肿瘤细胞治疗研究
英文原题：GPC2 CAR T Cells for Relapsed or Refractory Neuroblastoma and Metastatic Retinoblastoma
这是一项 I 期注册临床试验，评估 CAR-T 细胞治疗神经母细胞瘤的安全性、可行性及初步疗效。当前状态：邀请入组。计划入组 45 例。试验地点：美国 · 费城（共 1 个中心）。登记号：NCT05650749。
不限性别 · ≥ 1 Year
请注意，自2026年8月起，本研究不再入组神经母细胞瘤患者。本研究仍开放入组视网膜母细胞瘤患者。
神经母细胞瘤纳入标准：
1. 患者年龄必须≥ 1岁
2. 患者在研究入组时必须符合COG风险分类中的高危神经母细胞瘤。最初被判定为低危或中危、但随后被重新分类为高危的患者同样符合入组条件。
3. 患者既往必须经组织学确诊为神经母细胞瘤：
1. 根据INRC判定为复发/复发性或难治性/持续性，并且
2. 针对该疾病不存在标准治愈性治疗措施，或标准治愈性治疗措施已不再有效。
3. 首次复发的患者符合入组条件，因为复发性高危神经母细胞瘤目前尚无已知的治愈性疗法。
4. 患者在入组时必须患有可评估或可测量的病灶。
5. 此外，患者必须经历过以下至少一种情况：
a. 在以下至少一项中记录到新发病灶部位：i. 123I-间碘苄胍（MIBG）或 18F-mFBG（间氟苄胍）扫描；或 ii. CT/MRI；或 iii. FDG 或 Ga-68 Dotatate PET（适用于已知肿瘤不摄取 MIBG 的患者）且 MRI 所见与肿瘤一致（即骨病灶），或 iv. 对任何新发或进展病灶经活检证实为神经母细胞瘤。b. 经 CT/MRI 记录的软组织肿块至少一个维度增大超过 20%，且现有病灶最长维度绝对增大至少 5 mm。既往接受过放疗的病灶可包括在内。
c. 骨髓活检显示按修订版 INRC 判定为疾病进展 d. 疾病持续稳定存在，即前期治疗或挽救治疗结束时的缓解程度低于部分缓解，并且至少有一个部位的活检显示存在存活的神经母细胞瘤。
e. 有效但疾病持续存在，定义为对一线治疗至少达到部分缓解（即对一线治疗至少达到部分缓解，但通过 MIBG 扫描、CT/MRI 或骨髓穿刺/活检仍显示有残留病灶）。此类患者必须至少在一个残留部位经组织学确认存在存活的神经母细胞瘤（常规骨髓形态学检查中见到肿瘤即为足够）。
6. 患者的 Lansky 评分（<16 岁）或 Karnofsky 评分（≥ 16 岁）必须 ≥ 60
7. 患者必须具有足够的肾功能，定义为经年龄校正的血清肌酐 ≤1.5 ULN（针对相应年龄）。
8. 总胆红素 ≤ 1.5 x ULN（例外：Gilbert 病患者的总胆红素 ≤ 3 ULN）
9. 天冬氨酸氨基转移酶（AST）≤ 2.5 ULN（例外：肝转移患者的 AST ≤ 5 x ULN）。
10. 丙氨酸氨基转移酶（ALT）≤ 2.5 ULN（例外：肝转移患者的 ALT ≤ 5 x ULN）。
11. 患者在室内空气下的基线脉搏血氧饱和度必须至少为 92%。此外，如经治疗研究者判断临床上适合进行 PFTs，则要求 DLCO ≥ 60%（必要时经贫血校正）。
12. 经超声心动图（Echo）证实左心室短缩分数（LVSF）≥28%或射血分数（LVEF）≥ 50%，或经扫描检查或心脏病专科医生记录证实心室功能良好。
神经母细胞瘤排除标准：
1. 患有活动性乙型肝炎或活动性丙型肝炎的患者。
2. HIV感染的患者。
3. 患有未受控制的活动性感染的患者。
4. 患有原发性或获得性免疫缺陷疾病的患者。
5. 已知对DMSO过敏的患者。
6. 在细胞输注或细胞采集时合并使用全身性类固醇或免疫抑制治疗，或存在经主治医生判断在采集期间或输注后可能需要类固醇治疗或免疫抑制治疗的情况。允许在细胞采集以外的时间或细胞输注时为治疗疾病而使用类固醇。同样允许使用生理性替代剂量的氢化可的松或吸入性类固醇。
7. 患有正在进展的CNS转移的患者，包括脑实质或柔脑膜受累。（注：仅当临床有疑似CNS转移的指征时，才需要在筛选期进行CNS影像学检查）
8. 经研究者判断，活动性内科疾病会显著增加不可控 CRS 和/或神经毒性的风险。
9. 充血性心力衰竭（按纽约心脏协会心功能分级 III 级或 IV 级定义）、不稳定型心绞痛、严重未控制的心律失常、入组前 6 个月内发生心肌梗死或有心肌炎病史的患者。
10. 入组前 30 天内接种过任何活疫苗的患者。
11. 妊娠期或哺乳期患者。
12. 知情同意时预期寿命 < 6 个月的患者。
视网膜母细胞瘤纳入标准：
1. 患者年龄 ≥ 6 个月。
2. 研究入组时，患者必须符合国际
视网膜母细胞瘤分期系统（IRSS）风险分类（4）的转移性视网膜母细胞瘤标准：
a. 视网膜母细胞瘤队列1（CNS外转移）i. IVa期疾病 ii. CNS外疾病必须经组织学确认为视网膜母细胞瘤（初诊时或复发时均可）iii. 可测量疾病：定义为> 1cm2或经活检证实的骨髓疾病 iv. 既往治疗：作为初始治疗或复发治疗的一部分接受COG ARET0321类似或等效方案治疗后出现复发或难治性疾病 b. 视网膜母细胞瘤队列2（CNS疾病）i. IVb期疾病 ii. 不要求组织学确认 iii. CNS疾病定义为可测量疾病>1cm2、不可测量疾病，或仅CSF阳性 c. 既往治疗：i. IVb.1期和IVb.2期：作为初始治疗或复发治疗的一部分接受COG ARET0321类似或等效方案治疗后复发 i. IVb.3期：不要求既往治疗（即在初诊或复发时即可入组）
3. 患者的Lansky（< 16岁）或Karnofsky（≥ 16岁）评分必须≥ 60
4. 患者必须具有足够的肾功能，定义为经年龄校正的血清肌酐≤1.5 ULN。
5. 总胆红素≤ 1.5 x ULN（例外：Gilbert综合征患者总胆红素≤ 3 ULN）
6. 天冬氨酸氨基转移酶（AST）≤ 2.5 ULN（例外：肝转移患者的 AST ≤ 5 x ULN）。
7. 丙氨酸氨基转移酶（ALT）≤ 2.5 ULN（例外：肝转移患者的 ALT ≤ 5 x ULN）。
8. 患者在室内空气下基线脉搏血氧饱和度必须至少为 92%。此外，若主治研究者判定临床上适合进行肺功能检查（PFTs），则要求 DLCO ≥ 60%（必要时经贫血校正）。
9. 经 Echo 证实左心室短缩分数（LVSF）≥28% 或射血分数（LVEF）≥ 50%，或经扫描或心脏病专家记录的充分心室功能。
视网膜母细胞瘤排除标准：
1. 患有活动性乙型肝炎或活动性丙型肝炎的患者。
2. 感染 HIV 的患者。
3. 患有未控制的活动性感染的患者。
4. 患有原发性或获得性免疫缺陷疾病的患者。
5. 已知对 DMSO 过敏的患者。
6. 细胞输注或细胞采集时正在全身使用糖皮质激素或免疫抑制治疗，或经主治医生判断，在采集期间或输注后可能需要糖皮质激素治疗或免疫抑制的情况。在细胞采集以外的时间因疾病治疗使用糖皮质激素或在输注时使用是允许的。允许使用生理性替代剂量的氢化可的松或吸入性糖皮质激素。
7. 经研究者判断，会显著增加受试者风险的活动性医学疾病。
8. 患有充血性心力衰竭（按纽约心脏协会心功能分级 III 或 IV 级定义）、不稳定型心绞痛、严重未控制的心律失常、入组前 6 个月内发生过心肌梗死或有心肌炎病史的患者。
9. 入组前 30 天内接种过任何活疫苗的患者。
10. 怀孕或哺乳（泌乳）期的患者。
11. 知情同意时预期寿命 < 6 个月的患者。
12. 视网膜母细胞瘤队列 1（CNS 外疾病）：
1. 同时存在 CNS 疾病（他们可能符合视网膜母细胞瘤队列 2 的入组条件）
2. III期疾病（眼眶或淋巴结区域扩散，无其他血行转移）。
13. 视网膜母细胞瘤队列2（CNS疾病）：
1. 脑干或丘脑内或压迫脑干或丘脑的"巨大"病灶（直径>5 cm）。注意：仅接触脑干/丘脑而无压迫证据的肿瘤，和/或位于其他CNS部位的肿瘤，无最大尺寸标准。
2. 如果复发时有临床意义的颅内压升高证据，患者必须在入组时表现出改善。
Please note that effective August 2026, this study is no longer accruing neuroblastoma patients. The study remains open to accrual for retinoblastoma patients.
Neuroblastoma Inclusion Criteria:
1. Patients must be ≥ 1 year of age
2. Patients must have high-risk neuroblastoma according to COG risk classification at the time of study enrollment. Patients who were initially considered low- or intermediate-risk, but then reclassified as high-risk are also eligible.
3. Patients must have a previously histologically confirmed diagnosis of neuroblastoma:
1. That is recurrent/relapsed or refractory/persistent according to INRC AND
2. For which standard curative measures do not exist or are no longer effective.
3. patients at first relapse are eligible as no known curative therapies exist for relapsed high-risk neuroblastoma.
4. Patients must have evaluable or measurable disease at enrollment.
5. In addition, patient must have experienced at least one of the following:
a. New disease site documented on at least one of the following: i. 123I-meta-iodobenzylguanidine (MIBG) or 18F-mFBG (meta-fluorobenzylguanidine) scan; OR ii. CT/MRI; OR iii. FDG or Ga-68 Dotatate PET (in patients known to have MIBG non-avid tumor) and MRI findings consistent with tumor (i.e., bone lesions), OR iv. Biopsy confirmed neuroblastoma for any new or progressing lesion. b. Greater than 20% increase in a least one dimension of soft tissue mass documented by CT/MRI and a minimum absolute increase of 5 mm in longest dimension in existing lesion(s). Previously irradiated lesions may be included.
c. Bone marrow biopsy shows progressive disease according to the revised INRC d. Stable persistent disease, such that response at the completion of upfront therapy or salvage therapy is less than partial response AND has a biopsy of at least one site showing viable neuroblastoma.
e. Responding persistent disease, defined as at least a partial response to frontline therapy (i.e., at least a partial response to frontline therapy but still has residual disease by MIBG scan, CT/MRI, or bone marrow aspirations/biopsies). Patients in this category are required to have histologic confirmation of viable neuroblastoma from at least one residual site (tumor seen on routine bone marrow morphology is sufficient).
6. Patients must have a Lansky (\<16 years) or Karnofsky (≥ 16 years) score of ≥ 60
7. Patients must have adequate renal function defined as age-adjusted serum creatinine ≤1.5 ULN for age.
8. Total bilirubin ≤ 1.5 x ULN (exception: total bilirubin ≤ 3 ULN for patients with Gilbert's Disease)
9. Aspartate aminotransferase (AST) ≤ 2.5 ULN (exception: AST ≤ 5 x ULN for patients with liver metastases).
10. Alanine aminotransferase (ALT) ≤ 2.5 ULN (exception: ALT ≤ 5 x ULN for patients with liver metastases).
11. Patients must have a baseline pulse oximetry of at least 92% on room air. In addition, a DLCO ≥ 60% (corrected for anemia if necessary) is required if PFTs are clinically appropriate as determined by the treating investigator.
12. Left ventricular shortening fraction (LVSF) ≥28% or ejection fraction (LVEF) ≥ 50% confirmed by Echo, or adequate ventricular function documented by a scan or a cardiologist.
Neuroblastoma Exclusion Criteria:
1. Patients with active hepatitis B or active hepatitis C.
2. Patients with HIV infection.
3. Patients with uncontrolled active infection.
4. Patients with primary or acquired immunodeficiency disorder.
5. Patients with a known hypersensitivity to DMSO.
6. Concurrent use of systemic steroids or immunosuppression at the time of cell infusion or cell collection, or a condition, in the treating physician's opinion, that is likely to require steroid therapy or immunosuppression during collection or after infusion. Steroids for disease treatment at times other than cell collection or at the time of infusion are permitted. Use of physiologic replacement hydrocortisone or inhaled steroids is permitted as well.
7. Patients with actively progressing CNS metastases, including parenchymal or leptomeningeal involvement. (Note: CNS imaging at screening is only required if the there is a clinical indication of suspected CNS metastasis)
8. Active medical disorder that, in the opinion of the investigator, would substantially increase the risk of uncontrollable CRS and/or neurotoxicity.
9. Patients with congestive heart failure (as defined by New York Heart Association Functional Classification III or IV), unstable angina, serious uncontrolled cardiac arrhythmia, a myocardial infarction within 6 months prior to study entry or a history of myocarditis.
10. Patients who have received any live vaccines within 30 days prior to enrollment.
11. Patients who are pregnant or nursing (lactating).
12. Patients who have a life expectancy \< 6 months at time of consent.
Retinoblastoma Inclusion Criteria:
1. Patient age ≥ 6 months.
2. Patients must have metastatic retinoblastoma according to International
Retinoblastoma Staging System (IRSS) risk classification (4) at the time of study enrollment:
a. Retinoblastoma Cohort 1 (Extra-CNS metastasis) i. Stage IVa disease ii. Extra-CNS disease must be confirmed as retinoblastoma by histology (either at diagnosis or recurrence) iii. Measurable disease: Defined as \> 1cm2 or biopsy-proven bone marrow disease iv. Prior treatment: Recurrent or refractory disease following treatment with COG ARET0321-like or equivalent regimen as part of upfront or recurrent therapy b. Retinoblastoma Cohort 2 (CNS disease) i. Stage IVb disease ii. Histologic confirmation is not required iii. CNS disease defined as measurable disease \>1cm2, non-measurable, or CSF positivity alone c. Prior treatment: i. Stage IVb.1 and IVb.2: Recurrent after treatment with COG ARET0321-like or equivalent regimen as part of upfront or recurrent therapy i. Stage IVb.3: Prior treatment is not required (i.e., eligible at initial diagnosis or recurrence)
3. Patients must have a Lansky (\< 16 years) or Karnofsky (≥ 16 years) score of ≥ 60
4. Patients must have adequate renal function defined as age-adjusted serum creatinine ≤1.5 ULN .
5. Total bilirubin ≤ 1.5 x ULN (exception: total bilirubin ≤ 3 ULN for patients with Gilbert's Disease)
6. Aspartate aminotransferase (AST) ≤ 2.5 ULN (exception: AST ≤ 5 x ULN for patients with liver metastases).
7. Alanine aminotransferase (ALT) ≤ 2.5 ULN (exception: ALT ≤ 5 x ULN for patients with liver metastases).
8. Patients must have a baseline pulse oximetry of at least 92% on room air. In addition, a DLCO ≥ 60% (corrected for anemia if necessary) is required if PFTs are clinically appropriate as determined by the treating investigator.
9. Left ventricular shortening fraction (LVSF) ≥28% or ejection fraction (LVEF) ≥ 50% confirmed by Echo, or adequate ventricular function documented by a scan or a cardiologist.
Retinoblastoma Exclusion Criteria:
1. Patients with active hepatitis B or active hepatitis C.
2. Patients with HIV infection.
3. Patients with uncontrolled active infection.
4. Patients with primary or acquired immunodeficiency disorder.
5. Patients with a known hypersensitivity to DMSO.
6. Concurrent use of systemic steroids or immunosuppression at the time of cell infusion or cell collection, or a condition, in the treating physician's opinion, that is likely to require steroid therapy or immunosuppression during collection or after infusion. Steroids for disease treatment at times other than cell collection or at the time of infusion are permitted. Use of physiologic replacement hydrocortisone or inhaled steroids is permitted as well.
7. Active medical disorder that, in the opinion of the investigator, would substantially increase the risk to the subject.
8. Patients with congestive heart failure (as defined by New York Heart Association Functional Classification III or IV), unstable angina, serious uncontrolled cardiac arrhythmia, a myocardial infarction within 6 months prior to study entry or a history of myocarditis.
9. Patients who have received any live vaccines within 30 days prior to enrollment.
10. Patients who are pregnant or nursing (lactating).
11. Patients who have a life expectancy \< 6 months at time of consent.
12. Retinoblastoma Cohort 1 (Extra-CNS disease):
1. Concurrent CNS disease (they may be eligible for Retinoblastoma Cohort 2)
2. Stage III disease (orbital or lymph node regional extension without other hematogenous metastases).
13. Retinoblastoma Cohort 2 (CNS disease):
1. "Bulky" disease (\>5 cm in diameter) within or compressing the brainstem or thalamus. Note: Tumors touching the brainstem/thalamus without evidence of compression and/or tumors in other CNS locations do not have a maximal size criterion.
2. If evidence of clinically significant increased intracranial pressure at time of relapse, patient must demonstrate improvement by time of enrollment.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：Determine the Maximum Tolerated Dose of GPC2 CAR T cells · The Maximum Tolerated Dose of GPC2 CAR T cells will be determined by measuring the incidence of dose limiting toxicities following administration of the product. · 5 years；Frequency of Adverse Events Following GPC2 CAR T cell administration · Assess the frequency and severity of treatment related adverse events following administration of GPC2 CAR T cells. · 5 years
次要终点：Manufacturing Feasibility of GPC2 CAR T cells；Persistence of GPC2 CAR T cells；Preliminarily define the clinical activity of GPC2 CAR T in patients with relapsed or refractory neuroblastoma or metastatic retinoblastoma；Severity of Adverse Events Following GPC2 CAR T cell administration.
剂量递增组将采用标准3+3试验设计确定GPC2 CAR T细胞的最大耐受剂量。
如果剂量扩展组中至少有一个剂量被确定为安全，将额外入组患者至剂量扩展组，以初步评估对GPC2 CAR T细胞的缓解率，并进一步表征GPC2 CAR T细胞的安全性特征。
这是一项首次人体剂量递增试验，旨在确定对晚期神经母细胞瘤或视网膜母细胞瘤患者施用GPC2 CAR T细胞的安全性。
This is a first in human dose escalation trial to determine the safety of administering GPC2 CAR T cells in patients with advanced neuroblastoma or retinoblastoma.
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