肿瘤细胞治疗研究
英文原题：Anti-EGFRvIII synNotch Receptor Induced Anti-EphA2/IL-13Ralpha2 CAR (E-SYNC) T Cells
这是一项 I 期注册临床试验，评估 T 细胞治疗胶质母细胞瘤的安全性、可行性及初步疗效。当前状态：招募中。计划入组 20 例。试验地点：美国 · 旧金山（共 1 个中心）。登记号：NCT06186401。
不限性别 · ≥ 18 Years
纳入标准：
* 队列1的纳入标准：
1. 年龄 >= 18岁。
2. Karnofsky体能状态（KPS）评分 >=70。
3. 所有参与者必须具有足够的器官功能，定义如下：
1. 外周血绝对中性粒细胞计数 >=1000/mm^3。
2. 血小板计数 >=100,000/mm^3（不依赖输血，定义为入组前至少7天未接受血小板输注）。
3. 绝对淋巴细胞计数（ALC）>= 300/μL和/或分化簇3（CD3）计数 >=150/μL。
4. 肌酐清除率或放射性同位素肾小球滤过率 >= 50 mL/min/1.73m^2。
5. 总胆红素 <= 1.5 x ULN，Gilbert综合征除外，以及
6. 丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）<= 3x 正常上限（ULN）。
7. 超声心动图或多门控采集扫描（MUGA）显示左心室射血分数（LVEF）>= 50%。
8. 足够的肺功能，定义为静息时无呼吸困难证据，且呼吸室内空气时脉搏血氧饱和度 > 92%。
4. 病理学标准：最近一次手术的EGFRvIII+ GBM，由经临床实验室改进修正案（CLIA）认证的实验室使用下一代测序panel确认。
5. MGMT启动子必须为未甲基化或甲基化指数 < 3。
6. 必须已完成至少标准治疗（SOC）外照射放疗（EBRT）作为初始治疗。
7. 预计参与者能够在完成EBRT后12周内完成E-SYNC T细胞输注。
8. 所有参与者在白细胞分离术前必须已停用全身性类固醇3天或以上。
9. 必须愿意为单采（以及必要时的组织筛选）和研究治疗提供自愿知情同意。
注：队列2有两套资格标准。组织筛选：定义组织筛选的资格并确定H-score。
研究入组：定义研究入组和E-SYNC T细胞生产/治疗的资格。
* 队列2组织筛选的纳入标准：
1. 年龄 >=18岁。
2. 病理学标准：最近一次手术的EGFRvIII+ GBM，由经临床实验室改进修正案（CLIA）认证的实验室使用下一代测序panel确认。
* 队列2研究入组的纳入标准
1. Karnofsky体能状态量表（KPS）评分 >=70。
2. 已接受至少标准治疗外照射放疗（SOC EBRT）作为初始治疗，伴或不伴同步替莫唑胺（TMZ），且在研究入组前 ≥23天完成最后一剂TMZ）。注：患者可能已开始辅助TMZ +/- TTFields。
3. 病理学标准：最近一次手术的EGFRvIII+ GBM，根据中心审查定义为EGFRvIII H-score ≥ 150。
4. 可手术切除，预计能够切除至少500 mg肿瘤组织，由参与者的神经外科医生确认。
5. 有生育潜力的参与者同意在研究期间及末次研究干预后至少6个月内使用可靠的避孕措施和双重屏障避孕法，包括在此期间禁止捐献精子。
6. 有生育潜力的女性在接受研究干预前必须血清β-人绒毛膜促性腺激素（HCG）妊娠试验阴性。
7. 所有参与者必须具有足够的器官功能。
a. 足够的骨髓功能定义为：i. 外周血绝对中性粒细胞计数 ≥ 1000/mm3 且 ii. 血小板计数 ≥ 100,000/mm3（非输血依赖，定义为入组前至少7天未接受血小板输注）且 iii. 绝对淋巴细胞计数（ALC）≥ 300/µL 和/或 CD3 计数 ≥ 150/µL b. 足够的肾功能定义为：i. 肌酐清除率或放射性同位素肾小球滤过率 ≥ 50 mL/min/1.73m2 c. 足够的肝功能定义为：i. 总胆红素 ≤ 1.5 x 正常上限（ULN），吉尔伯特综合征除外，且 ii. 丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）≤ 3 x ULN d. 凝血试验凝血酶原时间（PT）和部分凝血活酶时间（PTT）必须在正常范围内，除非参与者因既往静脉血栓接受治疗性抗凝。e. 足够的肺功能，定义为静息时无呼吸困难证据，且呼吸室内空气时脉搏血氧饱和度 > 92%。
f. 足够的心脏功能，在过去12个月内确认，定义为：i. 超声心动图或多门控采集扫描（MUGA）左心室射血分数（LVEF）≥ 40%
8. 必须愿意为研究干预提供自愿知情同意。
排除标准：
* 队列1的排除标准
1. 在研究登记日期前 <= 4周内接受过任何针对GBM的研究性药物和化疗的参与者。例外情况包括：距末次替莫唑胺（TMZ）或放疗给药必须 >=23天，距末次亚硝基脲给药必须 >= 6周。
2. 怀孕或哺乳的有生育潜力的女性参与者。有生育潜力的女性研究参与者必须血清妊娠试验阴性作为资格确认的一部分。
3. 已知酒精或非法药物成瘾。
4. 既往接受过任何表皮生长因子受体（EGFR）靶向治疗。
5. 有软脑膜播散的参与者。
6. 患有已知影响免疫系统的疾病的参与者，如人类免疫缺陷病毒（HIV）或需要全身细胞毒性或免疫抑制治疗的自身免疫性疾病。目前使用非全身性类固醇（如吸入、鼻内、眼部、局部）的参与者不排除在研究之外。
7. 血清学状态反映活动性乙型或丙型肝炎感染的参与者。乙型肝炎表面抗原阳性（HBsAg+）的参与者将被排除。乙型肝炎核心抗体或丙型肝炎抗体阳性的参与者必须在入组前聚合酶链反应（PCR）阴性。PCR阳性的参与者将被排除。
8. 曾接受过实体器官或骨髓移植的参与者。
9. 未控制的并发疾病，包括但不限于持续或活动性感染、有症状的充血性心力衰竭、不稳定型心绞痛、心律失常、当前正在接受积极治疗或预计在未来一年内接受治疗的第二种癌症，或会限制遵守研究要求的精神疾病/社会状况。
10. 无法返回进行随访访视或无法获得评估治疗毒性所需的随访研究的参与者。
* 队列2组织筛选的排除标准
1. 如果临床认为合适，参与者不愿意接受另一次手术。
* 队列2研究入组的排除标准
1. 既往接受过任何EGFR靶向治疗
2. 在研究注册日期前≤4周内接受过任何研究性药物、化疗或针对GBM的生物治疗的参与者。例外情况包括：研究入组前≤23天未使用TMZ或≤6周未使用亚硝基脲。TTFields在研究入组前无需洗脱期，但必须在开始淋巴清除（LD）化疗前至少1周停止使用该设备。
3. 影像学或临床证据显示未控制的肿瘤占位效应的参与者；占位效应的评估将由研究者进行。
4. 有软脑膜播散的参与者。
5. 患有已知影响其免疫系统的疾病的参与者，如HIV或需要全身性细胞毒性或免疫抑制治疗的自身免疫性疾病。
目前正在使用吸入、鼻内、眼部、局部或其他非口服或非静脉注射类固醇的参与者不一定被排除在研究之外。
6. 血清学状态反映活动性乙型或丙型肝炎感染的参与者。乙型肝炎表面抗原阳性（HBsAg+）的参与者将被排除。乙型肝炎核心抗体或丙型肝炎抗体阳性的参与者必须在入组前聚合酶链反应（PCR）阴性。PCR阳性的参与者将被排除。
7. 曾接受过实体器官或骨髓移植的参与者。
8. 怀孕或哺乳的女性参与者。
9. 未控制的并发疾病，包括但不限于持续或活动性感染、有症状的充血性心力衰竭、不稳定型心绞痛、心律失常、目前正在接受积极治疗或预计在未来一年内接受治疗的第二癌症，或会限制遵守研究要求的精神疾病/社会状况。
10. 无法返回进行随访或无法获得评估治疗毒性所需的随访研究的参与者。
Inclusion Criteria:
* Inclusion Criteria for Cohort 1:
1. Age \>= 18 years.
2. Karnofsky performance status (KPS) score of \>=70.
3. All participants must have adequate organ function defined as:
1. Peripheral absolute neutrophil count \>=1000/mm\^3.
2. Platelet count \>=100,000/mm\^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment).
3. Absolute lymphocyte count (ALC) \>= 300/μL and/or Cluster of differentiation 3 (CD3) count of \>=150/μL.
4. Creatinine clearance or radioisotope glomerular filtration rate \>= 50 mL/min/1.73m\^2.
5. Total Bilirubin \<= 1.5 x ULN except for Gilbert's syndrome and
6. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<= 3x upper limit of normal (ULN).
7. Left ventricular ejection fraction (LVEF) \>= 50% by echocardiogram or multi-gated acquisition scanning (MUGA).
8. Adequate pulmonary function, defined as no evidence of dyspnea at rest and pulse oximetry \> 92% while breathing room air.
4. Pathological criteria: EGFRvIII+ GBM from most recent surgery, confirmed by a Clinical Laboratory Improvement Amendments (CLIA)-certified lab using a next-generation sequencing panel.
5. MGMT promoter must be unmethylated or with a methylation index \< 3.
6. Must have completed at least standard of care (SOC) external beam radiotherapy (EBRT) as initial therapy.
7. Participants must be anticipated to be able to complete E-SYNC T cell infusion within 12 weeks after completion of EBRT.
8. All participants must be off systemic steroids for 3 days or more prior to leukapheresis.
9. Must be willing to provide voluntary informed consent for apheresis (and tissue screening if needed) and for study treatment.
NOTE: There are two sets of eligibility criteria for Cohort 2. Tissue Screening: Defines eligibility for tissue screening and to determine H-score.
Study Enrollment: Defines eligibility for study enrollment and E-SYNC T cell manufacturing/treatment.
* Inclusion Criteria for Tissue Screening Cohort 2:
1. Age \>=18 years.
2. Pathological criteria: EGFRvIII+ GBM from most recent surgery, confirmed by a Clinical Laboratory Improvement Amendments (CLIA)-certified lab using a next-generation sequencing panel.
* Inclusion Criteria for Study Enrollment for Cohort 2
1. Karnofsky Performance Scale (KPS) score \>=70.
2. received at least standard of care external beam radiotherapy (SOC EBRT) as initial therapy, with or without concurrent temozolomide (TMZ), and completed the last dose of TMZ ≥23 days prior to study enrollment). Note: patients may have initiated adjuvant TMZ +/- TTFields.
3. Pathological criteria: EGFRvIII+ GBM from most recent surgery, as defined by an EGFRvIII H-score of ≥ 150 based on central review.
4. Is surgically amenable, with expectation for ability to resect at least 500 mg of tumor tissue confirmed by participant's neurosurgeon.
5. Participants with reproductive potential agree to use reliable and double barrier method of contraception during the study and for at least 6 months after the last study intervention, including refraining from donating sperm during this period.
6. Females of childbearing potential must have a negative serum beta-human chorionic gonadotropin (HCG) pregnancy test prior to receiving study interventions.
7. All participants must have adequate organ function.
a. Adequate bone marrow function is defined as: i. Peripheral absolute neutrophil account ≥ 1000/mm3 and ii. Platelet count ≥ 100,000/mm3 (transfusion dependent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) and iii. Absolute lymphocyte count (ALC) ≥ 300/µL and/or CD3 count of ≥ 150/µL b. Adequate renal function is defined as: i. Creatinine clearance or radioisotope glomerular filtration rate ≥ 50 mL/min/1.73m2 c. Adequate liver function is defined as: i. Total Bilirubin ≤ 1.5 x upper limit of normal (ULN) except for Gilbert's syndrome and ii. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN d. Coagulation tests prothrombin time (PT) and partial thromboplastin time (PTT) have to be within normal limits, unless the participant has been therapeutically anti-coagulated for previous venous thrombosis. e. Adequate pulmonary function, defined as no evidence of dyspnea at rest and pulse oximetry \> 92% while breathing room air.
f. Adequate cardiac function, confirmed within the last 12 months, defined as: i. Left ventricular ejection fraction (LVEF) ≥ 40% by echocardiogram or multi-gated acquisition scanning (MUGA)
8. Must be willing to provide voluntary informed consent for study intervention.
Exclusion Criteria:
* Exclusion Criteria for Cohort 1
1. Participant who has been treated with any investigational agents and chemotherapy targeting GBM \<= 4 weeks prior to date of study registration. Exceptions to this include: must be \>=23 days from last dose of temozolomide (TMZ) or radiotherapy, mush be \>= 6 weeks from last dose of nitrosourea.
2. Female participants of reproductive potential who are pregnant or lactating. Female study participants of reproductive potential must have a negative serum pregnancy test as part of eligibility confirmation.
3. Known addiction to alcohol or illicit drugs.
4. Prior treatment with any Epithelial Growth Factor Receptor (EGFR)-targeting therapy.
5. Participants with leptomeningeal dissemination.
6. Participants with a known disorder that affects their immune system, such as human immunodeficiency virus (HIV) or an autoimmune disorder requiring systemic cytotoxic or immunosuppressive therapy. Participants who are currently using non-systemic steroids (e.g., inhaled, intranasal, ocular, topical) are not excluded from the study.
7. Participants with serologic status reflecting active hepatitis B or C infection. Participants that are positive for hepatitis B surface antigen (HBsAg+) will be excluded. Participants that are positive for hepatitis B core antibody or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. PCR positive participants will be excluded.
8. Participants who have received prior solid organ or bone marrow transplantation.
9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, second cancer currently receiving active treatment or anticipated to receive treatment within the next year, or psychiatric illness/social situations that would limit compliance with study requirements.
10. Participants who are unable to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy.
* Exclusion Criteria for Tissue Screening for Cohort 2
1\. Participant is unwilling to undergo another surgery if felt clinically appropriate.
* Exclusion Criteria for Study Enrollment for Cohort 2
1. Prior treatment with any EGFR-targeting therapy
2. Participant who has been treated with any investigational agents, chemotherapy, or biological therapy targeting GBM \<= 4 weeks prior to date of study registration. Exceptions to this include: no TMZ \<= 23 days or nitrosourea \<= 6 weeks prior to study enrollment. There is no washout prior to study enrollment for TTFields, but use of the device must be stopped at least 1 week prior to initiation of lymphodepleting (LD) chemotherapy.
3. Participants with imaging or clinical evidence of uncontrolled tumor mass effect; the assessment of mass effect will be made by the Investigators.
4. Participants with leptomeningeal dissemination.
5. Participants with a known disorder that affects their immune system, such as HIV or an autoimmune disorder requiring systemic cytotoxic or immunosuppressive therapy.
Participants who are currently using inhaled, intranasal, ocular, topical, or other non-oral or non-IV steroids are not necessarily excluded from the study.
6. Participants with serologic status reflecting active hepatitis B or C infection. Participants that are positive for hepatitis B surface antigen (HBsAg+) will be excluded. Participants that are positive for hepatitis B core antibody or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. PCR positive participants will be excluded.
7. Participants who have received prior solid organ or bone marrow transplantation.
8. Female participants who are pregnant or breast-feeding.
9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, second cancer currently receiving active treatment or anticipated to receive treatment within the next year, or psychiatric illness/social situations that would limit compliance with study requirements.
10. Participants who are unable to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy.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：Proportion of participants reporting treatment-emergent adverse events · Treatment-emergent adverse events will be graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 · Up to 96 weeks
次要终点：Percentage of participants who successfully receive E-SYNC T cells；The percentage of primed E-SYNC T (Cohort 2 only) cells in TIL versus PBMC will be evaluated
新诊断的EGFRvIII+ GBM且MGMT启动子未甲基化的参与者将在完成非干预性标准放疗至少2周后接受白细胞分离术以制造E-SYNC T细胞。参与者在第-5、-4和-3天接受环磷酰胺IV和氟达拉滨IV，然后在第0天接受E-SYNC T细胞IV。参与者将接受单次输注药品（DP）（5 x 10^7 CAR+ T细胞），并监测安全性、外周血中DP的存在及可能的synNotch > CAR-T priming。
如果起始剂量队列中没有剂量限制性毒性，新诊断的EGFRvIII+ GBM且MGMT启动子未甲基化的参与者将在完成非干预性标准放疗至少2周后接受白细胞分离术以制造E-SYNC T细胞。参与者在第-5、-4和-3天接受环磷酰胺IV和氟达拉滨IV，然后在第0天接受E-SYNC T细胞IV。参与者将接受单次输注药品（DP）（1.5 x 10^8 CAR+ T细胞），并监测安全性、外周血中DP的存在及可能的synNotch > CAR-T priming。
EGFRvIII+胶质母细胞瘤且有适合手术的残留疾病的参与者将通过数字图像分析初始手术样本的免疫组织化学（IHC）切片评估EGFRvIII H-score，反映染色范围和强度。H-score ≥150且接受过初始肿瘤切除、完成非研究性标准放疗并符合资格标准的参与者将接受白细胞分离术，以根据队列1结果在最大耐受或推荐剂量下制造E-SYNC T细胞。参与者将接受淋巴细胞清除预处理，然后在第0天单次输注药品（DP）。血小板恢复后，参与者将在DP输注约2周后住院接受非研究性手术切除。参与者将监测安全性、DP synNotch > CAR-T priming以及E-SYNC T细胞的抗肿瘤反应。
该I期试验测试在淋巴细胞清除性化疗后使用E-SYNC嵌合抗原受体（CAR）T细胞治疗EGFRvIII阳性（+）胶质母细胞瘤患者的安全性、副作用和最佳剂量。嵌合抗原受体（CAR）T细胞疗法是一种治疗方法，其中患者的T细胞（一种免疫系统细胞）在实验室中被改变，使CAR T细胞能够攻击癌细胞。T细胞取自患者的血液。然后，在实验室中将一种能与患者癌细胞上特定蛋白质结合的特殊受体的基因添加到T细胞中。这种特殊受体称为嵌合抗原受体。大量CAR T细胞在实验室中培养，并通过输注给予患者以治疗某些癌症。在使用CAR T细胞治疗前，使用环磷酰胺和氟达拉滨进行淋巴细胞清除性化疗可能会使CAR T细胞更有效。
This phase I trial tests the safety, side effects, and best dose of E-SYNC chimeric antigen receptor (CAR) T cells after lymphodepleting chemotherapy in treating patients with EGFRvIII positive (+) glioblastoma. Chimeric antigen receptor (CAR) T-cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so the CAR T cells will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Lymphodepleting chemotherapy with cyclophosphamide and fludarabine before treatment with CAR T cells may make the CAR T cells more effective.
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