肿瘤细胞治疗研究
英文原题：C7R-GD2.CAR T Cells for Patients With GD2-expressing Brain Tumors (GAIL-B)
这是一项 I 期注册临床试验，评估 GD2T 细胞治疗胶质瘤的安全性、可行性及初步疗效。当前状态：招募中。计划入组 56 例。试验地点：美国 · 休斯顿（共 1 个中心）。登记号：NCT04099797。
不限性别 · ≥ 12 Months 且 ≤ 25 Years
采集阶段纳入标准： • 队列1：组织学确诊且GD2阳性的新诊断弥漫中线胶质瘤/高级别胶质瘤（包括脑桥），若组织不足以做GD2免疫组化，可确认H3K27改变；“新诊断”指尚无影像学进展/复发。或组织学确诊、GD2阳性的复发/难治/进展性弥漫中线胶质瘤/高级别胶质瘤（脑桥除外），组织不足时可确认H3K27改变；或GD2阳性的复发/难治/进展性高级别CNS肿瘤，如髓母细胞瘤、CNS胚胎性肿瘤、非典型畸胎样/横纹肌样肿瘤（AT/RT）、室管膜肿瘤、弥漫性胶质瘤或神经元-胶质混合肿瘤。队列2：GD2阳性的复发/难治/进展性脑桥高级别胶质瘤。 • 入组时肿瘤最大径<5 cm。放疗后4–8周MRI如任一径线增大≤25%，仍可入组；增大>25%者可于4–6周后复查，若较放疗前增大≤25%则可入组；肿瘤5–5.5 cm但已手术减瘤者可入组。MRI至少两个维度存在可测量病灶。 • 年龄12个月至25岁；输注时预计Karnofsky/Lansky评分≥50（队列2≥60）。 采集阶段排除标准： • 妊娠或哺乳；研究者认为研究药物不符合患者最佳利益的其他风险因素。 治疗阶段纳入标准： • 符合相应队列的组织学/分子诊断及GD2表达要求：队列1为新诊断或复发/难治/进展的GD2阳性DMG/HGG（脑桥病变按登记标准）或GD2阳性高级别CNS肿瘤；队列2为GD2阳性复发/难治/进展性脑桥H3K27改变DMG/HGG。肿瘤大小及MRI可测量标准同采集阶段。 • 已置入或计划置入中心静脉导管（PICC等）及Ommaya储液囊或脑室腹腔分流装置；未包含淋巴清除的周期可不要求中心静脉导管。年龄12个月至25岁；Karnofsky/Lansky≥50（队列2≥60）。 • 研究药物给药前至少4周完成标准放疗；如为放射性坏死接受bevacizumab，须在研究药物给药前至少4周完成。入组前7天神经系统检查稳定；激素剂量稳定或递减，研究治疗输注前7天内地塞米松≤0.1 mg/kg/日。 • 器官功能：ANC>1,000/μL；血小板>100,000/μL；总胆红素<ULN的1.5倍；ALT/AST<ULN的5倍；血清肌酐或肾功能指标≤年龄ULN的2倍。 治疗阶段排除标准： • 研究药物给药前≤42天接受其他免疫治疗；淋巴清除前14天内接受集落刺激因子；同时接受其他抗癌治疗（既往抗癌治疗后须至少间隔3个半衰期）。妊娠或哺乳。研究者认为会使研究药物不符合患者最佳利益的其他风险因素。
Procurement Inclusion Criteria:
Cohort 1:
1. Histologically confirmed, GD2-expressing newly diagnosed DMG/HGG (including pontine) or confirmation of H3K27 alteration if sufficient tissue for GD2 staining by IHC is not available. Newly diagnosed is defined as prior to radiographic progression or recurrence.
OR
Histologically confirmed, GD2-expressing recurrent, refractory, or progressive DMG/HGG (except pontine) or confirmation of positive H3K27 alteration if sufficient tissue for GD2 staining by IHC is not available.
OR
Recurrent, refractory, or progressive high-grade CNS tumor with confirmed GD2-expression. Examples include: medulloblastoma "CNS embryonal tumors, AT/RT, ependymal tumors, diffuse gliomas or glioneuronal tumors.
Cohort 2:
Recurrent, refractory, or progressive pontine HGG with confirmed GD2-expression or H3K27-altered DMG
2. Tumors less than 5 cm in maximum dimension at enrollment
1. Tumors with ≤25% increase in size (on any dimension) on MRI 4-8 weeks post-radiotherapy remain eligible for study
2. Tumors with \>25% increase in size on post-radiation imaging may be reassessed with repeat MRI in 4-6 weeks, and are eligible if tumor size is subsequently ≤ 25% increased compared with pre-irradiation MRI.
3. Tumors with sizes between 5 and 5.5 cm are eligible if the tumor was surgically debulked
3. Measurable disease on at least 2 dimensions on MRI
4. Age 12 months to 25 years
5. Functional score (Karnofsky/Lansky) ≥ 50 expected at infusion (≥60 for cohort 2)
Procurement Exclusion Criteria:
1. Patients who are pregnant or breast feeding
2. Any patient with other risk factors for whom administration of investigational agent is deemed not in the patient's best interest, in the opinion of the investigator.
Treatment Inclusion Criteria
Cohort 1:
1. Histologically confirmed, GD2-expressing newly diagnosed DMG/HGG (including pontine) or confirmation of H3K27 alteration if sufficient tissue for GD2 staining by IHC is not available. Newly diagnosed is defined as prior to radiographic progression or recurrence.
OR
Histologically confirmed, GD2-expressing recurrent, refractory, or progressive DMG/HGG (except pontine) or confirmation of positive H3K27 alteration if sufficient tissue for GD2 staining by IHC is not available.
OR
Recurrent, refractory, or progressive high -grade CNS tumor with confirmed GD2-expression. Examples include: medulloblastoma, CNS embryonal tumors, AT/RT, ependymal tumors, diffuse gliomas, or glioneuronal tumors.
Cohort 2:
Recurrent, refractory, or progressive pontine H3K27-altered for DMG or HGG with confirmed GD2-expression.
2. Tumors less than 5 cm in maximum dimension at enrollment
1. Tumors with ≤25% increase in size (on any dimension) on MRI 4-8 weeks post-radiotherapy remain eligible for study
2. Tumors with \>25% increase in size on post-radiation imaging may be reassessed with repeat MRI in 4-6 weeks, and are eligible if tumor size is subsequently ≤ 25% increased compared pre-irradiation MRI
3. Tumors with sizes between 5 and 5.5 cm are eligible if the tumor was surgically debulked
3. Measurable disease on at least 2 dimensions on MRI
4. Central line (PICC or other) and Ommaya reservoir or VP shunt in place or planned to be placed. Central line/PICC may be omitted for cycles that do not include lymphodepletion
5. Age 12 months to 25 years
6. Functional score (Karnofsky/Lansky) ≥ 50 (≥60 for cohort 2)
7. Patients must have completed standard of care radiation therapy at least 4 weeks prior to administration of investigational agent. If bevacizumab was administered for management of radiation necrosis, therapy must be completed at least 4 weeks prior to administration of investigational agent.
8. Stable neurologic exam for 7 days prior to enrollment
9. Stable or decreasing dose of steroids (max. allowable dose of dexamethasone is 0.1 mg/kg/day over the past 7 days prior to infusion of investigational therapy)
10. Organ function:
1. ANC \> 1000 cells/ul
2. Platelet count \> 100,000 cells/ul
3. Total bilirubin \< 1.5x ULN
4. ALT and AST \< 5x ULN
5. Serum creatinine or kidney within 2x ULN for age
Treatment Exclusion Criteria
1. Patients who received any other forms of immunotherapy ≤ 42 days before administration of investigational agent
2. Patients who received colony-stimulating factors within 14 days prior to administration of lymphodepletion
3. Patients receiving any concurrent anti-cancer therapy (treatment must occur at least three half-lives following prior anti-cancer therapy)
4. Patients who are pregnant or breast feeding
5. Any patient with other risk factors for whom administration of investigational agent is deemed not in the patient's best interest, in the opinion of the investigator.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 toxicity (DLT) rate · DLT rate is defined as the proportion of subjects with DLT evaluated as per the NCI CTCAE v5.0 with the exception of CRS and neurological toxicities that are related to T cell infusions. · 4 weeks post T cell infusion
次要终点：Response rate according to standard criteria
既往方案阶段确定了自体C7R-GD2 CAR-T细胞静脉输注剂量，标准静脉剂量为20×10⁶个细胞/m²并联合淋巴清除化疗。本阶段确定经Ommaya储液囊或可调压脑室腹腔分流装置脑室内输注的安全剂量。
既往方案阶段确定自体C7R-GD2 CAR-T细胞静脉输注剂量，标准静脉剂量为20×10⁶个细胞/m²并联合淋巴清除化疗。本研究第2–24周期经Ommaya储液囊或可调压脑室腹腔分流装置进行脑室内输注，确定安全剂量。
研究包括两个队列：队列1用于弥漫中线胶质瘤、弥漫性内生性脑桥胶质瘤、髓母细胞瘤或其他表达GD2的罕见高级别胶质瘤；队列2用于表达GD2的进展性弥漫性内生性脑桥胶质瘤。患者接受自体GD2特异性CAR-T细胞。研究者在GD2 CAR-T中加入C7R基因，为T细胞提供持续细胞因子信号，可能延长其存活；淋巴清除化疗可促进CAR-T扩增和持续。此前已确定安全静脉剂量，本阶段在静脉输注基础上探索经Ommaya储液囊或可调压脑室腹腔分流装置脑室内输注的安全剂量，并评估细胞在血液和脑脊液中的持续时间及对脑肿瘤的作用。
In this study, there are two treatment groups called Cohort 1 and Cohort 2. Cohort 1 is for patients with diffuse midline glioma, diffuse intrinsic pontine glioma, medulloblastoma, or another rare high-grade glioma that expresses GD2. Cohort 2 is for patients with a type of cancer called progressive diffuse intrinsic pontine glioma that expresses GD2. Because there is no standard treatment at this time, patients are asked to volunteer in a gene transfer research study using special immune cells called T cells. T cells are a type of white blood cell that help the body fight infection. This research study combines two different ways of fighting cancer: antibodies and T cells. Both antibodies and T cells have been used to treat cancer patients. They have shown promise but have not been strong enough to cure most patients. Researchers have found from previous research that they can put a new antibody gene into T cells that will make them recognize cancer cells and kill them. GD2 is a protein found on several different cancers. Researchers testing brain cancer cells found that many of these cancers also have GD2 on their surface. In a study for neuroblastoma in children, a gene called a chimeric antigen receptor (CAR) was made from an antibody that recognizes GD2. This gene was put into the patients own T cells and given back to 11 patients. The cells did grow for a while but started to disappear from the blood after 2 weeks. The researchers think that if T cells are able to last longer they may have a better chance of killing tumor cells. In this study, a new gene will be added to the GD2 T cells that can potentially cause the cells to live longer. T cells need substances called cytokines to survive. The gene C7R has been added that gives the cells a constant supply of cytokine and helps them to survive for a longer period of time. In other studies using T cells researchers found that giving chemotherapy before the T cell infusion can improve the amount of time the T cells stay in the body and therefore the effect the T cells can have. This is called lymphodepletion and it will allow the T cells to expand and stay longer in the body and potentially kill cancer cells more effectively. After treating 11 patients, the largest safe dose of GD2-CAR T cells given in the vein (IV) was determined. We are now combining an IV infusion with an infusion directly into the brain through the Ommaya reservoir or programmable VP shunt. The goal is to find the largest safe dose of GD2-C7R T cells that can be administered in this way. Patients will now be assigned to Cohort 1 and 2 based on their tumor type. The GD2.C7R T cells are an investigational product not approved by the FDA. The purpose of this study is to combine infusions into the vein in the first treatment cycle with infusions directly into the cerebrospinal fluid (CSF) in the brain (intracerebroventricularly) through the ommaya reservoir or programmable VP shunt for infusions cycles 2-24. The goal is to find the largest safe dose of GD2-C7R T cells that can be administered in this way, and additionally to evaluate how long they can be detected in the blood and CSF and what affect they have on brain cancer.
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