肿瘤细胞治疗研究
英文原题：CAR-20/19-T Cells in Patients With Relapsed Refractory B Cell Malignancies
这是一项 I/II 期注册临床试验，评估 CAR-T 细胞治疗非霍奇金淋巴瘤、套细胞淋巴瘤、慢性淋巴细胞白血病的安全性、可行性及初步疗效。当前状态：招募中。计划入组 100 例。试验地点：美国 · 密尔沃基（共 1 个中心）。登记号：NCT04186520。
不限性别 · ≥ 18 Years 且 ≤ 80 Years
所有患者的一般入选标准 1. 年龄18至80岁，患复发或难治性B细胞非霍奇金淋巴瘤。 2. CD3绝对计数≥50/mm³。 3. 仅对有中枢神经系统（CNS）受累史或入组时临床怀疑CNS受累者，需脑部MRI、腰椎穿刺以及脑脊液细胞学和流式细胞分析未见CNS受累；E组不适用此项。 4. 知情同意前4周内有可测量病灶：淋巴结长轴>15 mm，或结外病灶长、短轴均>10 mm；B细胞NHL骨髓受累须经活检证实。CLL和原发/继发CNS淋巴瘤另按各自标准。 5. Karnofsky体能状态≥70。 6. 肝功能充分：AST、ALT、胆红素和碱性磷酸酶均<正常上限（ULN）的5倍；Gilbert综合征、间接胆红素升高或基础疾病所致异常，经研究者判断无临床意义者可接受。 7. ANC≥1,000/mm³；此前72小时未使用G-CSF，且14天内未使用聚乙二醇化G-CSF。 8. 血小板≥50,000/mm³，且72小时内未输注血小板。 9. 肾功能充分：肌酐清除率>60 mL/min且血清肌酐≤1.5 mg/dL；资格评估前24小时内不得静脉补液；计划CAR输注前3个月内不得有透析依赖性肾衰竭。 10. 能提供书面知情同意。 11. 同意研究期间采取避孕措施。 12. 心功能：NYHA I或II级且左室射血分数≥45%（超声心动图或MUGA）；肺功能：室内空气血氧饱和度≥92%。 13. 预期生存期>12周。 14. 有生育能力女性入组时尿或血妊娠试验阴性。 15. 符合下述生育和避孕要求。 16. 无中心静脉导管置入禁忌。 17. 患者已证明能够依从其他治疗。 I期3+3队列入选标准 1. B细胞NHL诊断，包括滤泡性淋巴瘤、边缘区淋巴瘤（脾、淋巴结或结外）、套细胞淋巴瘤，以及DLBCL及其亚型：侵袭性B细胞淋巴瘤、高级别B细胞淋巴瘤、富含T细胞/组织细胞的B细胞淋巴瘤、原发性纵隔B细胞淋巴瘤、EB病毒阳性DLBCL、转化性淋巴瘤（如滤泡性或边缘区淋巴瘤转化）及Richter转化。 2. 有活动性可测量疾病，并符合以下至少一项：已接受利妥昔单抗或其他抗CD20抗体及至少两种适合该疾病的化疗方案，且不适合自体移植；自体移植后复发；异基因移植后复发。既往不得接受CAR-T治疗。 I期b及II期队列入选标准 A组（I期b，8天制备，扩展6至9例）：诊断为滤泡性或边缘区淋巴瘤（脾、淋巴结或结外）或DLBCL及相关亚型（侵袭性、富含T细胞/组织细胞、原发性纵隔、EBV阳性、转化性淋巴瘤或Richter转化）；有活动性可测量疾病，并符合以下之一：接受过利妥昔单抗/其他抗CD20抗体及至少两种适宜化疗且不适合自体移植；自体移植后复发；异基因移植后复发；抗CD19 CAR-T后复发。既往接受CAR-T者最多2例。 B组（I期b，12天制备，扩展6至9例）：诊断、疾病类型和既往治疗要求与A组相同，此外DLBCL亚型包括高级别B细胞淋巴瘤；活动性可测量疾病且符合A组所列的既往治疗/复发条件。既往接受CAR-T者最多2例。 C组（冻存的8/12天灵活制备，最多24例）：诊断为滤泡性或边缘区淋巴瘤（脾、淋巴结或结外）或DLBCL及相关亚型（侵袭性、富含T细胞/组织细胞、原发性纵隔、EBV阳性、转化性淋巴瘤或Richter转化）；有活动性可测量疾病，并符合以下之一：接受过利妥昔单抗/其他抗CD20抗体及至少两种适宜化疗且不适合自体移植；自体移植后复发；异基因移植后复发；抗CD19 CAR-T后复发。既往接受CAR-T者最多2例。 D组（I期/I期b：CLL）：诊断为B细胞CLL或小淋巴细胞淋巴瘤（SLL）；既往两线治疗失败、疾病进展或不耐受，其中至少一线必须为共价BTK抑制剂（如伊布替尼、阿卡替尼、泽布替尼等）或BCL2抑制剂（如维奈克拉或其他试验性BCL2抑制剂）；且符合治疗指征之一：可测量淋巴结最大横径≥1.5 cm和/或肝大、脾大；骨髓CLL浸润≥10%。 E组（I期/I期b：复发难治性原发或继发CNS淋巴瘤）：DLBCL及相关亚型（侵袭性、高级别、富含T细胞/组织细胞、原发性纵隔、EBV阳性、转化性或Richter转化）伴继发CNS受累，或原发CNS淋巴瘤。原发CNS淋巴瘤须在至少一线CNS靶向治疗后复发/难治；继发CNS淋巴瘤须在至少一线针对CNS淋巴瘤的治疗后复发/难治。若继发CNS淋巴瘤同时有系统性淋巴瘤，系统性疾病须在至少一线治疗（含抗CD20单抗和蒽环类药物）后复发。CNS可测量病灶须符合以下之一：腰椎穿刺脑脊液流式或形态学检出淋巴瘤细胞；或MRI见符合淋巴瘤且强化的病灶，大小≥1 cm。既往须接受大剂量甲氨蝶呤（静脉剂量≥2,500 mg/m²），至少一个疗程后出现进展/复发、疾病稳定或不耐受。 II期套细胞淋巴瘤队列：确诊套细胞淋巴瘤，有活动性可测量疾病且复发/难治，符合以下之一：含抗CD20抗体的两线细胞毒化疗后复发；至少二线BTK抑制剂治疗后进展；自体移植后复发；异基因移植后复发；抗CD19 CAR-T后复发。既往抗CD19 CAR-T者最多4例。 所有患者排除标准 符合以下任一项者不得参加： 1. 有生育能力女性β-HCG阳性。 2. 确诊活动性HIV、乙肝或丙肝感染。 3. 有严重自身免疫病史，或活动且未控制、需每日使用>20 mg泼尼松（或等效剂量）治疗的自身免疫现象。 4. 既往治疗导致CTCAE v5.0≥3级非血液学毒性（研究者认为由基础疾病导致者除外）。 5. 同时使用试验性治疗药物或参加其他机构的治疗性临床试验。单采前须停药至少14天或5个半衰期（取较短者）。 6. 拒绝参加长期随访。 7. MRI或腰椎穿刺提示恶性肿瘤活动性CNS受累（E组除外）。既往CNS疾病已有效治疗者可入组，但治疗须在入组前>4周完成，并须在计划CAR-T输注前8周内通过脑MRI和脑脊液检查证实缓解。 8. 既往异基因造血干细胞移植者，如移植后<100天、有任何级别活动性GVHD或正在接受免疫抑制治疗，则排除。 9. 既往接受异基因CAR-T治疗。 10. 既往接受靶向CD19或CD20的自体CAR-T者，如距既往CAR-T治疗<100天（再入组者除外），或流式细胞术检测到残留循环CAR-T>5%（使用Miltenyi Biotec CD19 CAR检测试剂），则排除。既往接受靶向CD19或CD20 CAR-T者须在CAR-T后重复活检，经免疫组化或流式确认CD19或CD20阳性细胞至少5%。 11. 细胞输注前4周内接受抗CD20抗体治疗。 12. 细胞输注前4周内接受抗CD19抗体治疗。 13. CAR-T输注前14天内接受淋巴细胞清除治疗以外的细胞毒性化疗。 14. CAR-T单采前14天内接受细胞毒性化疗，或前7天内接受非替代剂量的类固醇治疗。 15. 单采前7天内接受口服化疗药或抗体靶向治疗。BTK抑制剂可用至单采前1天，并可在淋巴细胞清除前1天重新开始停药。 16. 实体器官移植后发生高级别淋巴瘤或白血病。 17. 同时患其他活动性恶性肿瘤（皮肤基底细胞癌或鳞状细胞癌除外）。转化性大细胞淋巴瘤患者可合并原有低级别淋巴瘤、CLL、FL或MZL。 生育及避孕特别要求 有生育能力的女性（已初潮、尚未连续绝经至少24个月，或过去24个月内有月经，且未接受绝育手术如子宫切除或双侧卵巢切除）须按入选标准接受血清或尿妊娠试验且结果阴性。研究风险较高，所有受试者在研究期间不得参与任何受孕行为（如主动备孕/使他人受孕、捐精或体外受精）。如发生可能导致妊娠的性行为，受试者须同意在方案规定的随访期间采用可靠的双重屏障避孕。 可接受的避孕包括以下两种方法联合使用：男用或女用避孕套（可合用或不合用杀精剂）；含杀精剂的隔膜或宫颈帽；宫内节育器；激素避孕。有生育能力者不包括未初潮女性、连续绝经至少24个月者、接受子宫切除/输卵管结扎/输卵管切除和/或双侧卵巢切除者，或有记录证实无精子症的男性；上述人员可入组且无需避孕。
GENERAL INCLUSION CRITERIA FOR ALL PATIENTS
1. Patients must be aged ≥18 years and ≤80 years with relapsed or refractory B-cell non-Hodgkin Lymphoma.
2. Absolute cluster of differentiation 3 (CD3) count ≥50 mm\^3.
3. Magnetic resonance imaging (MRI) brain and lumbar puncture with cerebrospinal fluid (CSF) analysis by cytology and flow cytometry without evidence of central nervous system (CNS) involvement ONLY in patients with history of CNS involvement or clinical suspicion at the time of enrollment EXCEPT Arm E subjects.
4. Measurable disease must be documented within four weeks of the time of consent defined as nodal lesions greater than 15 mm in the long axis or extranodal lesions \>10 mm in long and short axis OR bone marrow involvement that is biopsy proven for B-cell NHL (see separate criteria for CLL and primary/secondary CNS lymphoma).
5. Karnofsky performance score ≥70.
6. Adequate hepatic function, defined as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<5 x upper limit of normal (ULN); serum bilirubin and alkaline phosphatase \<5 x ULN, or considered not clinically significant as per the clinical PIs discretion (e.g. Gilbert's or indirect hyperbilirubinemia) or felt to be due to underlying disease.
7. ANC≥1000 with no G-CSF within 72 hours or pegylated G-CSF within 14 days.
8. Platelets≥50,000 with no transfusion within 72 hours.
9. Adequate renal function, defined as creatinine clearance \>60 ml/min AND serum Cr≤1.5 mg/dL.
a. No IV hydration within 24 hours of eligibility. b. No dialysis dependent renal failure within three months of planned CAR infusion.
10. Able to provide written informed consent.
11. Agree to practice birth control during the study.
12. Adequate cardiac function as indicated by New York Heart Association (NYHA) classification I or II AND left ventricular ejection fraction of ≥45% (by cardiac echocardiogram (ECHO) or multigated acquisition scan (MUGA)) and adequate pulmonary function as indicated by room air oxygen saturation of ≥92%.
13. Expected survival \>12 weeks.
14. Negative urine or serum pregnancy test in females of child bearing potential at study entry.
15. Meet criteria regarding fertility and contraception.
16. No contraindication to central line access.
17. Patient has demonstrated compliance to other therapies.
Phase 1: 3+3 COHORT ELEGIBILITY CRITERIA
1. Diagnosis of B-cell NHL including Follicular Lymphoma, Marginal Zone Lymphoma (splenic, nodal, extranodal), Mantle Cell Lymphoma, and DLBCL with associated subtypes (aggressive B-cell lymphoma, high grade B-cell lymphoma, T-cell/histocyte rich B-cell lymphoma, primary mediastinal B-cell lymphoma, Epstein-Barr virus-positive (EBV+) diffuse large B-cell lymphoma, transformed lymphoma such as transformed follicular or marginal zone, and Richter's transformation).
2. Patients must have active, measurable disease as defined and meet one of the following criteria.
1. Must have received Rituximab or another cluster of differentiation 20 (CD20) antibody and at minimum two different chemotherapy regimens appropriate for their disease and be ineligible to receive autologous transplant.
2. Relapse post-autologous transplant
3. Relapse post-allogeneic transplant
4. Patients not previously treated with CAR-T cell therapy
PHASE 1b and 2 COHORT ELEGIBILITY CRITERIA
ARM A: Six to nine patient expansion with 8-day manufacturing (Phase 1b)
1. Diagnosis of B-cell NHL including Follicular Lymphoma, Marginal Zone Lymphoma (splenic, nodal, extranodal), and DLBCL with associated subtypes (aggressive B-cell lymphoma, T-cell/histocyte rich B-cell lymphoma, primary mediastinal B-cell lymphoma, EBV+ diffuse large B-cell lymphoma, transformed lymphoma such as transformed follicular or marginal zone, and Richter's transformation).
2. Patients must have active, measurable disease as defined and meet one of the following criteria:
1. Must have received Rituximab or another cluster of differentiation 20 (CD20) antibody and at minimum two different chemotherapy regimens appropriate for their disease and be ineligible to receive autologous transplant.
2. Relapse post-autologous transplant.
3. Relapse post-allogeneic transplant.
4. Relapse post-anti-cluster of differentiation 19 (CD19) CAR-T cell therapy.
i. A maximum of two patients with prior CAR-T will be allowed in this cohort.
ARM B: Six to nine patient expansion with 12-day manufacturing (Phase 1b)
1\. Diagnosis of B-cell NHL including Follicular Lymphoma, Marginal Zone Lymphoma (splenic, nodal, extranodal), and DLBCL with associated subtypes (aggressive B-cell lymphoma, high grade B-cell lymphoma, T-cell/histocyte rich B-cell lymphoma, primary mediastinal B-cell lymphoma, EBV+ diffuse large B-cell lymphoma, transformed lymphoma such as transformed follicular or marginal zone, and Richter's transformation).
2\. Patients must have active, measurable disease as defined and meet one of the following criteria:
1. Must have received Rituximab or another CD20 antibody and at minimum two different chemotherapy regimens appropriate for their disease and be ineligible to receive autologous transplant.
2. Relapse post-autologous transplant.
3. Relapse post-allogeneic transplant.
4. Relapse post-anti-CD19 CAR-T cell therapy.
i. A maximum of two patients with prior CAR-T will be allowed in this cohort.
ARM C: 24 patient cryopreservation 8/12 flexible manufacturing arm
1. Diagnosis of B-cell NHL including Follicular Lymphoma, Marginal Zone Lymphoma (splenic, nodal, extranodal), and DLBCL with associated subtypes (aggressive B-cell lymphoma, high grade B-cell lymphoma, T-cell/histocyte rich B-cell lymphoma, primary mediastinal B-cell lymphoma, EBV+ diffuse large B-cell lymphoma, transformed lymphoma such as transformed follicular or marginal zone, and Richter's transformation).
2. Patients must have active, measurable disease as defined and meet one of the following criteria a. Must have received Rituximab or another CD20 antibody and at minimum two different chemotherapy regimens appropriate for their disease and be ineligible to receive autologous transplant b. Relapse post-autologous transplant c. Relapse post-allogeneic transplant d. Relapse post-anti-CD19 CAR-T cell therapy i. A maximum of 2 patients with prior CAR-T will be allowed in this cohort
ARM D: Phase 1 and Phase 1b: CLL
1\. Diagnosis of B-cell CLL or small lymphocytic leukemia (SLL) 2. Failed/progressed or been intolerant to two prior lines of therapy one of which MUST be either a covalent BTK inhibitor (e.g. ibrutinib, acalabrutinib, zanabrutinib, etc) or BCL2 inhibitors (e.g. venetoclax or other investigational BCL2) 3. Indication for treatment as defined as any of the following:
1. measurable lymph nodes ≥ 1.5 cm in the greatest transverse diameter and/or hepatomegaly or splenomegaly)
2. bone marrow involvement with ≥10% CLL involvement
ARM E: Phase 1 and Phase1b Relapsed/Refractory Primary or Secondary CNS Lymphoma
1. Diagnosis of diffuse large B cell lymphoma (DLBCL) with associated subtypes (aggressive B-cell lymphoma, high grade B-cell lymphoma, T-cell/histocyte rich B-cell lymphoma, primary mediastinal B-cell lymphoma, EBV+ diffuse large B-cell lymphoma, transformed lymphoma such as transformed follicular or marginal zone, and Richter's transformation) with secondary CNS lymphoma involvement OR primary CNS lymphoma.
2. For Primary CNS lymphoma, relapsed or refractory following at least one line of CNS-directed therapy.
3. Secondary CNS lymphoma relapsed or refractory following at least one line of CNS-directed therapy for treatment of CNS lymphoma.
1. For patients with secondary central nervous system lymphoma (CNSL) with concurrent systemic lymphoma, the concurrent systemic lymphoma must have relapsed following at least 1 prior line of therapy (which must have included an anti-CD20 monoclonal antibody and an anthracycline)
4. Measurable CNS disease by either lumbar puncture (LP) with positivity in CNS by flow cytometry or morphology for lymphoma cells OR magnetic resonance imaging (MRI) with enhancing lesions ≥1 cm in size consistent with lymphoma
5. Must have had prior treatment with high dose methotrexate defined as methotrexate given intravenously at a dose ≥2500 mg/m\^2 and either progression/relapse, stable disease, or intolerance to at least one cycle of treatment.
Phase II Cohort: Mantle Cell Lymphoma
1\. Diagnosis of Mantle Cell Lymphoma. 2. Patients must have active, measurable disease as previously defined and have relapsed, refractory disease as defined as one of the following:
1. Relapsed disease after two lines of cytotoxic chemotherapy including administration of anti-CD20 antibody.
2. Progressive disease after ≥second line Bruton tyrosine kinase (BTK) inhibitor.
3. Relapse post-autologous transplant.
4. Relapse post-allogeneic transplant.
5. Relapse post anti-CD19 CAR-T cell therapy.
i. A maximum of four patients with history of prior anti-CD19 CAR-T will be allowed in this cohort.
EXCLUSION CRITERIA (ALL PATIENTS)
A potential subject who meets any of the following exclusion criteria is ineligible to participate in the study.
1. Positive beta- human chorionic gonadotropin (HCG) in female of childbearing potential.
2. Confirmed active human immunodeficiency virus (HIV), Hepatitis B or C infection.
3. History of significant autoimmune disease OR active, uncontrolled autoimmune phenomenon requiring steroid therapy defined as \>20 mg of prednisone or equivalent daily.
4. Presence of ≥grade 3 non-hematologic toxicities as per CTCAE version 5.0 from any previous treatment unless it is felt to be due to underlying disease.
5. Concurrent use of investigational therapeutic agents or enrollment on another therapeutic clinical trial at any institution. Minimum of 14 days or 5 half-lives of the drug (whichever is shorter) washout prior to apheresis.
6. Refusal to participate in the long-term follow-up protocol
7. Patients with active CNS involvement by malignancy on MRI or by lumbar puncture (Not applicable to Arm E cohort.)
a. Patients with prior CNS disease that has been effectively treated will be eligible providing treatment was \>4 weeks before enrollment and a remission documented within 8 weeks of planned CAR-T cell infusion by MRI brain and CSF analysis.
8. Previous recipients of allogeneic hematopoietic stem cell transplantation (AHCT) are excluded if they are \<100 days' post-transplant, have evidence of active graft-versus-host-disease (GVHD) of any grade, or are currently on immunosuppression.
9. Prior allogeneic CAR T-cell therapy
10. Previous recipients of autologous CAR-T cell therapy directed at either CD19 or CD20 are excluded if they are \<100 days post prior CAR-T cell treatment (does not include re-enrollment) or have \>5% residual circulating CAR-T as measured by flow cytometry using a CD19 CAR detection reagent (Miltenyi Biotec)
a. Patients with prior CAR-T treatment against CD19 or CD20 must have repeat biopsy post-CAR-T cell therapy confirming a minimum of 5% CD19 or CD20 positivity by immunohistochemistry or flow cytometry
11. Anti-CD20 antibody treatment within 4 weeks of cell infusion
12. Anti-CD19 antibody treatment within 4 weeks of cell infusion
13. Cytotoxic chemotherapy other than lymphodepletion within 14 days of CAR-T cell infusion
14. Cytotoxic chemotherapy treatment within 14 days or steroid treatment (other than replacement dose steroids) within 7 days prior to apheresis collection for CAR-T cells
15. Oral chemotherapeutic agents or antibody directed treatment within 7 days of apheresis
a. BTK inhibitors are allowed until 1-day prior to apheresis and can re-start until 1-day prior to lymphodepletion
16. Patients post solid organ transplant who develop high grade lymphomas or leukemias
17. Concurrent active malignancy other than basal or squamous cell carcinomas of the skin (underlying low-grade lymphoma chronic lymphocytic leukemia/follicular lymphoma (FL)/marginal zone lymphoma (MZL) is allowable in patients with transformed large cell lymphoma)
SPECIAL CRITERIA REGARDING FERTILITY AND CONTRACEPTION
Female subjects of reproductive potential (women who have reached menarche or women who have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses within the preceding 24 months, or have not undergone a sterilization procedure \[hysterectomy or bilateral oophorectomy\]) must have a negative serum or urine pregnancy test performed as part of eligibility criteria Due to the high-risk level of this study, while enrolled, all subjects must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization). Additionally, if participating in sexual activity that could lead to pregnancy, the study subject must agree to use reliable and double barrier methods of contraception during the follow-up period of the protocol.
Acceptable birth control includes a combination of two of the following methods:
* Condoms (male or female) with or without a spermicidal agent.
* Diaphragm or cervical cap with spermicide
* Intrauterine device (IUD)
* Hormonal-based contraception Subjects who are not of reproductive potential (women who are premenarche or have been post-menopausal for at least 24 consecutive months or have undergone hysterectomy tubal ligation, salpingectomy, and/or bilateral oophorectomy or men who have documented azoospermia) are eligible without requiring the use of contraception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：Number of Adverse Events after CAR 20/19-T cell infusion · Incidence of adverse events using NCI CTCAE version 5.0. · Within the first 28 days after infusion
I期：评估IL-7/IL-15扩增的CAR-20/19-T细胞（2.5×10^6个细胞/kg）治疗复发难治性B细胞NHL的安全性，采用3+3剂量递增。I期b：按8天或12天制备分别扩展入组6至9例；若I期已入组6例，则增加6例；若入组3例，则增加9例，每组总计12例。
I期：评估IL-7/IL-15扩增的CAR-20/19-T细胞（2.5×10^6个细胞/kg）治疗CLL的安全性，采用3+3设计。I期b最多入组24例。
采用8/12天灵活制备方案；输注LV20.19 CAR-T细胞前必须冻存。最多入组24例。
I期：评估IL-7/IL-15扩增的CAR-20/19-T细胞（2.5×10^6个细胞/kg）治疗复发难治性B细胞NHL的安全性，采用3+3设计。I期b：按12天制备扩展入组6至9例；若I期已入组6例，则增加6例；若入组3例，则增加9例，每组总计12例。
I期：评估IL-7/IL-15扩增的CAR-20/19-T细胞（2.5×10^6个细胞/kg）治疗原发或继发中枢神经系统淋巴瘤的安全性。I期b评估安全性和疗效，计划入组12至24例。
单阶段II期设计，以3个月时完全缓解率为目标终点。
本I/II期、干预性、单臂、开放标签治疗研究旨在评估IL-7和IL-15制备的嵌合抗原受体（CAR）-20/19-T细胞治疗既往治疗失败的成年B细胞恶性肿瘤患者的安全性和疗效，并评估灵活制备方案的可行性。
This is a Phase I/II, interventional, single-arm, open-label, treatment study designed to evaluate the safety and efficacy of Interleukin-7 and Interleukin-15 (IL-7/IL-15) manufactured chimeric antigen receptor (CAR)-20/19-T cells as well as the feasibility of a flexible manufacturing schema in adult patients with B cell malignancies that have failed prior therapies.
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