase 3 (PR3-ANCA) antibody detected during screening or in previous tests.
• ③ AAGN: Availability of a renal biopsy pathological report within 2 years; if eGFR \< 30 mL/min/1.73 m², a renal biopsy pathological report obtained during the screening period is required. Presence of active lesions according to the 2010 Berden classification criteria for AAGN.
• ④ Renal-uninvolved AAV: Birmingham Vasculitis Activity Score (BVAS) version 3.0 ≥ 3 points, indicating active vasculitis.
• ⑤ Failure of standard of care (SOC), defined as any of the following:
• a) Failure to achieve remission after at least 3 months of treatment with glucocorticoids combined with cyclophosphamide or rituximab.
• b) Disease relapse after achieving remission. c) Persistent disease activity despite receiving SOC for at least 6 months, including glucocorticoids, cyclophosphamide, rituximab, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, as well as other biological agents (including but not limited to mepolizumab) or avacopan.
• 6\. Participants with membranous nephropathy (MN) must meet the following criteria:
‣ Definite pathological diagnosis of primary (idiopathic) MN confirmed by renal biopsy (renal biopsy must be performed within 2 years prior to screening or during the screening period).
‣ ② Elevated serum anti-PLA2R antibody titer detected during screening or in previous tests, or positive PLA2R antigen staining in renal tissue.
‣ ③ eGFR ≥ 30 mL/min/1.73 m².
‣ ④ Meeting the criteria for high-risk or relapsed/refractory MN: c) High-risk patients, defined as meeting any of the following: Normal eGFR, urinary protein \> 3.5 g/24h, \< 50% reduction in urinary protein after 6 months of ACEI/ARB treatment, and serum albumin \< 25 g/L or anti-PLA2R antibody \> 50 RU/mL.
‣ eGFR \< 60 mL/min/1.73 m² and/or urinary protein \> 8 g/24h for more than 6 months.
‣ d) Relapsed/refractory patients: Relapsed patients: Defined as achieving complete or partial remission with previous SOC treatment, followed by recurrence of urinary protein ≥ 3.5 g/24h.
‣ Refractory patients: Defined as refractory to previous SOC treatment (persistent urinary protein ≥ 3.5 g/24h with \< 50% reduction compared to baseline).
• 7\. Participants with refractory podocytopathy:
• ① Pathological diagnosis of minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS) confirmed by renal biopsy (renal biopsy must be performed within 2 years prior to screening or during the screening period).
• ② Meet at least one of the following requirements:
‣ Previous diagnosis of steroid-resistant nephrotic syndrome (SRNS): 24-hour urinary protein \> 3 g or UPCR ≥ 3.5 g/g, serum albumin \< 30 g/L, failure to achieve complete remission after 4 weeks of standard-dose glucocorticoid treatment.
‣ Previous diagnosis of steroid-dependent nephrotic syndrome (SDNS): Remission achievable with glucocorticoid treatment, but relapse within 2 weeks of glucocorticoid tapering or discontinuation, or two consecutive relapses during glucocorticoid tapering.
‣ Previous diagnosis of frequently relapsing nephrotic syndrome (FRNS): ≥ 3 relapses within 1 year or ≥ 2 relapses within 6 months after achieving complete remission with glucocorticoid treatment.
‣ Previous treatment with one immunosuppressant (including cyclosporine A, tacrolimus, mycophenolate mofetil, cyclophosphamide) or biological agent (including but not limited to anti-CD20 monoclonal antibodies, telitacicept, daratumumab) for ≥ 6 months without achieving remission or with intolerance.
‣ Failure to achieve remission within 6 months of adequate treatment with one immunosuppressant or biological agent, but the investigator judges that the benefits outweigh the risks and the patient has provided full informed consent, the patient may be considered for inclusion.
• 8\. Participants with proliferative glomerulonephritis with monoclonal immunoglobulin deposition (PGNMID):
‣ Definite pathological diagnosis of PGNMID confirmed by renal biopsy (renal biopsy must be performed within 3 years prior to screening or during the screening period).
• Meet at least one of the following requirements:
‣ Persistent 24-hour urinary protein ≥ 1 g or UPCR ≥ 1 g/g despite treatment with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) for at least 4 weeks.
‣ eGFR ≥ 30 mL/min/1.73 m² with progressive decline (≥ 20% decrease in eGFR) within the recent 6-12 months.
‣ Development of nephrotic syndrome or nephrotic-range proteinuria (24-hour urinary protein ≥ 3 g or UPCR ≥ 3 g/g) without stable remission with short-term glucocorticoid treatment.
‣ ③ Exclusion of hematological malignancies (leukemia, lymphoma, multiple myeloma, systemic light chain amyloidosis) by bone marrow aspiration and biopsy (bone marrow aspiration must be performed within 6 months prior to screening or during the screening period).
• 9\. Screening laboratory test results must meet the following criteria (excluding indicators related to the study disease):
∙ Neutrophil count ≥ 1.5 × 10⁹/L;
‣ Hemoglobin ≥ 80 g/L; Platelet count ≥ 50 × 10⁹/L;
‣ Alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN); Aspartate aminotransferase (AST) ≤ 3 × ULN; Total bilirubin (TBIL) \< 2 × ULN (for participants with Gilbert syndrome, direct bilirubin (DBIL) ≤ 1.5 × ULN);
‣ Creatinine clearance rate ≥ 30 mL/min; (except for anti-GBM glomerulonephritis, AAV/ANCA-associated glomerulonephritis);
‣ Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN; Prothrombin time (PT) ≤ 1.5 × ULN;
‣ Left ventricular ejection fraction (LVEF) ≥ 50% diagnosed by echocardiography.
‣ Pulmonary function: Defined as dyspnea ≤ CTCAE Grade 1 and oxygen saturation (SpO₂) ≥ 92% at rest while breathing room air (measured by pulse oximetry).
• 10\. Female participants of childbearing potential must:
• a. Have a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test result at screening, confirmed by the investigator; b. Agree to avoid breastfeeding during study participation until at least 1 year after GT719 cell infusion or until GT719 cells are no longer detected by two consecutive flow cytometry tests, whichever is later.
• 11\. Male participants with sexual partners and female participants of childbearing potential must agree to use highly effective contraceptive methods (e.g., contraceptive pills, intrauterine devices, or condoms) starting from screening until at least 1 year after GT719 cell infusion or until GT719 cells are no longer detected by two consecutive flow cytometry tests, whichever is later. Male participants must agree to use condoms during sexual contact with pregnant women or women of childbearing potential for at least 1 year after GT719 cell infusion, even after successful vasectomy.