An Exploratory Clinical Study to Evaluate the Safety and Efficacy of Autologous CD19-CD20-NKG2D-nsBicephali CAR-T for Relapsed/Refractory Central Nervous System Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 暂停
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Proportion of participants with dose-limiting toxicity (DLT) within 28 days after infusion; determination of MTD or RP2D.
研究概览
简要总结
Central nervous system lymphoma (CNSL) includes primary CNS lymphoma (PCNSL) and secondary CNS lymphoma (SCNSL), with diffuse large B-cell lymphoma as the predominant pathological type. Disease progression is often rapid and the relapse rate is high. Current standard treatment is centered on CNS-directed regimens based on high-dose methotrexate (HD-MTX), but salvage options for relapsed or refractory disease remain limited. In addition, the blood-brain barrier restricts effective exposure of many drugs within the central nervous system, making deep remission and durable disease control difficult to achieve. This study evaluates autologous CD19-CD20-NKG2D-nsBicephali CAR-T in patients with relapsed or refractory PCNSL or SCNSL. By engineering the patient's T cells into effector cells capable of recognizing both CD19 and CD20, this approach is intended to address tumor antigen heterogeneity and reduce immune escape associated with downregulation or loss of a single target. CAR-T cells may also migrate into cerebrospinal fluid and brain parenchyma, expand within the CNS compartment, and directly eliminate CD19/CD20-positive lymphoma cells. The study is designed to systematically evaluate the safety and preliminary efficacy of this investigational CAR-T therapy in relapsed or refractory CNSL.
详细描述
This is a single-center, open-label exploratory clinical study to evaluate the safety, tolerability, and efficacy of autologous CD19-CD20-NKG2D-nsBicephali CAR-T in relapsed/refractory central nervous system lymphoma. The study has two stages. The first stage is a dose-escalation stage with two planned dose groups: a low-dose group of 1×10^6 CAR-positive T cells/kg and a high-dose group of 2×10^6 CAR-positive T cells/kg. A 3+3 design will be used for dose escalation. After enrollment and completion of the DLT observation period in each dose group, available safety and pharmacokinetic data will be reviewed to determine subsequent enrollment and treatment decisions, including whether additional dose groups should be added. The second stage is a dose-expansion stage. Once a given dose group is confirmed to be safe, that dose group and any lower confirmed dose groups may be expanded concurrently. Participants will be followed for safety and efficacy for 24 months after cell infusion. After completion of the main study, participants will be re-consented for long-term safety follow-up until 15 years after cell infusion.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 18-75 years, male or female.
- •Good performance status: ECOG 0-2 or Karnofsky Performance Status (KPS) ≥
- •Diagnosis of relapsed/refractory primary CNS lymphoma (PCNSL) or secondary CNS lymphoma (SCNSL).
- •PCNSL: prior treatment with at least 2 lines and unsuitable for autologous hematopoietic stem cell transplantation; or prior treatment with at least 3 lines; or disease progression/relapse within 12 months after autologous transplantation. Participants must previously have received at least 1 line of HD-MTX-based CNS-directed therapy (intravenous dose ≥2500 mg/m²) and have documented progression, relapse, or intolerance.
- •SCNSL: relapse or refractory disease after at least 1 line of CNSL-directed therapy; if systemic lymphoma is also present, the systemic component must have relapsed after treatment including an anti-CD20 monoclonal antibody and an anthracycline.
- •Presence of measurable CNS disease (at least one enhancing lesion ≥1 cm on contrast-enhanced brain MRI, or positive CSF by flow cytometry and/or cytology).
- •Positive expression of CD19 and/or CD20 in tumor biopsy tissue or malignant CSF cells. Participants with prior failure of single-target CD19- or CD20-directed therapy are allowed, provided the washout period since the last treatment is at least 6 months.
- •Estimated life expectancy ≥12 weeks.
- •Adequate organ function:
- •Bone marrow and immune function: peripheral blood absolute CD3 count ≥50/mm³ and absolute lymphocyte count ≥0.2×10^9/L; ANC ≥1000/μL; platelets ≥50,000/μL, without recent red blood cell or platelet transfusion.
- •Hepatic and renal function: creatinine clearance (Cockcroft-Gault) ≥45 mL/min; if relaxed to 30-45 mL/min, fludarabine dose must be reduced strictly; AST and ALT ≤3×ULN; total bilirubin and alkaline phosphatase ≤1.5×ULN.
- •Cardiopulmonary function: LVEF ≥50% (NYHA class I-II); oxygen saturation on room air >92%.
- •Prior-treatment washout: anti-B-cell chemotherapy/immunotherapy stopped for at least 3 weeks; intrathecal CNS therapy stopped for at least 1 week; systemic corticosteroids (except physiologic replacement) stopped for at least 1 week; short-acting cytotoxic drugs stopped for at least 3 days.
- •Negative pregnancy test for women of childbearing potential; participants with partners of childbearing potential must agree to use effective contraception during treatment and for 24 months after infusion.
- •Voluntary participation and signed informed consent.
排除标准
- •High-risk CNS status: imaging showing high-risk brain herniation or uncontrollable intracranial pressure elevation risk (large subcortical mass effect with significant cerebral edema), or severe status epilepticus or poorly controlled seizures within 14 days.
- •Prior severe CAR-T toxicity: prior CD19/CD20-targeted therapy (including CAR-T or bispecific antibodies) with grade IV CRS or ICANS, or grade III CRS/ICANS without full recovery after treatment.
- •Uncontrolled serious active infection requiring systemic intravenous therapy.
- •Positive virology: active hepatitis B (HBsAg positive and peripheral blood HBV DNA ≥10^3 copies/mL); hepatitis C (HCV RNA positive); positive syphilis screening with titer ≥1:8; HIV antibody positive.
- •Toxicity from prior antitumor therapy not recovered to CTCAE v5.0 grade ≤2, except alopecia or fatigue.
- •Severe cardiovascular or respiratory disease, including myocardial infarction, unstable angina, or severe arrhythmia within the past 6 months; moderate-to-severe pulmonary arterial hypertension; or need for ventilatory support or oxygen reservoir mask assistance.
- •Prior history of, or concurrent, other active malignancy, except cured carcinoma in situ or basal cell skin cancer.
- •History of major solid organ transplantation.
- •Active tuberculosis at screening, or latent tuberculosis without systematic prophylaxis.
- •Live vaccine received within 6 weeks before lymphodepleting conditioning.
- •Pregnancy or breastfeeding; severe allergy to any lymphodepleting drug or any component of the CAR-T product.
- •Severe psychiatric disease, major depression, suicidal tendency, or any other condition that, in the investigator's judgment, makes the participant unsuitable for enrollment.
研究组 & 干预措施
Experimental - Low-dose autologous CD19-CD20-NKG2D-nsBicephali CAR-T
a low-dose group of 1×10^6 CAR-positive T cells/kg
干预措施: Autologous CD19-CD20-NKG2D-nsBicephali CAR-T Cell Injection (Biological)
Experimental - High-dose autologous CD19-CD20-NKG2D-nsBicephali CAR-T
a high-dose group of 2×10^6 CAR-positive T cells/kg
干预措施: Autologous CD19-CD20-NKG2D-nsBicephali CAR-T Cell Injection (Biological)
结局指标
主要结局
Proportion of participants with dose-limiting toxicity (DLT) within 28 days after infusion; determination of MTD or RP2D.
时间窗: Within 28 days after infusion.
Grade and frequency of adverse events (AEs), serious adverse events (SAEs), laboratory abnormalities, and adverse events of special interest (AESIs, including CRS and ICANS).
时间窗: From signing of informed consent through 24 months after infusion or the end-of-study visit, whichever occurs first.
次要结局
- Proportion of participants achieving objective response(at Day 28 and Months 2, 3, 4, 5, 6, 9, 12, 15, 18, and 24.)
- Proportion of participants achieving complete response (CR)(Month 3 (3 months ±14 days))
- Response categories (CR/CRu/PR/SD/PD)(Day 28 and Months 2, 3, 4, 5, 6, 9, 12, 15, 18, and 24)
- Best overall response (BOR)(From Day 0 (CAR-T infusion) until disease progression, initiation of new anti-tumor therapy, death, or Month 24 after infusion, whichever occurs first; response is assessed at Day 28 and Months 2, 3, 4, 5, 6, 9, 12, 15, 18, and 24.)
- Time to response (TTR)(From Day 0 to the first documented PR or CR/CRu, assessed through Month 24 after infusion; tumor assessments are performed at Day 28 and Months 2, 3, 4, 5, 6, 9, 12, 15, 18, and 24.)
- Duration of response (DOR)(From the date of first documented CR/CRu/PR until first documented PD or death, whichever occurs first, assessed through Month 24 after infusion.)
- Progression-free survival (PFS)(From Day 0 until first documented disease progression or death, whichever occurs first, assessed through Month 24 after infusion.)
- Overall survival (OS)(From Day 0 until death from any cause, assessed through Month 24 after infusion.)
- CNS response components(Assessed at Day 28 and Months 2, 3, 4, 5, 6, 9, 12, 15, 18, and 24 after infusion.)
- In baseline CSF-positive participants only: CSF conversion to negative, CSF MRD conversion to negative if MRD is performed, and duration of CSF MRD negativity(Assessed at Day 28 and Months 2, 3, 4, 5, 6, 9, 12, 15, 18, and 24 after infusion; duration of CSF MRD negativity is assessed through Month 24.)
- Cmax(Assessed from Day 0 through Month 24 after infusion on Days 0, 1, 3, 5, 7, 9, 11, 14, 21, and 28; Months 2, 3, 6, 9, 12, 15, 18, and 24; and through study completion or early withdrawal, up to 24 months.)
- Tmax(Assessed from Day 0 through Month 24 after infusion on Days 0, 1, 3, 5, 7, 9, 11, 14, 21, and 28; Months 2, 3, 6, 9, 12, 15, 18, and 24; and through study completion or early withdrawal, up to 24 months.)
- AUC0h-28d(Assessed from Day 0 through Month 24 after infusion on Days 0, 1, 3, 5, 7, 9, 11, 14, 21, and 28; Months 2, 3, 6, 9, 12, 15, 18, and 24; and through study completion or early withdrawal, up to 24 months.)
- AUC0-last(Assessed from Day 0 through Month 24 after infusion on Days 0, 1, 3, 5, 7, 9, 11, 14, 21, and 28; Months 2, 3, 6, 9, 12, 15, 18, and 24; and through study completion or early withdrawal, up to 24 months.)
- PD parameters, including changes in peripheral blood CD19-CD20-NKG2D-positive cells and serum cytokines such as TNF-alpha and IFN-gamma before and after infusion(Assessed from Day 0 through Month 24 after infusion on Days 0, 1, 3, 5, 7, 9, 11, 14, 21, and 28; Months 2, 3, 6, 9, 12, 15, 18, and 24; and through study completion or early withdrawal, up to 24 months.)