肿瘤细胞治疗研究
英文原题：PHOX2B PC-CAR T Cells for Relapsed Neuroblastoma
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：进行中（不再招募）。计划入组 38 例。试验地点：美国 · 费城（共 1 个中心）。登记号：NCT07007117。
不限性别 · ≥ 1 Year
纳入标准：
1. 患者必须≥1岁
2. 患者必须通过HLA基因分型（在CHOP进行）证明至少表达以下一种HLA等位基因才有资格：
HLA-A*24:02, HLA-A*24:03, HLA-A*24:04, HLA-A*24:07, HLA-A*24:124, HLA-A*24:143, HLA-A*24:17, HLA-A*24:242, HLA-A*24:305, HLA-A*24:314, HLA-A*24:33, HLA-A*24:353, HLA-A*24:41, HLA-A*24:51, HLA-A*24:63, HLA-A*24:87, HLA-A*24:92, HLA-A*23:01, HLA-A*23:17, HLA-A*23:25, HLA-A*23:39,
3. 疾病状态 A. 患者在入组研究时必须根据COG风险分类患有高危神经母细胞瘤。最初被认为是低危或中危，但后来被重新分类为高危的患者也符合条件。
B. 患者必须先前有组织学确诊的神经母细胞瘤诊断。
C. 患者必须患有复发性/进展性、难治性或持续性神经母细胞瘤。
D. 患者必须患有不存在标准治愈措施或标准治愈措施不再有效的神经母细胞瘤。注：首次复发的患者符合条件，因为对于复发性高危神经母细胞瘤尚无已知的治愈性疗法。
E. 患者在入组时必须具有可评估或可测量的疾病，并且至少满足以下一项：
* 骨部位
a) MIBG avid肿瘤：
1. 患有复发性/进展性或难治性疾病的患者：
a. 至少1个MIBG avid骨部位。
2. 患有持续性疾病的患者：
1. 3个或更多MIBG avid部位（包括软组织和/或骨）。
2. 1个或2个MIBG avid部位（包括软组织和/或骨），且在入组时存在的至少一个MIBG avid部位经活检确认有神经母细胞瘤和/或节细胞神经母细胞瘤。
b) MIBG non-avid肿瘤：至少1个骨病变，且在入组前任何时间经活检确认有神经母细胞瘤和/或节细胞神经母细胞瘤，或FDG-PET摄取和MRI均与转移一致。
* 骨髓：骨髓中有任何数量的肿瘤细胞（包括神经母细胞、成熟和成熟中神经节细胞）。
* 软组织部位 a) 至少一个符合靶病变标准的软组织病变，定义如下： 1. 大小：病变可在至少一个维度上准确测量，最长直径≥10 mm，或对于离散淋巴结短轴≥15 mm。
2. 除大小外，病变需要满足以下标准之一：
a. MIBG avid肿瘤： i. 患有复发性/进展性或难治性疾病的患者：
1. 至少一个MIBG avid软组织部位。 ii. 患有持续性疾病的患者：
1. 3个或更多MIBG avid部位（包括软组织和/或骨）。
2. 1个或2个MIBG avid部位（包括软组织和/或骨），且在入组时存在的至少一个MIBG avid部位经活检确认有神经母细胞瘤和/或节细胞神经母细胞瘤。
b. MIBG 非亲合性肿瘤：入组时存在的软组织部位经活检证实为神经母细胞瘤和/或节细胞神经母细胞瘤（伴或不伴 FDG 摄取），或 FDG-PET 摄取和 MRI 均与转移一致。
b) 至少有一个软组织病灶不符合靶病灶的大小标准，但在入组前任何时间活检为神经母细胞瘤和/或节细胞神经母细胞瘤阳性，或存在于复发/进展或难治性疾病患者中且为 MIBG 亲合性。
4. 患者必须具有 Lansky（≤ 16 岁）或 Karnofsky（> 16 岁）评分 ≥ 60。
5. 患者必须具有足够的肾功能，定义为年龄校正的血清肌酐 ≤ 年龄对应的 1.5 ULN。
6. 肝功能如下：
a. 总胆红素 ≤ 1.5 x ULN（例外：Gilbert 病或肝转移患者总胆红素 ≤ 3 ULN）。
b. 丙氨酸氨基转移酶（ALT）≤ 3.0 ULN（例外：肝转移患者 ALT ≤ 5 x ULN）。
c. 天冬氨酸氨基转移酶（AST）≤ 3.0 ULN（例外：肝转移患者 ALT ≤ 5 x ULN）。
7. 肺功能如下：
a. 如果治疗研究者确定 PFTs 临床适用，患者需要在室内空气中的基线脉搏血氧饱和度至少为 92%，且 DLCO ≥ 60%（必要时针对贫血进行校正）。
8. 心功能如下：
a. 经 Echo 证实的左心室缩短分数（LVSF）≥ 28% 或射血分数（LVEF）≥ 50%，或由扫描或心脏病专家记录的足够心室功能。
9. 有生育潜力的患者（已达到月经初潮且未经历治疗相关卵巢早衰的患者）必须在筛选时进行血清妊娠试验且结果为阴性。建议所有有生殖潜力的患者在末次输注 PHOX2B PC-CAR T 细胞后至少 1 年内使用至少一种医学上可接受的避孕方式。研究者应就预防妊娠的重要性以及意外妊娠的后果向患者提供咨询。
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. 患有活动性 HIV 感染的患者（正在接受抗逆转录病毒治疗且 HIV 病毒载量检测不到的患者符合条件）。
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. 在细胞输注或细胞采集时同时使用全身性类固醇或免疫抑制，或治疗医生认为在采集期间或输注后可能需要类固醇治疗或免疫抑制的病症。在细胞采集以外的时间或输注时用于疾病治疗的类固醇是允许的。使用生理替代性氢化可的松或吸入性类固醇也是允许的。
6. 有活动性进展的CNS转移的患者，包括实质或软脑膜受累。（注：仅当临床怀疑CNS转移时，才需要在筛选时进行CNS影像学检查）
7. 研究者认为会显著增加不可控CRS和/或神经毒性风险的活动的医学疾病。
8. 入组前30天内接种过任何活疫苗的患者。
9. 妊娠或哺乳（泌乳）期患者。
Inclusion Criteria:
1. Patients must be ≥ 1 years of age
2. Patients must demonstrate expression of at least one of the following HLA alleles by HLA genotyping (conducted at CHOP) to be eligible:
HLA-A\*24:02, HLA-A\*24:03, HLA-A\*24:04, HLA-A\*24:07, HLA-A\*24:124, HLA-A\*24:143, HLA-A\*24:17, HLA-A\*24:242, HLA-A\*24:305, HLA-A\*24:314, HLA-A\*24:33, HLA-A\*24:353, HLA-A\*24:41, HLA-A\*24:51, HLA-A\*24:63, HLA-A\*24:87, HLA-A\*24:92, HLA-A\*23:01, HLA-A\*23:17, HLA-A\*23:25, HLA-A\*23:39,
3. Disease Status A. 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.
B. Patients must have a previously histologically confirmed diagnosis of neuroblastoma.
C. Patients must have recurrent/progressive, refractory or persistent neuroblastoma.
D. Patients must have neuroblastoma for which standard curative measures do not exist or are no longer effective. Note: Patients at first relapse are eligible as no known curative therapies exist for relapsed high-risk neuroblastoma.
E. Patients must have evaluable or measurable disease at enrollment and at least one of the following:
* Bone Sites
a) MIBG avid tumors:
1. Patients with recurrent/progressive or refractory disease:
a. At least 1 MIBG avid bone site.
2. Patients with persistent disease:
1. 3 or more MIBG avid sites (including soft tissue and/or bone).
2. 1 or 2 MIBG avid sites (including soft tissue and/or bone) with biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma in at least one MIBG avid site present at the time of enrollment.
b) MIBG non-avid tumors: at least 1 bone lesion with either biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma at any time prior to enrollment OR both FDG-PET uptake AND MRI consistent with metastasis.
* Bone marrow: Any amount of tumor cells in the bone marrow (including neuroblasts, mature and maturing ganglion cells).
* Soft tissue site(s) a) At least one soft tissue lesion that meets criteria for a target lesion as defined by: 1. Size: Lesion can be accurately measured in at least one dimension with a longest diameter ≥ 10 mm or for discrete lymph nodes ≥ 15 mm short axis.
2\. In addition to size, a lesion needs to meet ONE of the following criteria:
a. MIBG avid tumors: i. Patients with recurrent/progressive or refractory disease:
1\. At least one MIBG avid soft tissue site. ii. Patients with persistent disease:
1. 3 or more MIBG avid sites (including soft tissue and/or bone).
2. 1 or 2 MIBG avid sites (including soft tissue and/or bone), with biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma in at least one MIBG avid site present at the time of enrollment.
b. MIBG non-avid tumors: biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma (with or without FDG uptake) in a soft tissue site present at time of enrollment OR both FDG-PET uptake AND MRI consistent with metastasis.
b) At least one soft tissue lesion that does not meet size criteria for a target lesion but had a biopsy positive for neuroblastoma and/or ganglioneuroblastoma at any time prior to enrollment OR is in a patient with recurrent/progressive or refractory disease and is MIBG avid.
4\. Patients must have a Lansky (≤ 16 years) or Karnofsky (\> 16 years) score of ≥ 60.
5\. Patients must have adequate renal function defined as age-adjusted serum creatinine ≤1.5 ULN for age.
6\. Liver Function as follows:
a. Total bilirubin ≤ 1.5 x ULN (exception: total bilirubin ≤ 3 ULN for patients with Gilbert's Disease or liver metastases).
b. Alanine aminotransferase (ALT) ≤ 3.0 ULN (exception: ALT ≤ 5 x ULN for patients with liver metastases).
c. Aspartate aminotransferase (AST) ≤ 3.0 ULN (exception: ALT ≤ 5 x ULN for patients with liver metastases).
7\. Pulmonary Function as follows:
a. Patients need to have a baseline pulse oximetry of at least 92% on room air and DLCO ≥ 60% (corrected for anemia if necessary) if PFTs are clinically appropriate as determined by the treating investigator.
8\. Cardiac Function as follows:
a. 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.
9\. Patients of child-bearing potential ( patients who have reached menarche and have not experienced treatment-related premature ovarian failure) must have a negative serum pregnancy test performed at the time of screening It is recommended that all patients of reproductive potential use at least one medically acceptable form of contraception for at least 1 year after their last infusion of PHOX2B PC-CAR T cells. Investigators shall counsel patients on the importance of pregnancy prevention and the implications of an unexpected pregnancy.
Exclusion Criteria:
1. Patients with active hepatitis B or active hepatitis C.
2. Patients with active HIV infection (patients undergoing anti-retroviral therapy with undetectable HIV viral load are eligible).
3. Patients with uncontrolled active infection.
4. Patients with primary or acquired immunodeficiency disorder.
5. 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.
6. Patients with actively progressing CNS metastases, including parenchymal or leptomeningeal involvement. (Note: CNS imaging at screening is only required if there is a clinical indication of suspected CNS metastasis)
7. Active medical disorder that, in the opinion of the investigator, would substantially increase the risk of uncontrollable CRS and/or neurotoxicity.
8. Patients who have received any live vaccines within 30 days prior to enrollment.
9. Pregnant or nursing (lactating) patients.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 PHOX2B PC-CAR T Cells · The Maximum Tolerated Dose of PHOX2B-PC 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 PHOX2B PC-CAR T cell administration · Assess the frequency and severity of treatment related adverse events following administration of PHOX2B PC-CAR T cells. · 5 years
次要终点：Manufacturing Feasibility of PHOX2B PC-CAR T cells；Persistence of PHOX2B PC-CAR T cells；Preliminarily define the clinical activity of PHOX2B PC-CAR T cells in patients with relapsed or refractory neuroblastoma；Severity of Adverse Events Following Repeated dosing of PHOX2B PC-CAR T Cells
剂量递增组将采用标准3+3试验设计确定PHOX2B PC-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是安全的，将招募更多患者进入剂量扩展组，以初步评估对PHOX2B-PC CAR T细胞的缓解率，并进一步描述PHOX2B-PC CAR T细胞的安全性特征
这是一项首次人体剂量递增试验，旨在确定对晚期高危神经母细胞瘤患者施用PHOX2B PC-CAR T细胞的安全性。
This is a first in human dose escalation trial to determine the safety of administering PHOX2B PC-CAR T cells in patients with advanced, high-risk neuroblastoma.
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