An Exploratory Clinical Study on CAR-T Cell Immunotherapy Targeting CD22/CD19 for Consolidation Therapy in Relapsed/Refractory Aggressive B-cell Lymphoma After Second-line Treatment
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- 1-year progression free survival rate (1-year-PFSR)
研究概览
简要总结
The purpose of this study is to determine the efficacy and safety of CD22/CD19-targeted CAR-T cell immunotherapy as consolidation therapy after second-line treatment in patients with high-risk aggressive B-cell lymphoma.
详细描述
Only a proportion of patients with aggressive B-cell lymphoma can achieve complete response with standard first-line immunochemotherapy such as R-CHOP, and a considerable number of patients experience relapse or disease progression, facing challenges such as drug resistance and poor prognosis.
According to previous National Comprehensive Cancer Network guidelines, patients with high-risk diffuse large B-cell lymphoma (DLBCL) who achieve complete response after first-line induction therapy may receive consolidation treatments such as autologous stem cell transplantation (ASCT) or involved-site radiation therapy (ISRT). However, evidence from the SWOG 9704 study demonstrated that, among patients with intermediate-high or high-risk disease who achieved at least partial response after first-line therapy, ASCT consolidation did not significantly improve progression-free survival (PFS) or overall survival (OS) in the intermediate-high-risk group, with limited benefit observed only in selected high-risk populations. Similarly, the DLCL04 study showed that patients with an age-adjusted International Prognostic Index (aaIPI) score of 2-3 who achieved complete or partial response after first-line therapy did not derive significant benefit from ASCT consolidation.
In the 2024 NCCN guidelines for DLBCL, consolidation strategies after first-line therapy have been largely de-escalated, with recommendations mainly limited to observation or localized radiotherapy in selected cases. For patients who relapse or are refractory after first-line treatment, second-line salvage therapy remains the standard approach; however, even after achieving response to second-line therapy, patients with high-risk features still face a substantial risk of disease progression, and there is currently no well-established consolidation strategy to improve long-term outcomes in this setting.
Chimeric antigen receptor T-cell (CAR-T) immunotherapy has demonstrated remarkable efficacy in relapsed/refractory B-cell malignancies. As a result, CAR-T therapy has been increasingly explored not only as a salvage treatment but also as a potential consolidation strategy. Compared with autologous hematopoietic stem cell transplantation, CAR-T therapy allows for more controllable management of treatment-related toxicities, such as cytokine release syndrome and neurotoxicity, using immunosuppressive agents including glucocorticoids and tocilizumab. In addition, ASCT is associated with higher risks of treatment-related complications, including infection, bleeding, and non-relapse mortality (NRM).
Therefore, for patients with high-risk aggressive B-cell lymphoma who achieve partial or complete response after second-line therapy, there remains an unmet clinical need for effective consolidation strategies to further reduce relapse risk and improve survival outcomes.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •1. With the patient's consent and signed informed consent form, willing and able to comply with the planned visits, research treatments, laboratory tests, and other experimental procedures;
- •CD19 and/or CD22-positive large B-cell lymphoma (LBCL) diagnosed by cytology or histology according to WHO 2016 criteria, including diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBL), etc., whose disease has achieved complete response (CR) after induction treatment with a standard second-line chemotherapy regimen and who are within 3 months from the time of CR.
- •3. The possible high-risk factors for the patient's onset of the disease are as follows: 1) FISH confirmed high-grade B-cell lymphoma with double or triple strikes, accompanied by MYC and BCL2 and/or BCL6 rearrangements; 2) Advanced B-cell lymphoma with 11q abnormalities/Burkitt like lymphoma with 11q abnormalities; 3) The International Prognostic Index (IPI) at the time of initial diagnosis is 2-5 points; The Age Adjusted International Prognostic Index (aaIPI) is 2-3 points; The National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) score ranges from 4-8 points in the United States; 4) Immunohistochemical CD5 positivity; 5) Immunohistochemistry suggests dual expression of MYC and BCL-2 (recommended dual expression threshold is MYC ≥ 40%, BCL2 ≥ 50%); 6) Gene sequencing shows TP53 mutation; 7) The second-generation sequencing (NGS) suggests molecular typing as MCD subtype and N1 subtype;
- •Age range from 18 to 85 years old, male or female;
- •Subjects with physical fitness status scores ranging from 0 to 2 in the Eastern Cooperative Oncology Group (ECOG) in the United States;
- •Expected survival period from the date of signing the informed consent form is greater than 3 months;
- •HGB ≥ 60g/L;
- •The absolute value of neutrophils in peripheral blood is ≥ 1000/μl, and the platelet count is ≥ 45000/μl;
- •Liver and kidney function, as well as heart and lung function, meet the following requirements: 1) Total bilirubin (TBIL) ≤ 1.5 times the upper limits of normal (ULN), except for subjects with Gilbert's syndrome; 2) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times ULN; 3) Serum Creatinine (Cr) ≤ 1.5 times ULN or Creatinine Clearance Rate (CCr) ≥ 60mL/min, estimated based on the Cockcroft Gault formula; 4) The left ventricular ejection fraction (LVEF) of the heart is ≥ 50%. Echocardiography (ECHO) confirms no pericardial effusion and no clinically significant arrhythmia; 5) Baseline transcutaneous oxygen saturation under indoor ventilation>92%; 6) No clinically significant pleural effusion;
- •Participants with pregnancy plans must agree to take contraceptive measures for a continuous period of 6 months from before enrollment in the study until the end of the study; If the subject is pregnant or suspected of being pregnant, the researcher should be notified immediately.
- •11.Patients who are not eligible for hematopoietic stem cell transplantation (HSCT) or who refuse HSCT.
排除标准
- •1. Have received any form of chimeric antigen receptor cell therapy or other genetically modified T cell therapy;
- •Has a history of severe immediate hypersensitivity reactions to aminoglycoside antibiotics and other essential medications;
- •Known history of human immunodeficiency virus (HIV) infection or active hepatitis B virus (HBV) infection, or any uncontrolled active systemic infection requiring intravenous antibiotics (active HBV infection is defined as: a. HBV DNA quantification ≥ 2000 IU/ml; b. ALT ≥ 2 times the normal upper limit value; c. Exclude hepatitis caused by the disease itself, medication, or other reasons; All three conditions must be met simultaneously. If a patient is diagnosed with active HBV infection at the time of initial diagnosis and becomes non active HBV infection after anti HBV treatment, they can be included in this study under the premise of sufficient anti HBV treatment;
- •Non hematological tumors (such as lymphoma) associated liver and kidney dysfunction: ALT>3 times the upper limit of normal, AST>3 times the upper limit of normal, TBIL>2 times the upper limit of normal, serum creatinine clearance rate<30 mL/min;
- •History of myocardial infarction, cardiac angioplasty or coronary stent implantation, unstable angina, active arrhythmia, or other clinically significant cardiovascular diseases within the 12 months prior to enrollment;
- •Other serious medical diseases may have an impact on this study (such as diabetes, gastric ulcer, other serious respiratory and circulatory diseases, severe autoimmune diseases or congenital immune defects, severe infection and inability to be effectively controlled), as well as other diseases with high risk of disease change;
- •Has a history of severe immediate hypersensitivity reactions to any medication necessary for use in this study; History of severe allergy to biological products (including antibiotics);
- •Female subjects who are currently pregnant or breastfeeding (with potential risks to the fetus or infant from pre-treatment chemotherapy regimens);
- •The researchers determined that the subjects were unable to complete all the required visit surveys or diagnostic procedures (including medium - and long-term follow-up visits) as per the study protocol, had poor willingness to participate in the study, were unwilling to join and fully comply with the study arrangements, and had insufficient compliance with the study by the subjects and their families. The decision-making power belongs to the researcher;
- •The subjects who have previously suffered from other malignant tumors cannot be included in this study unless they are disease-free and have not received any form of anti-tumor treatment for at least 3 years (except for skin tumors of non malignant melanoma and in situ cancers occurring in the cervix, bladder, breast, etc.);
- •History of receiving live vaccines within 6 weeks prior to initiating the pre-treatment plan;
- •Those who have undergone large-scale surgical treatment (excluding lymph node biopsy) within the past 14 days, or those who are expected to undergo large-scale surgical treatment during the treatment process;
- •There are other serious physical or mental illnesses or laboratory abnormalities that may increase the risk of participating in the study, or interfere with the study results, as well as patients deemed unsuitable by the researchers to participate in this study.
研究组 & 干预措施
CD19/CD22 CAR-T cell immunotherapy treatment
干预措施: CD22/CD19 CAR-T cell immunotherapy (Drug)
结局指标
主要结局
1-year progression free survival rate (1-year-PFSR)
时间窗: 1 year after treatment
The 1-year progression-free survival rate (1-year PFSR) is defined as the proportion of patients who are alive and progression-free at 1 year after CAR-T cell infusion.
次要结局
- overall survival (OS)(2 years after treatment)
- progression free survival (PFS)(2 years after treatment)
- time to progression (TTP)(2 years after treatment)
- disease free survival (DFS)(2 years after treatment)
- event free survival (EFS)(2 years after treatment)
- Relapse Rate(2 years after treatment)
- Incidence and Severity of Treatment-Emergent Adverse Events(2 years after treatment)
研究者
Liping Dou
Director, Department of Hematology
Chinese PLA General Hospital