肿瘤细胞治疗研究
英文原题：Allogenic CD19-targeting CAR-γδT Cell Therapy in R/R NHL
这是一项 I/II 期注册临床试验，评估异体 CAR-T 细胞治疗淋巴瘤的安全性、可行性及初步疗效。当前状态：招募中。计划入组 30 例。试验地点：中国 · 北京（共 2 个中心，其中中国 2 个）。登记号：NCT05554939。
不限性别 · ≥ 18 Years 且 ≤ 75 Years
患者的纳入标准：
1. 年龄18-75岁（含）。
2. 经组织学确诊为CD19阳性B细胞NHL的患者，包括以下由世界卫生组织（WHO）2016年定义的亚型：
* 非特指型弥漫性大B细胞淋巴瘤（DLBCL-NOS），包括活化B细胞型（ABC）/生发中心B细胞型（GCB）；
* 原发性纵隔（胸腺）大B细胞淋巴瘤（PMBCL）；
* 转化型滤泡性淋巴瘤（TFL）；
* 伴有MYC和BCL2和/或BCL6重排的高级别B细胞淋巴瘤（HGBCL）；
* 滤泡性淋巴瘤（FL）；
* 套细胞淋巴瘤（MCL）（经病理学确认，并有单克隆B细胞具有染色体易位t(11;14)(q13;q32)和/或过表达cyclin D1的记录）；
* 边缘区淋巴瘤（MZL），包括结内或脾边缘区B细胞淋巴瘤和黏膜相关淋巴组织（MALT）淋巴瘤。
3. 对于上述所有疾病类型，接受≥2线全身治疗后复发，或对于侵袭性类型（DLBCL-NOS、PMBCL、TFL和HGBCL）为难治性疾病。复发性疾病定义为末次方案后疾病进展。难治性疾病定义为一線治疗未达CR：
* 一線治疗最佳疗效为PD，或
* 至少4周期一線治疗（如4周期R-CHOP）后最佳疗效为SD，或
* 至少6周期后最佳疗效为PR且活检证实残留病灶或治疗≤6个月内疾病进展，或
* 自体干细胞移植（ASCT）后难治 i. ASCT后≤12个月内疾病进展或复发（复发者必须有活检证实的复发） ii. 如果ASCT后给予挽救治疗，个体必须对末线治疗无应答或末线治疗后复发。
4. 个体必须接受过充分的前期治疗：
* 对于MCL，前期治疗必须包括：
* 含蒽环类或苯达莫司汀的化疗和
* 抗CD20单克隆抗体（除非研究者确定肿瘤为CD20阴性）和
* Bruton酪氨酸激酶抑制剂（BTKi）
* 对于其他类型，前期治疗必须包括：
* 抗CD20单克隆抗体（除非研究者确定肿瘤为CD20阴性）和
* 含蒽环类的化疗方案。
* 对于转化型FL的个体，必须在转化为DLBCL后出现复发或难治性疾病。
5. 预计生存时间超过3个月。
6. 东部肿瘤协作组（ECOG）评分为0-2。
7. 根据2014年Lugano疗效标准，应至少有一个可评估的肿瘤病灶。可评估肿瘤病灶定义为通过计算机断层扫描（CT）或磁共振成像（MRI）评估的结内病灶最长直径>1.5cm，结外病灶最长直径>1.0cm。
8. 受试者必须愿意接受切除或粗针淋巴结或组织活检，或提供福尔马林固定石蜡包埋（FFPE）肿瘤组织块或新鲜切片的未染色玻片。
9. 重要器官功能符合以下要求：超声心动图显示左心室射血分数≥50%。血清肌酐≤1.5×正常范围上限（ULN）或内生肌酐清除率≥45mL/min（cockcroft-gault公式）；丙氨酸氨基转移酶（ALT）/天冬氨酸氨基转移酶（AST）≤3倍ULN，总胆红素≤1.5×ULN；肺功能：≤CTCAE 1级呼吸困难且室内空气环境下血氧饱和度（SaO2）≥91%。
10. 血常规（不得使用生长因子获得正常值，淋巴瘤侵犯骨髓导致的血细胞减少不受以下条件限制）：血红蛋白（Hgb）≥80g/L，中性粒细胞计数≥1×10^9/L，血小板（PLT）≥75×10^9/L。
11. 育龄期女性妊娠试验应为阴性；男性和女性均同意在治疗期间及随后1年内使用有效避孕措施。
12. 既往抗肿瘤治疗的毒性≤1级（根据CTCAE 5.0版）或降至可接受的纳入/排除标准水平（脱发和白癜风等其他毒性，研究者认为对受试者无安全风险）。
13. 无明显的遗传性疾病。
14. 能够理解试验的要求和事项，并愿意按要求参与临床研究。
15. 必须签署知情同意书。
患者排除标准：
1. 筛选期存在中枢神经系统（CNS）侵犯或具有临床意义的中枢神经系统疾病史，如癫痫和脑血管疾病。
2. 妊娠或哺乳期女性，或不同意在治疗期间及随后1年内使用有效避孕措施的女性。
3. 异基因造血干细胞移植史或器官移植史。
4. 未缓解的其他恶性肿瘤病史。
5. 需要免疫抑制治疗的原发性免疫缺陷或自身免疫性疾病患者。
6. 入组前3个月内接受过放疗。
7. 入组前4周内接受过免疫治疗药物，如抗程序性死亡1（PD-1）抗体、抗程序性死亡配体1（PD-L1）抗体、CD19/CD3双特异性抗体等。
8. 入组前3个月内接受过任何免疫细胞治疗的患者。
9. 有确凿证据显示患者血清中抗CD19 scFv反应阳性。
10. 入组前4周内参加过其他临床试验的患者。
11. 无法控制的感染性疾病或其他严重疾病，包括但不限于感染[如人类免疫缺陷病毒（HIV）感染或急性或慢性活动性乙型肝炎（HBV）或丙型肝炎（HCV）感染]、充血性心力衰竭、不稳定型心绞痛、心律失常，或经主治医师判断存在不可预测的风险。
12. 存在无法控制的浆膜腔积液，如大量胸腔积液或腹水。
13. 入组前3个月内有卒中或颅内出血史。
14. 入组前28天内发生过大手术或创伤，或重大副作用尚未恢复。
15. 入组前6周内接受过异体细胞治疗，如供者淋巴细胞输注。
16. 对细胞产品中任何成分有过敏史。
17. 已知精神或躯体疾病影响配合研究要求，或干扰结果或结果解读，且经治疗研究者判断使患者不适合参加研究的情况。
18. 存在研究者判断会干扰整个研究参与的情况；存在对受试者构成显著风险的情况；或干扰研究数据解读的情况。
19. 无法理解或不愿签署知情同意书。
20. 研究者认为存在其他不适合进行临床试验的原因。
Inclusion Criteria for patients:
1. Age 18-75 (inclusive).
2. Patients with histologically confirmed CD19-positive B-cell NHL, including the following types defined by the World Health Organization (WHO) 2016:
* Diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), including Activated B-cell type (ABC）/Germinal center B-cell type（GCB）;
* Primary mediastinal (thymic) large B-cell lymphoma (PMBCL);
* Transformed follicular lymphoma (TFL);
* High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBCL);
* Follicular lymphoma (FL);
* Mantle cell lymphoma (MCL) (pathologically confirmed, with documentation of monoclonal B cells that have a chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1);
* Marginal zone lymphoma (MZL), including nodal or splenic marginal zone B-cell lymphoma and mucosa-associated lymphoid tissue (MALT) lymphoma.
3. Relapse after treatment with ≥2 lines systemic therapy for all the above disease types, or refractory disease for aggressive types (DLBCL-NOS, PMBCL, TFL and HGBCL). Relapse disease is defined as disease progression after last regimen. Refractory disease is defined as no CR to first-line therapy:
* PD as best response to first-line therapy, or
* SD as best response after at least 4 cycles of first-line therapy (eg,4 cycles of R-CHOP), or
* PR as best response after at least 6 cycles and biopsy-proven residual disease or disease progression ≤ 6 months of therapy, or
* Refractory post-autologous stem cell transplant (ASCT) i. Disease progression or relapsed less than or equal to 12 months of ASCT (must have biopsy proven recurrence in relapsed individuals) ii. If salvage therapy is given post-ASCT, the individual must have had no response to or relapsed after the last line of therapy.
4. Individuals must have received adequate prior therapy:
* For MCL, prior therapy must have included:
* Anthracycline or bendamustine-containing chemotherapy and
* Anti-CD20 monoclonal antibody (unless investigator determines that tumor is CD20-negative) and
* Bruton's tyrosine kinase inhibitor (BTKi)
* For other types, prior therapy must have included:
* Anti-CD20 monoclonal antibody (unless investigator determines that tumor is CD20-negative) and
* Anthracycline containing chemotherapy regimen.
* For individual with transformed FL must have relapse or refractory disease after transformation to DLBCL.
5. The estimated survival time is over 3 months.
6. The Eastern Cooperative Oncology Group (ECOG) score is 0-2.
7. According to Lugano response criteria 2014, there should be at least one evaluable tumor focus. Evaluable tumor focus was defined as that with the longest diameter of intranodal focus \> 1.5cm, the longest diameter of extranodal focus \> 1.0cm assessed by computed tomography (CT) or magnetic resonance imaging (MRI).
8. Subjects must be willing to undergo either excised or large-needle lymph node or tissue biopsy, or provide formalin-fixed paraffin-embedded (FFPE) tumor tissue block or freshly cut unstained slides.
9. Functions of important organs meet the following requirements: Echocardiography showed left ventricular ejection fraction ≥50%. Serum creatinine ≤1.5 × upper limit of normal range (ULN) or endogenous creatinine clearance ≥45mL/min (cockcroft-gault formula); Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤3 times ULN, Total bilirubin ≤1.5× ULN; Pulmonary function: ≤CTCAE grade 1 dyspnea and oxygen saturation of blood (SaO2) ≥91% in indoor air environment.
10. Blood routine (normal values shall not be obtained with growth factors, and hemocytopenia caused by lymphoma invasion of bone marrow is not subject to conditions below): hemoglobin (Hgb) ≥80g/L, neutrophil count≥1×10\^9/L, platelet (PLT) ≥75×10\^9/L.
11. Pregnancy tests for women of childbearing age shall be negative; Both men and women agreed to use effective contraception during treatment and during the subsequent 1 year.
12. Toxicity from previous antitumor therapy ≤ grade 1 (according to CTCAE version 5.0) or to an acceptable level of inclusion/exclusion criteria (other toxicities such as alopecia and vitiligo considered by the investigator to pose no safety risk to the subject).
13. No obvious hereditary diseases.
14. Able to understand the requirements and matters of the trial, and willing to participate in clinical research as required.
15. Informed consent must be signed.
Exclusion Criteria for patients:
1. During the screening period, there was central nervous system (CNS) invasion or a history of clinically significant central nervous system diseases, such as epilepsy and cerebrovascular diseases.
2. Women who are pregnant or breastfeeding, or who do not agree to use effective contraception during treatment and during the subsequent 1 year.
3. History of allogeneic hematopoietic stem cell transplantation, or organ transplantation.
4. History of other malignancies that have not been in remission.
5. Patients with primary immunodeficiency or autoimmune diseases requiring immunosuppressive therapy.
6. Received radiotherapy within 3 months before enrollment.
7. Received immunotherapy drugs within 4 weeks before enrollment, such as anti-programmed death 1 (PD-1) antibody, anti-programmed death ligand 1 (PD-L1) antibody, CD19/CD3-bispecific antibody, and so on.
8. Patients who received any immunocellular therapy within 3 months before enrollment.
9. Confirmed evidence showing positiveness of anti-CD19 scFv reaction in patient serum.
10. Patients who participated in other clinical trials within 4 weeks prior to enrollment.
11. Uncontrolled infectious diseases or other serious illnesses, including but not limited to infections \[e.g., human immunodeficiency virus (HIV) infection or acute or chronic active hepatitis B (HBV) or C (HCV) infection\], congestive heart failure, unstable angina, arrhythmias, or that pose an unpredictable risk in the opinion of the attending physician.
12. The presence of uncontrollable serous membrane fluid, such as massive pleural effusion or ascites.
13. A history of stroke or intracranial hemorrhage within 3 months prior to enrollment.
14. Major surgery or trauma occurred within 28 days prior to enrollment, or major side effects have not been recovered.
15. Received allogeneic cell therapy within 6 weeks prior to enrollment, such as donor lymphocyte infusion.
16. History of allergies to any of the ingredients in cell products.
17. Conditions in which a known mental or physical illness interferes with cooperation with the requirements of the study or disrupts the results or interpretation of the results and, in the opinion of the therapeutic investigator, makes the patient unfit for study participation.
18. There is the situation that the researcher's judgment will interfere with the whole study participation; Situations where there is significant risk to the subject; Or interferes with the interpretation of research data.
19. Inability to understand or unwillingness to sign informed consent.
20. Researchers believe that other reasons are not suitable for clinical trials.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：Phase 1: Incidence of Adverse Events (AEs) · AE is defined as any adverse medical event from the date of lymphodepletion to 12 months after CD19 CAR-γδT cells infusion. Among them, cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS) were graded according to American Society for Transplantation and Cellular Therapy (ASTCT) criteria, graft-versus-host disease (GVHD) according to criteria defined by the Mount Sinai Acute GVHD International Consortium. Other AEs were graded according to common terminology criteria for adverse events (CTCAE) v5.0. · 12 months；Phase 1: Incidence of Dose-Limiting Toxicities (DLTs) · DLT was defined as CD19 CAR-γδT cells-related events with onset within first 28 days following infusion:
* Grade 3 aGVHD that does not resolve to Grade 1 or 2 within 7 days, with the exception of isolated skin involvement aGVHD;
* Grade 4 CRS or grade 3 CRS that does not resolve to grade 2 or lower within 2 weeks;
* Grade 3 ICANS lasting for ≥7 days or Grade 4 ICANS;
* Any other Grade ≥4 and Grade 3 AE related to the CAR-γδT that lasts for ≥14 days, except hematology toxicity. · First infusion date of CD19 CAR-γδT cells up to 28 days；Phase 1: Recommended Phase 2 Dose (RP2D) · The recommended dose for phase 2 was determined through phase 1 study. · 12 months；Phase 2: Best Objective Response Rate · The incidence of complete response (CR) and partial response (PR) as the best response to treatment assessed by investigatorand based on the Lugano 2014 assessment criterion. · 24 months；Phase 2: Best Complete Response Rate · The incidence of complete response (CR) as the best response to treatment assessed by investigatorand based on the Lugano 2014 assessment criterion. · 24 months
次要终点：Phase 2: Overall Survival (OS)；Phase 2: Progression Free Survival (PFS)；Phase 2: Time to Response (TTR)；Phase 2: Duration of Response (DOR)；Pharmacokinetics: Number and Copy Number of CD19 CAR-γδT cells (phase 1 and phase 2)；Pharmacokinetics: Persistence of CD19 CAR-γδT (phase 1 and phase 2)；Pharmacodynamics: Peak Level of Cytokines in Serum (phase 1 and phase 2)
将给予氟达拉滨和环磷酰胺的清淋化疗方案，随后进行试验性治疗，即异体靶向CD19嵌合抗原受体γδT细胞。
这是一项单中心、前瞻性、开放标签、单臂的1/2期研究，针对r/r B细胞NHL患者，评估基因编辑同种异体CD19 CAR-γδT细胞的安全性和有效性。这些细胞来自健康成年志愿者供者，在体外使用CRISPR-Cas9进行基因编辑以减弱HLA表达，并进一步克服宿主免疫系统排斥（HvGR）。在本研究中，构建了第二代抗CD19 CAR原型，携带鼠源FMC63单链可变区片段（scFv），以及由包含铰链和跨膜结构域的CD8α序列连接的胞内4-1BB共刺激和CD3ζ信号结构域。该升级版CAR-γδT产品将在2024年3月20日之后用于本研究。 本研究将总共入组约30例r/r B细胞NHL患者，并接受同种异体CD19 CAR-γδT细胞输注。1期（n=9至12）为剂量递增部分，2期（n=15至20）为扩展队列部分。本研究的主要目的是评估同种异体CD19 CAR-γδT细胞疗法在r/r B细胞NHL患者中的安全性和有效性。
This is a single center, prospective, open-label, single-arm, phase 1/2 study for patients with r/r B-cell NHL to evaluate the safety and efficacy of gene edited allogenic CD19 CAR-γδT cells. The cells are from healthy adult volunteer donors that are gene edited ex vivo using CRISPR-Cas9 to weaken HLA expression and further to overcome host immune system rejection (HvGR). In this study, a second generation anti-CD19 CAR prototype was constructed, bearing murine FMC63 single-chain variant fragment (scFv) together with intracellular 4-1BB co-stimulatory and CD3ζ signaling domains linked by a CD8α sequence comprising the hinge and transmembrane domains. This upgraded version of the CAR-γδT product will be used in this study after March 20th, 2024. A total of around 30 patients with r/r B-cell NHL will be enrolled in the study and receive allogeneic CD19 CAR-γδT cell infusion. Phase 1 (n=9 to 12) is dose escalation part, and phase 2 (n=15 to 20) is expansion cohort part. The primary objective of this study was to evaluate the safety and efficacy of allogeneic CD19 CAR-γδT cell therapy in patients with r/r B-cell NHL.
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