肿瘤细胞治疗研究
英文原题：Phase 1b Study Of TRICK-NK In Combination With T-Dxd In Treatment-Refractory Breast Cancers
这是一项 I 期注册临床试验，评估 NK 细胞治疗乳腺癌的安全性、可行性及初步疗效。当前状态：尚未开始招募。计划入组 60 例。试验地点：美国 · 休斯顿（共 1 个中心）。登记号：NCT07553390。
不限性别 · ≥ 18 Years
纳入标准：
1. 患者必须经组织学确诊为转移性或不可切除的乳腺癌，且不存在或已不再有效标准治愈性或姑息性治疗措施。
2. 患者必须具有可测量病灶，定义为至少一个病灶可在至少一个维度上被准确测量（非淋巴结病灶记录最长直径，淋巴结病灶记录短轴），经胸部X线检查≥20 mm（≥2 cm），或经CT扫描、MRI或临床检查卡尺测量≥10 mm（≥1 cm）。
3. 年龄≥18岁。由于目前尚无TRICK-NK细胞用于<18岁患者的给药或不良事件数据，儿童被排除在本研究之外。
4. 对于三阴性亚型患者（TNBC，ER<1%，PR 1%，根据ASCO/CAP 2018指南HER2阴性），必须已接受至少一剂Sacituzumab govitecan或抗TROP2抗体药物偶联物（ADC）。
5. 患者在给予淋巴细胞清除性化疗时，必须距末次细胞毒性化疗、酪氨酸激酶抑制剂或其他靶向治疗至少2周。
6. 患者必须距任何针对恶性肿瘤的细胞治疗至少3个月（这不是重复治疗的标准）。
7. 如果存在额外的可测量非照射病灶，允许在淋巴细胞清除性化疗前对1个或多个疾病部位进行局部放疗。
8. 东部肿瘤协作组体能状态评分为0或1（对于>16岁患者，体能水平按Karnofsky评分测量，见附录A）。
9. 筛选时器官功能充分，定义如下：
10. 肾脏：估计肾小球滤过率（慢性肾脏病流行病学协作组方程）≥50 ml/min/1.73 m2
11. 肝脏：丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）≤2.5 x 正常上限（ULN），或如有记录的肝转移则≤5 x ULN，总胆红素≤1.5 mg/dL，或对于Gilbert综合征患者≤3.0 mg/dL。无肝硬化病史。
心脏：心脏射血分数≥50%，经超声心动图（ECHO）或多门控采集（MUGA）扫描确定无临床显著心包积液，且无有症状的心脏病或严重室性心律失常（即室性心动过速或心室颤动）、高度房室传导阻滞或其他需要抗心律失常药物治疗的心律失常病史（除外经抗心律失常药物控制良好的心房颤动） 肺：无临床显著胸腔积液（根据主要研究者[PI]判断），且基线室内空气下血氧饱和度≥92%。需要全身性类固醇治疗的活动性间质性肺病（ILD）/肺炎受试者将被排除。
血液学：中性粒细胞绝对计数（ANC）≥ 1000/mm3，血小板计数 ≥ 75,000/mm3，血红蛋白 ≥ 8 g/dL。凝血功能：国际标准化比值（INR）≤ 1.5 ULN，活化部分凝血活酶时间（aPTT）≤ 1.5 ULN。接受治疗剂量抗凝药物的患者，其 INR 和/或 aPTT 必须 ≤ 预期用途治疗范围的上限。
12. 能够提供书面知情同意。
13. 体重 ≥40 kg（基于NK细胞的安全性）。
14. 女性患者符合以下至少一项条件时，可参与研究：
a. 非附录5中定义的育龄女性（WOCBP），或
15. 同意在研究治疗期间及TROP2 CAR/IL-15 TGFBR2 KO NK细胞输注后6个月内遵循附录5中避孕指南的WOCBP。
WOCBP必须在开始淋巴细胞清除性化疗前72小时内进行尿液妊娠试验且结果为阴性。如果WOCBP的尿液妊娠试验结果无法确认为阴性，则需要进行血清（β-人绒毛膜促性腺激素[β-hCG]）妊娠试验。
TROP2 CAR/IL-15 TGFBR2 KO NK细胞对发育中的人类胎儿的影响尚不明确。放射治疗对孕妇绝对禁忌。因此，有生育能力的女性和男性必须同意在研究入组前及整个研究参与期间采取充分的避孕措施（激素或屏障避孕法；禁欲）。（参见妊娠评估政策MD Anderson机构政策# CLN1114）。这包括所有女性患者，从月经初潮开始（最早8岁）至55岁，除非患者存在适用的排除因素，可能为以下之一：
* 绝经后（连续12个月或以上无月经）。
* 子宫切除术或双侧输卵管卵巢切除术史。
* 卵巢功能衰竭（促卵泡激素和雌二醇处于绝经范围，且接受过全盆腔放射治疗）。
* 双侧输卵管结扎或其他外科绝育手术史。
16. 批准的避孕方法如下：激素避孕（即避孕药、注射剂、植入物、透皮贴剂、阴道环）、宫内节育器（IUD）、输卵管结扎或子宫切除术、受试者/伴侣输精管切除术后、植入式或注射式避孕药，以及避孕套加杀精剂。在整个试验期间及药物洗脱期内不进行性活动是可接受的做法；然而，周期性禁欲、安全期避孕法和体外射精法不是可接受的避孕方法。如果女性在她或她的伴侣参与本研究期间怀孕或怀疑怀孕，她应立即告知其主治医生。
17. 在本方案中接受治疗或入组的男性患者必须同意在研究入组前、整个研究参与期间以及TROP2 CAR/IL-15 TGFBR2 KO NK细胞输注后6个月内遵循附录5中的避孕指南。使配偶怀孕或怀疑已使配偶怀孕的男性患者必须立即通知其医生。
18. 愿意按研究要求接受强制性血液采集和活检。
19. 愿意签署方案PA17-0483长期随访的知情同意书。
20. 愿意在TROP2 CAR/IL-15 TGFBR2 KO NK细胞输注后的前4周内居住在距研究 site 2小时车程范围内（约100英里半径）。
排除标准：
符合以下任一标准的患者将被排除在研究入组之外：
1. 存在与既往抗癌治疗明确相关的、持续存在的临床显著≥2级毒性，由PI判定。与既往手术、放疗、既往全身性免疫检查点抑制剂和化疗相关的毒性必须在淋巴细胞清除前恢复至1级或以下。
2. 存在需要静脉抗菌药物治疗的或对适当治疗无应答的真菌、细菌、病毒或其他感染。注：单纯性尿路感染和未并发细菌性咽炎的患者如对积极治疗有应答则允许入组。
3. 已知活动性乙型或丙型肝炎。
4. 已知人类免疫缺陷病毒（HIV）。
5. 存在活动性神经系统疾病。
6. 入组前12个月内有活动性自身免疫性疾病（不包括低度银屑病或控制良好的自身免疫性甲状腺疾病）。
7. 淀粉样变性或POEMS综合征。
8. 有症状或未控制的中枢神经系统受累或脊髓压迫征象。如需放疗，洗脱期必须至少14天。
9. 患者在过去2年内不得患有任何其他恶性肿瘤，但以下情况除外：任何部位的原地癌、经充分治疗（切除后或放疗后无复发）的宫颈癌或皮肤基底细胞癌或鳞状细胞癌，或研究者认为不会潜在干扰患者参与和/或完成本试验能力的活动性非危及生命的第二恶性肿瘤。示例包括但不限于尿路上皮癌Ta或T1级以及通过主动监测治疗的前列腺腺癌。
10. 存在研究者认为可能危及患者的任何其他严重医学状况，包括但不限于：
11. 纽约心脏协会III级或IV级心力衰竭
12. CAR NK细胞输注前≤26周内发生心肌梗死或卒中
13. CAR NK细胞输注前≤13周内发生不稳定型心绞痛，除非基础疾病已通过手术干预（如支架、搭桥）纠正
14. 严重主动脉瓣狭窄
15. 未控制的心律失常。对于可能作为例外纳入的心律失常患者，需要PI批准。
16. 先天性长QT综合征。需要PI批准。
17. 筛选过程中记录到根据Fredericia标准（QTcF）QTc > 470毫秒，基于3次心电图（ECGs）的平均值，每次间隔约1分钟且所有心电图均在10分钟内完成。患者应在进行ECGs前平卧5分钟。此排除标准可使用本地判读结果。
18. 首次给予淋巴细胞清除性化疗前 < 4周内接受过大手术。
19. 合并使用其他研究性药物。
20. 合并使用其他抗癌药物。
21. 入组时正在接受全身性类固醇治疗，但局部、眼部、鼻内和吸入性皮质类固醇，或等效剂量 ≤ 10 mg泼尼松/天的全身性皮质类固醇除外（允许生理替代剂量）。
22. 入组前14天内接受过抗胸腺细胞球蛋白或28天内接受过阿仑单抗。
23. 正在接受免疫抑制治疗的患者。
24. 妊娠或哺乳期。
25. 在CAR NK细胞输注前6周内接种过活疫苗。活疫苗的例子包括但不限于以下：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，是允许的；然而，鼻内流感疫苗（如FluMist®）为减毒活疫苗，不允许使用。
Inclusion Criteria:
1. Patients must have histologically confirmed breast cancer that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective.
2. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for nonnodal lesions and short axis for nodal lesions) as ≥20 mm (≥2 cm) by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.
3. Age ≥18 years. Because no dosing or adverse event data are currently available on the use of TRICK-NK cells in patients \<18 years of age, children are excluded from this study.
4. For patients with triple negative subtype (TNBC, ER\<1%, PR 1%, HER2 negative per ASCO/ CAP 2018 guideline), must have received at least one dose of Sacituzumab govitecan or anti-TROP2 antibody drug conjugate (ADC)
5. Patients must be at least 2 weeks from last cytotoxic chemotherapy, tyrosine kinase inhibitors or other targeted therapies at the time of administration of lymphodepleting chemotherapy.
6. Patients must be at least 3 months from any cell therapy for malignancy (this is not a criteria for repeated treatments).
7. Localized radiotherapy to 1 or more disease sites is allowed prior to the lymphodepleting chemotherapy, if there are additional measurable non-irradiated disease sites.
8. Eastern Cooperative Oncology Group performance status 0 or 1 (Performance level as measured by Karnofsky for patients \> 16 years of age, see Appendix A).
9. Adequate organ function at screening, as defined by the following:
10. Renal: Estimated glomerular filtration rate (Chronic Kidney Disease Epidemiology Collaboration equation) ≥50 ml/min/1.73 m2
11. Hepatic: alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5 x upper limit of normal (ULN) or ≤ 5 x ULN if documented liver metastases, total bilirubin ≤ 1.5 mg/dL or ≤ 3.0 mg/dL for patients with Gilbert's Syndrome. No history of liver cirrhosis.
Cardiac: Cardiac ejection fraction ≥ 50%, no clinically significant pericardial effusion as determined by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan, and no symptomatic cardiac disease or history of serious ventricular arrhythmia (ie, ventricular tachycardia or ventricular fibrillation), high-grade atrioventricular block, or other cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation that is well controlled with anti-arrhythmic medication) Pulmonary: No clinically significant pleural effusion (per principal investigator \[PI\] judgement), and baseline oxygen saturation ≥ 92% on room air. Subjects with active interstitial lung disease (ILD)/pneumonitis requiring treatment with systemic steroids will be excluded.
Hematological: absolute neutrophil count (ANC) ≥ 1000/mm3, platelet count ≥ 75,000/mm3, and hemoglobin ≥ 8 g/dL. Coagulation: International normalized ratio (INR) ≤ 1.5 ULN and activated partial thromboplastin time (aPTT) ≤ 1.5 ULN. Patients on therapeutic doses of anticoagulation medication must have INR and/or aPTT ≤ the upper limit of the therapeutic range for intended use.
12. Able to provide written informed consent.
13. Weight ≥40 kg (due to safety of NK-cell).
14. A female patient is eligible to participate if at least one of the following conditions applies:
a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 5 OR
15. A WOCBP who agrees to follow the contraceptive guidelines in Appendix 5 during the study treatment period and for 6 months post-TROP2 CAR/IL-15 TGFBR2 KO NK cell infusion.
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 \[β-hCG\]) pregnancy test will be required.
The effects of TROP2 CAR/IL-15 TGFBR2 KO NK cells on the developing human fetus are unknown. Radiation therapy is absolutely contraindicated in pregnant women. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. (Refer to Pregnancy Assessment Policy MD Anderson Institutional Policy # CLN1114). This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following:
* Postmenopausal (no menses in greater than or equal to 12 consecutive months).
* History of hysterectomy or bilateral salpingo-oophorectomy.
* Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy).
* History of bilateral tubal ligation or another surgical sterilization procedure.
16. Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, Implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
17. Male patients treated or enrolled on this protocol must agree to follow the contraceptive guidelines in Appendix 5 prior to study entry and for the duration of study participation and for 6 months post-TROP2 CAR/IL-15 TGFBR2 KO NK cell infusion. Male patients who father a child or suspect that they have fathered a child must immediately notify their doctor.
18. Willing to undergo mandatory blood collections and biopsies as required by the study.
19. Willing to sign consent for long-term follow-up on protocol PA17-0483.
20. Willing to stay within a 2-hour drive (approximately 100-mile radius) of the study site during the first 4 weeks after the TROP2 CAR/IL-15 TGFBR2 KO NK cell infusion.
Exclusion Criteria:
Patients who meet any of the following criteria will be excluded from study entry:
1. Presence of clinically significant ongoing Grade ≥ 2 toxicity unequivocally associated with the previous anticancer treatment, as determined by the PI. Toxicities related to prior surgery, radiation, prior systemic immune checkpoint inhibitors and chemotherapy should be resolved to Grade 1 or below prior to lymphodepletion.
2. Presence of fungal, bacterial, viral, or other infection requiring IV antimicrobials for management or not responding to appropriate therapy. Note: Patients with simple urinary tract infection and uncomplicated bacterial pharyngitis are permitted if responding to active treatment.
3. Known active hepatitis B or C.
4. Known human immunodeficiency virus (HIV).
5. Presence of active neurological disorder(s).
6. Active autoimmune disease within 12 months of enrollment (excluding low-grade psoriasis or well-controlled autoimmune thyroid disease).
7. Amyloidosis or POEMS syndrome.
8. Symptomatic or uncontrolled central nervous system involvement or signs of cord compression. In the case radiation therapy is indicated, the washout must be at least 14 days.
9. Patients must not have any other malignancies within the past 2 years except for in situ carcinoma of any site, adequately treated (without recurrence post resection or post radiotherapy) carcinoma of the cervix or basal or squamous cell carcinomas of the skin, or active non-life-threatening second malignancy that would not, in the investigator's opinion, potentially interfere with the patient's ability to participate and/or complete this trial. Examples include but are not limited to urothelial cancer Grade Ta or T1 and adenocarcinoma of the prostate treated by active surveillance.
10. Presence of any other serious medical condition that may endanger the patient at investigator's discretion, including but not limited to:
11. New York Heart Association Class III or IV heart failure
12. Myocardial infarction or stroke ≤ 26 weeks prior to CAR NK cell infusion
13. Unstable angina within ≤ 13 weeks prior to CAR NK cell infusion unless the underlying disease has been corrected by procedural intervention (e.g., stent, bypass)
14. Severe aortic stenosis
15. Uncontrolled arrhythmia. PI approval is required for patients with arrhythmia who may be included as an exception.
16. Congenital long QT syndrome. PI approval is required.
17. Documentation, during the screening process, of a QTc \> 470 milliseconds by Fredericia criteria (QTcF) based on the average of 3 electrocardiograms (ECGs) taken approximately 1 minute apart and all within 10 minutes of each other. The patient should be reclining for 5 minutes prior to ECGs. Local readings may be used for this exclusion criterion.
18. Major surgery \< 4 weeks prior to first dose of lymphodepleting chemotherapy.
19. Concomitant use of other investigational agents.
20. Concomitant use of other anticancer agents.
21. Patients receiving systemic steroid therapy at time of enrollment, with an exception for topical, ocular, intranasal, and inhaled corticosteroids, or systemic corticosteroids at an equivalent dose ≤ 10 mg of prednisone daily (physiological substitutive doses are allowed).
22. Received anti-thymocyte globulin within 14 days or alemtuzumab within 28 days of enrollment.
23. Patients receiving immunosuppressive therapy.
24. Pregnant or breastfeeding.
25. Has received a live vaccine within 6 weeks prior to CAR NK cell 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-Guérin, 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., FluMist®) are live attenuated vaccines and are not allowed.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
本阶段将入组最多21名受试者，考察三个递增细胞剂量水平和一个递减细胞剂量水平（-1水平）联合T-Dxd（细胞输注与每剂T-Dxd治疗之间间隔21天±3天），以确定安全性和选择RP2D。
研究者将入组两个队列的受试者，每个队列最多15名受试者，接受RP2D治疗，以进一步评估安全性和初步疗效。
这项临床研究的目标是找到TGFBR-2 KO CD70 CAR NK（TRICK-NK）与2剂T-Dxd联合给药时，可给予晚期乳腺癌参与者的最高耐受剂量。TRICK-NK的安全性也将被研究。 这项临床研究第1部分（剂量递增）的目标是找到TRICK-NK（与T-Dxd联合）可给予晚期乳腺癌参与者的最高耐受剂量。 这项临床研究第2部分（剂量扩展）的目标是了解第1部分中确定的TRICK-NK剂量是否有助于控制疾病。 可选的时间表优化阶段将测试NK细胞输注与首剂T-Dxd之间更短的间隔。
The goal of this clinical research study is to find the highest tolerable dose of TGFBR-2 KO CD70 CAR NK (TRICK-NK) in combination with 2 doses of T-Dxd that can be given to participants who have advanced breast cancer. The safety of TRICK-NK will also be studied. The goal of Part 1 (dose escalation) of this clinical research study is to find the highest tolerable dose of TRICK-NK (in combination with T-Dxd) that can be given to participants who have advanced breast cancer. The goal of Part 2 (dose expansion) of this clinical research study is to learn if the dose of TRICK-NK found in Part 1 can help to control the disease. The optional schedule optimization phase will test a shorter interval between the NK cell infusion and the first dose of T-Dxd.
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