肿瘤细胞治疗研究
英文原题：Dose Escalation and Expansion Study of TROP2 CAR Engineered IL-15- Transduced Cord Blood-derived NK Cells in Combination With Cetuximab in Patient With Colorectal Cancer (CRC) With Minimal Residual Disease (MRD)
这是一项 I 期注册临床试验，评估 NK 细胞治疗结直肠癌的安全性、可行性及初步疗效。当前状态：进行中（不再招募）。计划入组 10 例。试验地点：美国 · 休斯顿（共 1 个中心）。登记号：NCT06358430。
不限性别 · ≥ 18 Years
纳入标准：
1. 受试者必须年满18岁。
2. 受试者必须愿意且能够提供知情同意。
3. 愿意且能够遵守临床试验的指示和要求。根据合理的医学判断，缺乏理解并领会参与本研究性质和后果能力的个体将不符合参与资格。
4. 在剂量递增和剂量扩展队列中，受试者必须记录有结直肠癌（CRC），在完全疾病切除并接受标准辅助治疗后存在MRD。MRD定义为无放射学疾病证据（包括最大直径<1 cm或淋巴结短轴<1 cm的不可定义病灶的患者）且血液中存在循环ctDNA。
5. 受试者的东部肿瘤协作组（ECOG）体能状态必须为0或1（附录3）。
6. 预期寿命> 3个月。
7. 如果满足以下至少一项条件，女性患者有资格参与：
* 非附录4中定义的育龄女性（WOCBP）或
* 同意在研究治疗期间及TROP2-CAR-NK细胞输注后6个月内遵循附录4中避孕指南的WOCBP。
8. 怀孕或怀疑怀孕的女性受试者必须立即通知其医生。怀孕的女性受试者将被退出研究。
9. 男性受试者必须同意在研究治疗期间及TROP2-CAR-NK细胞输注后6个月内遵循附录4中的避孕指南。使伴侣怀孕或怀疑已使伴侣怀孕的男性受试者必须立即通知其医生。
10. WOCBP必须在开始淋巴细胞清除化疗前72小时内进行尿液妊娠试验且结果为阴性。如果WOCBP的尿液妊娠试验无法确认为阴性，则需要进行血清（β-人绒毛膜促性腺激素[β-hCG]）妊娠试验。
11. 受试者在开始淋巴细胞清除化疗前10天内必须具有以下定义的足够器官功能（表1）：
表1. 足够器官功能实验室值 全身功能检测 实验室值 血液学 ANC = ≥1500/µL 血小板 = ≥100,000/µL 血红蛋白 = ≥9.0 g/dLa 肾脏 肌酐>1.5 x ULNb的患者，按Cockcroft-Gault公式计算的CrCl = ≥45 mL/min 肝脏 总胆红素 = ≤1.5 x ULN 或总胆红素水平>1.5 x ULN的患者直接胆红素≤ULN AST和ALT = ≤2.5 x ULN（有切除肝转移史的患者≤5 x ULN） 凝血 PT/INR aPT = ≤1.5 x ULN，除非患者正在接受抗凝治疗且PT或aPTT在治疗范围内
12. 左心室射血分数 >50%。需注意，对于具有危险因素和/或 LVEF <55% 的患者，可能需要根据机构指南和/或 PI 指导进行额外检查。
13. 呼吸储备充足，定义为呼吸困难 Grade 0 或 1 级，且室内空气中血氧饱和度 >92%。
14. 愿意按照研究要求接受强制性血液采集和活检。
15. 愿意在 TROP2-NK 细胞输注后的前 4 周内居住在距研究中心 2 小时车程（约 100 英里半径）范围内。
排除标准：
1. 经 RECIST v1.1 评估存在已知活动性疾病的受试者。
2. 妊娠期、哺乳期，或在研究预计期间内（从筛选访视开始至 TROP2-CAR-NK 细胞输注后 6 个月）计划怀孕。
3. 在开始淋巴细胞清除性化疗前 2 周或 3 个半衰期内（以较短者为准）接受过全身性抗癌治疗。对于接受单克隆抗体治疗的患者，距开始淋巴细胞清除性化疗前必须至少已过 3 周。已进入一项研究性研究随访阶段的受试者，只要距上次研究性药物末次给药后已过 3 周，即可参加。
4. 受试者因既往治疗导致的所有 AE 必须恢复至 Grade 1 或基线水平。≤ Grade 2 的神经病变、脱发或其他非相关 AE 的受试者，可由主要研究者（PI）酌情判定为合格。如果受试者接受过大手术，则必须在开始淋巴细胞清除性化疗前从干预措施的毒性和/或并发症中充分恢复。
5. 在开始淋巴细胞清除性化疗前 2 周内接受过放疗。受试者必须已从所有放疗相关毒性中恢复，不需要皮质类固醇，且未发生过放射性肺炎或结肠炎。
6. 在 TROP2-CAR-NK 输注前 6 周内以及输注后至少 24 个月内接受过活疫苗。活疫苗的例子包括但不限于：麻疹、腮腺炎、风疹、水痘/带状疱疹（水痘）、黄热病、狂犬病、卡介苗和伤寒疫苗。季节性流感和 COVID-19 注射疫苗通常为灭活病毒疫苗，允许使用；但鼻内流感疫苗（如 FluMistR）为减毒活疫苗，不允许使用。
7. 既往接受过基因修饰的 T 或 NK 细胞治疗。
8. 诊断为免疫缺陷或正在接受慢性全身性类固醇治疗（剂量超过每日 10 mg 泼尼松等效剂量）。
9. 有第二种恶性肿瘤病史，除非已完成可能治愈的治疗且2年内无恶性肿瘤证据。对于成功接受皮肤基底细胞癌、皮肤鳞状细胞癌、浅表性膀胱癌、宫颈原位癌或其他原位癌根治性切除术的患者，该时间要求不适用。
10. 过去2年内需要全身治疗的活动的自身免疫性疾病（即使用疾病修饰药物、皮质类固醇或免疫抑制药物）。允许替代治疗（例如，甲状腺素、胰岛素或针对肾上腺或垂体功能不全的生理性皮质类固醇替代治疗等）。
11. 需要类固醇治疗的间质性肺病（ILD）病史或当前患有肺炎/ILD。
12. 需要全身治疗的活动的感染。
13. 已知的人类免疫缺陷病毒（HIV）感染。
14. 已知的活动性或慢性乙型或丙型肝炎病毒感染。
15. 已知的活动性结核病（结核分枝杆菌）病史。
16. 根据治疗研究者的意见，存在可能混淆研究结果、干扰参与者在整个研究期间的参与、或不符合参与者最佳利益的任何病症、治疗或实验室异常的病史或当前证据。
17. 已知会干扰配合研究要求的精神疾病或物质滥用障碍。
18. 曾接受过同种异体组织/实体器官移植。
19. 在开始淋巴细胞清除性化疗前12个月内有临床显著的心血管疾病，包括纽约心脏协会III级或IV级充血性心力衰竭、不稳定型心绞痛、心肌梗死、脑血管事件或与血流动力学不稳定相关的心律失常。注：如果符合附录X的标准，医学上控制的心律失常将被允许。
20. 使用Fridericia公式校正的QT间期延长至>480毫秒，除非经心脏病学评估后排除。
21. 患有出血或血栓性疾病或有严重出血风险的参与者。已知深静脉血栓形成/肺栓塞且正在接受适当抗凝治疗的参与者符合条件。
Inclusion Criteria:
1. Participants must be 18 years or older.
2. Participants must be willing and able to provide informed consent.
3. Willing and able to comply with clinical trial instructions and requirements. Individuals lacking the ability, based on reasonable medical judgment, to understand and appreciate the nature and consequences of participation in this study will not be eligible for participation.
4. In both the dose escalation and dose expansion cohorts, participants must have documented colorectal cancer (CRC) with MRD following complete disease resection followed by standard-of-care adjuvant treatment. MRD is defined as NO evidence of radiological disease (including patients with undefinable lesion with max diameter \<1 cm or with a short axis \< 1cm for lymph nodes) and presence of circulating ctDNA in the bloodstream.
5. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix 3).
6. Life expectancy \> 3 months.
7. A female patient is eligible to participate if at least one of the following conditions applies:
* Not a woman of childbearing potential (WOCBP) as defined in Appendix 4 OR
* A WOCBP who agrees to follow the contraceptive guidelines in Appendix 4 during the study treatment period and for 6 months post TROP2-CAR-NK cell infusion.
8. Female participants who become pregnant or suspect pregnancy must immediately notify their doctor. Females' participants who become pregnant will be taken off study.
9. Male participants must agree to follow the contraceptive guidelines in Appendix 4 during the study treatment period and for 6 months post TROP2-CAR-NK cell infusion. Male participants who father a child or suspect that they have fathered a child must immediately notify their doctor.
10. WOCBP must have a negative urine pregnancy test within 72 hours prior to the start of lymphodepleting chemotherapy. If a WOCBP has a urine pregnancy test that cannot be confirmed as negative, a serum (beta-human chorionic gonadotropin \[â-hCG\]) pregnancy test will be required.
11. Participants must have adequate organ function as defined below (Table 1) within 10 days prior to the start of lymphodepleting chemotherapy:
Table 1. Adequate Organ Function Laboratory Values Systemic Function Test Laboratory Value Hematologic ANC = ≥1500/ƒÊL Platelets = ≥100,000/ƒÊL Hemoglobin = ≥9.0 g/dLa Renal CrCl by Cockcroft-Gault formula = ≥45 mL/min for patients with creatinine \>1.5 x ULNb Hepatic Total bilirubin = ≤1.5 x ULN OR direct bilirubin ≤ULN for patients with total bilirubin levels \>1.5 x ULN AST and ALT = ≤2.5 x ULN (≤5 x ULN for patients with history of resected liver metastases) Coagulation PT/INR aPT = ≤1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range
12. Left ventricular ejection fraction \>50%. Of note, those patients with risk factors and/or with LVEF \<55% additional testing may need to be performed as per institutional guidelines and/or PI guidance.
13. Adequate respiratory reserve defined as dyspnea Grade 0 or 1 and saturated oxygen \>92% in room air.
14. Willing to undergo mandatory blood collections and biopsies as required by the study.
15. Willing to stay within a 2-hour drive (approximately 100-mile radius) of the study site during the first 4 weeks after the TROP2-NK cell infusion.
Exclusion Criteria:
1. Participants with known active disease by RECIST v1.1.
2. Pregnant, breastfeeding, or expecting to conceive within the projected duration of the study, starting with the screening visit through 6 months post TROP2-CAR-NK cell infusion.
3. Has received systemic anticancer therapy within 2 weeks or 3 half-lives, whichever is shorter, prior to the start of lymphodepleting chemotherapy. For patients treated with monoclonal antibodies, at least 3 weeks must have elapsed prior to the start of lymphodepleting chemotherapy. Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 3 weeks after the last dose of the previous investigational agent.
4. Participants must have recovered from all AEs due to previous therapies to . Grade 1 or baseline. Participants with ≤ Grade 2 neuropathy, alopecia, or other non-relevant AEs may be deemed eligible at the discretion of the principal investigator (PI). If a participants received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to the start of lymphodepleting chemotherapy.
5. Has received prior radiotherapy within 2 weeks of the start of lymphodepleting chemotherapy. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis or colitis.
6. Has received a live vaccine within 6 weeks prior to TROP2-CAR-NK infusion and for at least 24 months post infusion. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette. Guerin, and typhoid vaccine. Seasonal influenza and COVID-19 vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMistR) are live attenuated vaccines and are not allowed.
7. Prior genetically modified T or NK cell therapy.
8. Has diagnosis of immunodeficiency or receiving chronic systemic steroid therapy (in doses exceeding 10 mg daily of prednisone equivalent).
9. History of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years. The time requirement does not apply to patients who underwent successful definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, or other in situ cancers.
10. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is allowed.
11. History of interstitial lung disease (ILD) that required steroids or has current pneumonitis/ILD.
12. Active infection requiring systemic therapy.
13. Known human immunodeficiency virus (HIV) infection.
14. Known active or chronic hepatitis B or hepatitis C virus infection.
15. Known history of active tuberculosis (Mycobacterium Tuberculosis).
16. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participants to participate, in the opinion of the treating investigator.
17. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
18. Has had an allogenic tissue/solid organ transplant.
19. Clinically significant cardiovascular disease within 12 months prior to the start of lymphodepleting chemotherapy, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebrovascular event, or cardiac arrhythmia associated with hemodynamic instability. NOTE: medically controlled arrhythmia would be permitted if meet criteria per Appendix X.
20. Prolongation of corrected QT interval using Fridericia's formula to \>480 milliseconds, unless cleared after cardiology evaluation.
21. Participant with bleeding or thrombotic disorders or at risk for severe hemorrhage. Participants with known deep vein thrombosis/pulmonary embolism who are on appropriate anti-coagulation treatment are eligible.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：Safety and adverse events (AEs) · Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0 · Through study completion; an average of 1 year.
在剂量递增阶段将测试最多5个剂量水平的TROP2-CAR-NK细胞。每个剂量水平最多入组12名受试者，每次3名受试者为一组。第一组受试者将接受最低剂量水平。 如果没有观察到不可耐受的副作用，每个新组将接受比前一组更高的剂量。这一过程将持续进行，直到确定TROP2-CAR-NK细胞的推荐剂量。当该剂量水平得到确认后，最后12名受试者将按该剂量水平入组。
确定TROP2-CAR-NK细胞联合西妥昔单抗在MRD CRC受试者中的最高剂量和/或推荐剂量。
To find the highest and/or recommended dose of TROP2-CAR-NK cells combined with cetuximab in participants with MRD CRC.
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