肿瘤细胞治疗研究
英文原题：Biomarker-Guided Dual-Target CAR-T Cells for Advanced Solid Tumors
这是一项 I/II 期注册临床试验，评估自体 CAR-T 细胞治疗相关疾病的安全性、可行性及初步疗效。当前状态：招募中。计划入组 72 例。试验地点：中国 · 深圳（共 1 个中心，其中中国 1 个）。登记号：NCT07523529。
不限性别 · ≥ 18 Years 且 ≤ 75 Years
纳入标准： • 签署知情同意时年龄18–75岁。 • 组织学或细胞学确诊晚期、不可切除、转移性或复发性实体恶性肿瘤（中枢神经系统特异性靶点队列可包括复发性高级别胶质瘤）；不存在标准根治治疗、不能耐受标准治疗或标准治疗已失败。 • 经中心生物标志物审核，至少有一组预设双靶点组合符合条件。建议阈值为：主要抗原在≥50%的存活肿瘤细胞中表达强度≥2+（或符合该靶点组合的特定标准），且次要抗原在≥25%的存活肿瘤细胞中可检出；病理审核确认正常组织风险可接受。 • 至少有1个按RECIST 1.1可测量病灶；中枢神经系统队列可按RANO标准判定为可测量或可评估疾病。 • ECOG体能状态0–1分；中枢神经系统队列如有理由，可接受Karnofsky评分≥70分或ECOG 0–2分。 • 器官功能充分：ANC≥1.0×10⁹/L、血小板≥75×10⁹/L、血红蛋白≥8 g/dL、肌酐清除率≥50 mL/min、AST/ALT≤ULN的3倍（肝脏受累时≤5倍）、总胆红素≤ULN的1.5倍（Gilbert综合征除外）、左室射血分数≥45%、室内空气下血氧饱和度≥92%。 • 既往抗癌治疗引起的急性毒性已恢复至≤1级；脱发、稳定的内分泌疾病及方案允许的其他残留毒性除外。 • 静脉通路充分，能够接受白细胞单采；并成功制备出符合放行标准的自体双靶点CAR-T产品。 • 预期生存期≥12周。 • 有生育能力者妊娠试验阴性，并同意按方案采取高效避孕措施。 • 能理解并签署知情同意书，遵守研究随访要求，包括对基因修饰细胞进行长期监测。 排除标准： • 中心审核后无符合条件的靶点组合，或因预测的靶向正常组织/肿瘤外风险不可接受而判定该组合不安全。 • 过去6个月内接受过针对相同靶点组合的基因修饰细胞治疗，或既往细胞/基因治疗后仍有具有临床意义的持续毒性。 • 活动性未控制感染，包括未控制的细菌、真菌或病毒感染、活动性结核、未控制的HIV，或存在可检出且风险不可接受的活动性乙肝/丙肝病毒负荷。 • 淋巴清除治疗前7天内需要每日使用剂量>10 mg泼尼松等效剂量的全身性糖皮质激素，或其他全身免疫抑制治疗；方案明确允许的生理替代治疗或特定队列的脑水肿治疗除外。 • 过去2年内有需要全身免疫抑制治疗的活动性自身免疫病；方案允许且病情稳定者除外。 • 有临床意义的心血管疾病（如未控制心律失常、近期心肌梗死、不稳定型心绞痛或失代偿性心力衰竭）、严重肺功能受损或其他使细胞治疗不安全的重大合并症。 • 活动性且有症状的中枢神经系统出血、未控制癫痫或未控制颅内压升高；需要紧急干预的软脑膜疾病，除非中枢神经系统特定队列明确允许。 • 妊娠或哺乳期。 • 同时患有需接受积极全身治疗的第二种恶性肿瘤；方案允许的部分低风险肿瘤或已根治性治疗的肿瘤除外。 • 研究者判断可能妨碍安全参加研究、产品制备、细胞输注或结果解释的任何情况。
Inclusion Criteria: * Age 18-75 years at consent * Histologically or cytologically confirmed advanced unresectable, metastatic, or recurrent solid malignancy (including recurrent high-grade glioma for CNSspecific pairs) for which standard curative therapy does not exist, is not tolerated, or has failed. * At least one predefined dual-target pair qualifies on central biomarker review. Recommended working thresholds: primary antigen \>= 2+ intensity in \>= 50% of viable tumor cells (or pair-specific equivalent) AND secondary antigen detectable in \>= 25% of viable tumor cells, with acceptable normal-tissue risk after pathology review * At least 1 measurable lesion by RECIST 1.1, or measurable / evaluable disease by RANO for CNS cohorts. * ECOG performance status 0-1 (CNS cohort may allow Karnofsky \>= 70 or ECOG 0-2 if justified). * Adequate organ function: ANC \>= 1.0 x 10\^9/L, platelets \>= 75 x 10\^9/L, hemoglobin \>= 8 g/dL, creatinine clearance \>= 50 mL/min, AST / ALT \<= 3 x ULN (\<= 5 x ULN if liver involvement), total bilirubin \<= 1.5 x ULN unless Gilbert syndrome, LVEF \>= 45%, oxygen saturation \>= 92% on room air. * Recovered to Grade \<= 1 from acute toxicities of prior anticancer therapy (except alopecia, stable endocrinopathies, or other protocol-allowed residual toxicities). * Adequate venous access and ability to undergo leukapheresis; successful manufacture of a release-qualified autologous dual-target CAR-T product. * Life expectancy \>= 12 weeks. * Negative pregnancy test for persons of childbearing potential and agreement to use highly effective contraception per protocol. * Ability to understand and sign informed consent and comply with study follow-up, including long-term gene-modified cell monitoring. Exclusion Criteria: * No qualifying target pair after central review, or target pair considered unsafe because of unacceptable predicted ontarget / off-tumor risk. * Prior gene-modified cellular therapy directed against the same target pair within 6 months, or persistent clinically significant toxicity from prior cell / gene therapy. * Active uncontrolled infection, including uncontrolled bacterial, fungal, or viral infection; active tuberculosis; uncontrolled HIV; active hepatitis B or C with detectable / unsafe viral burden. * Need for systemic corticosteroids \> 10 mg prednisone equivalent daily or other systemic immunosuppressive therapy within 7 days before lymphodepletion, unless specifically allowed for physiologic replacement or CNS edema management per cohort rules. * Active autoimmune disease requiring systemic immunosuppression within the past 2 years, except protocol-allowed stable conditions. * Clinically significant cardiovascular disease (for example uncontrolled arrhythmia, recent myocardial infarction, unstable angina, decompensated heart failure), severe pulmonary compromise, or other major comorbidity making cell therapy unsafe. * Active symptomatic CNS hemorrhage, uncontrolled seizures, or uncontrolled intracranial hypertension; leptomeningeal disease requiring urgent intervention unless explicitly allowed in a CNS-specific cohort. * Pregnancy or breastfeeding. * Concurrent second malignancy requiring active systemic treatment, except certain low-risk or definitively treated cancers allowed by protocol. * Any condition that, in the investigator's judgment, would interfere with safe participation, product manufacture, infusion, or interpretation of results.
以上为辅助阅读译文。是否适合入组须由主治医生判断，最终以登记平台与研究者确认为准。
主要终点：Dose-limiting toxicities (DLTs) · 28 Days；Incidence and severity of treatment-emergent adverse events · 12 Months
次要终点：Objective response rate (ORR) by RECIST 1.1 or RANO；Disease control rate (DCR)；Duration of response (DoR)
受试者先接受中心抗原组合筛查，随后接受氟达拉滨/环磷酰胺淋巴细胞清除治疗，再输注从预设库中选出的最匹配自体双靶点CAR-T细胞。若产品可用、所分配剂量仍符合安全要求且满足再治疗标准，部分受试者可再次输注。
本多中心、开放标签Ⅰ/Ⅱ期主方案研究评估自体双靶点CAR-T细胞治疗成人晚期实体瘤。中心实验室完成生物标志物筛查后，为每位受试者从预设靶点组合库中选择最匹配的双靶点构建体。研究拟评估生物标志物指导的双靶向策略能否改善肿瘤控制、降低抗原逃逸风险，并保持可接受的安全性。
This is a multicenter, open-label, Phase 1/2 master protocol evaluating autologous dual-target CAR-T cell therapy in adults with advanced solid cancers. After central biomarker screening, each participant is assigned the best-matched dual-target construct from a predefined target-pair library. The trial is designed to test whether biomarkerguided dual targeting can improve tumor control, reduce antigenescape risk, and preserve safety in solid tumors.
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