肿瘤细胞治疗研究
英文原题：Study on the Safety and Tolerability of PD-1 Knockout Tumor-infiltrating T Cells (TILs) in the Treatment of Advanced Colorectal Cancer
⚠ 该试验的登记信息已有 15 个月未更新， 页面上显示的「招募中」可能已经失效。联系研究中心之前，建议先到 ClinicalTrials.gov 核对登记原文的最新状态与联系方式。
这是一项 I 期注册临床试验，评估TIL（肿瘤浸润淋巴细胞）治疗结直肠癌的安全性、可行性及初步疗效。当前状态：招募中。计划入组 29 例。试验地点：中国 · 上海（共 1 个中心，其中中国 1 个）。登记号：NCT07035002。
不限性别 · ≥ 18 Years 且 ≤ 70 Years
纳入标准： * 经组织学或细胞学确诊的晚期结直肠癌患者，现阶段不适合标准治疗。 * 患者自愿接受手术或活检以获取肿瘤组织用于TILs制备。 * 年龄≥18岁且≤70岁。 * 根据RECIST 1.1版，至少有一个可评估的肿瘤病灶。 * ECOG评分为0或1。 * 骨髓和器官功能充足。 * 入组患者的预期生存时间不少于6个月。 排除标准： * 采样前2周内接受过化疗、放疗、生物治疗、内分泌治疗、免疫治疗、具有抗肿瘤适应症的中药及其他抗肿瘤治疗，但以下情况除外： 1. 手术前6周内使用过亚硝基脲或丝裂霉素C； 2. 手术前1周内使用过口服氟尿嘧啶类和小分子靶向药物。 * 采样前4周内接受过其他未上市的研究药物或治疗； * 采样前4周内接受过重大器官手术（不包括穿刺活检）或有显著病变创伤，或试验期间需要进行择期手术； * 采样前14天内接受过全身性糖皮质激素（泼尼松>10mg/天或等效剂量）或其他免疫抑制治疗；局部、眼部、关节腔内、鼻部和吸入性糖皮质激素治疗除外。短期预防性使用糖皮质激素（如预防造影剂过敏） * 采样前14天内使用过免疫调节药物，包括但不限于胸腺肽、白介素-2、干扰素等； * 采样前4周内接种过减毒活疫苗； * 既往抗肿瘤治疗的毒性未恢复至CTCAE 5.0级≤1级（脱发及其他研究者判断无安全风险的情况除外）； * 有症状的中枢神经系统或脑膜转移，或研究者判断有其他证据表明中枢神经系统或脑膜转移未得到控制而不适合入组的患者； * 采样前1周内有活动性感染且目前需要全身抗感染治疗的患者； * 有免疫缺陷病史，包括HIV抗体检测阳性； * 乙肝（HBsAg阳性）和/或丙肝（抗-HCV阳性）和/或梅毒螺旋体抗体阳性； * 目前患有间质性肺病的患者； * 有严重心脑血管疾病史，包括但不限于： 1. 严重的心律或传导异常，如需要临床干预的室性心律失常、II-III度房室传导阻滞等。 2. 首次给药前6个月内发生急性冠脉综合征、充血性心力衰竭、主动脉夹层、卒中或其他3级及以上心脑血管事件。 3. 纽约心脏病协会（NYHA）心功能分级≥II级或左心室射血分数（LVEF）<50%，或其他研究者判断的高风险结构性心脏病； 4. 临床未控制的高血压。 * 患有活动性或既往自身免疫性疾病（如系统性红斑狼疮、类风湿关节炎、血管炎等）的患者，除外临床稳定的自身免疫性甲状腺疾病和良好控制的I型糖尿病患者； * 接受过免疫治疗且发生≥3级irAE； * 临床不可控制的浆膜腔积液，研究者判断不适合入组； * 已知酒精或药物依赖； * 精神疾病或依从性差者； * 妊娠或哺乳期妇女；
Inclusion Criteria: * Patients with advanced colorectal cancer confirmed by histology or cytology, who were not eligible to standard treatment at this stage. * Patients volunteered to receive surgery or biopsy to obtain tumor tissue for TILs preparation. * Aged ≥18 and ≤70 years old. * At least one tumor lesion that could be evaluated according to RECIST, version 1.1. * ECOG score was 0 or 1. * Adequate bone marrow and organ function. * The expected survival time of the enrolled patients was no less than 6 months. Exclusion Criteria: * Received chemotherapy, radiotherapy, biological therapy, endocrine therapy, immunotherapy, traditional Chinese medicine with anti-tumor indications and other anti-tumor treatments within 2 weeks before sampling, except the following: 1. Nitrosourea or mitomycin C within 6 weeks before surgery; 2. Oral fluorouracils and small molecule targeted drugs for 1 week before surgery. * Received other unmarketed investigational drug or treatment within 4 weeks before sampling; * Had undergone major organ surgery (excluding needle biopsy) within 4 weeks before sampling or had significant lesions Trauma, or the need for elective surgery during the trial; * Received systemic glucocorticoid (prednisone \>10mg/ day or equivalent dose) or other immunosuppressive therapy within 14 days before sampling; Treatment with topical, ocular, intra-articular, nasal, and inhaled glucocorticoids was excluded. Short-term prophylaxis with glucocorticoids (e.g., to prevent contrast allergy) * Use of immunomodulatory drugs, including but not limited to thymosin, interleukin-2, interferin, etc., within 14 days before sampling; * Administration of live attenuated vaccine within 4 weeks before sampling; * The toxicity of previous antineoplastic therapy has not recovered to CTCAE 5.0 grade ≤1 (except for alopecia and other researchers who judged that there was no safety risk); * Patients with symptomatic central nervous system or leptomeningeal metastases or other evidence of uncontrolled central nervous system or leptomeningeal metastases as judged by the investigator to be ineligible for enrollment; * Patients with active infection within 1 week before sampling and currently requiring systemic anti-infective treatment; * A history of immunodeficiency, including positive HIV antibody test; * Hepatitis B (HBsAg positive and/or hepatitis C (anti-HCV positive) and/or treponema pallidum antibody positive; * Patients with current interstitial lung disease; * Has a history of severe cardiovascular and cerebrovascular diseases, including but not limited to: 1. severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmia requiring clinical intervention, degree II-III atrioventricular block, etc. 2. Acute coronary syndrome, congestive heart failure, aortic dissection, stroke, or other grade 3 or higher cardiovascular and cerebrovascular events occurred within 6 months before the first dose of dose. 3. New York Heart Association (NYHA) functional class ≥II or left ventricular ejection fraction (LVEF) \<50%, or structural heart disease at high risk as judged by other investigators; 4. clinically uncontrolled hypertension. * Patients with active or previous autoimmune diseases (such as systemic lupus erythematosus, rheumatoid arthritis, vasculitis, etc.), excluding patients with clinically stable autoimmune thyroid diseases and well-controlled type I diabetes; * Received immunotherapy with grade ≥ 3 irAE; * Clinically uncontrollable serous cavity effusion, which was judged by the investigator as not suitable for enrollment; * Known alcohol or drug dependence; * Persons with mental disorders or poor compliance; * Pregnant or lactating women;
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：Tolerance as the highest dose without side effects · Without the following side effects from each drug:
1. Cyclophosphamide: suppression of bone marrow, nausea, mucositis, rash, hemorrhagic cystitis, myocardial injury, alopecia, infertility, nausea and vomiting, syndrome of abnormal secretion of antidiuretic hormone (SIADH).
2. Fludarabine: myelosuppression, fever, chills, nausea and vomiting, malaism, fatigue, anorexia, weakness, neurotoxicity and interstitial pneumonia.
3. General antibiotics: anaphylaxis, renal insufficiency, nausea, vomiting, liver damage, myelosuppression, photosensitivity.
4. High-dose IL-2: High-dose IL-2 has a variety of side effects. Since the most common side effects are due to the adjuvant drugs used in the treatment, the main interventions we will take to reduce the occurrence of serious side effects include: timely monitoring of patients after drug administration and cell infusion, providing adequate clinical support measures and complete first aid protocols, and adjusting according to patients' response. · From enrollment to the end of follow up at 12 months；Safety as severe treatment related complications · The rates of complications occurred, including :
1. Cyclophosphamide: suppression of bone marrow, nausea, mucositis, rash, hemorrhagic cystitis, myocardial injury, alopecia, infertility, nausea and vomiting, syndrome of abnormal SIADH.
2. Fludarabine: myelosuppression, fever, chills, nausea and vomiting, malaism, fatigue, anorexia, weakness, neurotoxicity and interstitial pneumonia.
3. General antibiotics: anaphylaxis, renal insufficiency, nausea, vomiting, liver damage, myelosuppression, photosensitivity.
4. High-dose IL-2: High-dose IL-2 has a variety of side effects. Since the most common side effects are due to the adjuvant drugs used in the treatment, the main interventions we will take to reduce the occurrence of serious side effects include: timely monitoring of patients after drug administration and cell infusion, providing adequate clinical support measures and complete first aid protocols, and adjusting in real time according to patients' response. · From enrollment to the end of follow up at 12 months
次要终点：Objective response rate；Overall survival
将5×10^8 PD-1编辑的TILs每公斤体重的剂量输注给3例入组病例。如果3例患者均未出现剂量限制性毒性，研究将继续进行，并将剂量递增至B组。如果1例患者出现剂量限制性毒性（DLT），将再增加3例相同A组剂量的患者进行扩展研究。如果A组患者中发生DLT的比例低于1/6，研究将继续进行，并将剂量递增至B组。
将1×10^9 PD-1编辑的TILs每公斤体重的剂量输注给3例入组病例。如果3例患者均未出现剂量限制性毒性，研究将继续进行，并将剂量递增至C组。如果1例患者出现DLT，将再增加3例相同B组剂量的患者进行扩展研究。如果B组患者中发生DLT的比例低于1/6，研究将继续进行，并将剂量递增至C组。如果B组患者中发生DLT的比例超过2/6，研究将继续进行，但剂量将降至A组。
将2×10^9 PD-1编辑的TILs每公斤体重的剂量输注给3例入组病例。如果3例患者均未出现剂量限制性毒性，研究将继续进行至D组。如果1例患者出现DLT，将再增加3例相同C组剂量的患者进行扩展研究。如果B组患者中发生DLT的比例超过2/6，研究将继续进行，但剂量将降至B组。
将输注A、B和C组中无副作用的最高TILs剂量。如果A、B和C组均无DLT，D组总共将有11例病例。
从晚期结直肠癌患者肿瘤组织中提取的TIL，在体外进行培养、修饰和扩增，经质量控制后回输给患者，探讨该治疗的安全性和有效性。肿瘤发生的根本原因在于基因突变的积累。肿瘤细胞中大量的基因突变导致所编码的氨基酸序列发生变化，从而产生肿瘤特异性蛋白。人体T细胞识别肿瘤细胞表面MHC分子呈递的肿瘤特异性肽（肿瘤新抗原），导致T细胞在肿瘤内富集。然而，由于肿瘤通过多种途径产生免疫抑制作用，肿瘤内富集的T细胞无法有效杀伤肿瘤细胞。最常见的例子之一是肿瘤上调免疫检查点蛋白PD-L1的表达，其与T细胞表面的PD-1结合，抑制T细胞功能。因此，在本研究中，我们将通过手术切除或活检获取肿瘤组织，然后在GMP条件下分离肿瘤内的TIL细胞，并进一步利用基因编辑技术敲除PD-1，所获得的基因编辑T细胞将具有特异性识别肿瘤细胞的特征，但对肿瘤细胞的免疫抑制功能不敏感，从而实现对肿瘤患者的治疗效果。
TIL from tumor tissue of advanced colorectal cancer patients were cultured, modified and expanded in vitro, and then transfused back to the patients after quality control. The safety and efficacy of the treatment were investigated. The fundamental cause of oncogenesis lies in the accumulation of gene mutations. A large number of gene mutations in tumor cells lead to changes in the encoded amino acid sequence, resulting in the production of tumor-specific proteins. Human T cells recognize tumor-specific peptides (tumor neoantigens) that are presented on the MHC molecules on the surface of tumor cells, leading to T cell enrichment within the tumor. However, due to the immunosuppressive effect of tumors through various ways, the enriched T cells in tumors cannot effectively kill tumor cells. One of the most common examples is that tumors up-regulate the expression of immune checkpoint protein PD-L1, which binds to PD-1 on the surface of T cells and inhibits T cell function. Therefore, in this study, we will obtain tumor tissue via surgery resection or biopsy, and then isolate TIL cells in the tumor under GMP conditions, and further use gene editing technology to knockout PD-1, the obtained gene-edited T cells will have the characteristics of specific recognition of tumor cells, but not sensitive to the immunosuppressive function of tumor cells, so as to achieve the therapeutic effect on tumor patients.
MEMBER ACCOUNT
登录成功会直接打开下一页。
