肿瘤细胞治疗研究
英文原题：Ph I/II Trial of Cord Blood-derived NK Cells With NY-ESO-1 TCR/IL-15 for R/R Myeloma
Ph I/II Trial of Cord Blood-derived NK Cells With NY-ESO-1 TCR/IL-15 for R/R Myeloma
这是一项 I/II 期注册临床试验，评估异体NK 细胞治疗骨髓瘤的安全性、可行性及初步疗效。当前状态：招募中。计划入组 44 例。试验地点：美国 · 休斯顿（共 1 个中心）。登记号：NCT06066359。
不限性别 · ≥ 18 Years 且 ≤ 80 Years
入选标准 1. 筛选前或筛选时肿瘤样本经免疫组化证实表达NY-ESO-1，或病理科PCR检测NY-ESO-1阳性。检测NY-ESO-1前通过CD138免疫染色识别浆细胞。受试者须经HLA分型证实为HLA-A*02:01、HLA-A*2:05或HLA-A*2:06阳性（既往任一时间的结果均可）。 2. 复发/难治性多发性骨髓瘤（MM），孤立性浆细胞瘤不符合条件，并须符合以下要求：既往接受≥2线治疗（包括至少接受过一种蛋白酶体抑制剂、免疫调节酰亚胺药物[IMiD]及抗CD38抗体），且对末线治疗难治；存在可测量疾病（血清单克隆M蛋白≥0.5 g/dL，和/或尿M蛋白≥200 mg/24小时，和/或受累血清游离轻链[FLC]≥10 mg/dL且血清游离轻链比值异常）。难治定义为：有文件记录的进展性疾病发生在研究入组前最后一线抗骨髓瘤方案治疗期间或完成治疗后60天内（从方案中任一药物末次给药日起算）。 3. 淋巴清除治疗前7天内未接受抗骨髓瘤治疗。注：类固醇可使用至淋巴清除前；姑息性局部放疗可进行至NK细胞输注前。 4. 允许既往自体/异基因移植。 5. 允许既往接受靶点不是NY-ESO-1的细胞治疗。 6. 开始淋巴清除时，既往抗骨髓瘤治疗导致的全身毒性须已恢复。 7. ECOG体能状态≤2。 8. 估算肾小球滤过率（eGFR，按慢性肾脏病流行病学协作组[CKD-EPI]公式计算）≥30 mL/min/1.73 m²。 9. ALT/AST≤2.5×ULN；有文件记录的肝转移者≤5×ULN。 10. 总胆红素≤1.5 mg/dL；Gilbert综合征受试者≤3.0 mg/dL。 11. 无肝硬化史。 12. 无腹水。 13. 心脏射血分数≥50%。 14. 超声心动图或MUGA检查未见有临床意义的心包积液。 15. 无未控制的心律失常或有症状的心脏病。 16. 无有临床意义的胸腔积液（由主要研究者[PI]判断）。 17. 室内空气下基线血氧饱和度>92%。 18. 能够提供书面知情同意。 19. 年龄18至80岁。 20. 体重≥40 kg。 21. 中性粒细胞绝对计数（ANC）≥1000（原登记未注明单位）。注：淋巴清除化疗前可使用生长因子支持；任何时间均可输血支持。若血细胞减少与多发性骨髓瘤相关，且骨髓浆细胞≥50%，可不满足上述血液学指标仍继续入组。 22. 血红蛋白≥8 g/dL。注：淋巴清除化疗前可使用生长因子支持；任何时间均可输血支持。若血细胞减少与多发性骨髓瘤相关，且骨髓浆细胞≥50%，可不满足上述血液学指标仍继续入组。 23. 血小板≥25,000/μL。注：淋巴清除化疗前可使用生长因子支持；任何时间均可输血支持。若血细胞减少与多发性骨髓瘤相关，且骨髓浆细胞≥50%，可不满足上述血液学指标仍继续入组。 24. 所有有生育能力的受试者须在研究期间及研究治疗结束后3个月内采取有效避孕。女性可采用激素避孕、宫内节育器、含杀精剂的隔膜、含杀精剂的避孕套或禁欲。女性若怀孕或怀疑怀孕，须立即通知医生；怀孕者将退出研究，研究团队将收集妊娠相关信息。有生育能力的男性须在研究期间采取有效避孕；若男性受试者使他人怀孕或怀疑已使他人怀孕，须立即通知医生。 25. 签署PA17-0483长期随访方案知情同意，以履行机构对相关监管机构的职责。 26. 复发/难治性浆细胞白血病患者须既往至少接受过两种方案治疗。 淋巴清除条件 患者应继续符合上述入选标准，但血小板计数要求为≥25,000/μL。注：淋巴清除化疗前允许使用生长因子支持，任何时间均允许输血支持；若血细胞减少与多发性骨髓瘤相关且骨髓浆细胞≥50%，可不满足上述血液学指标仍继续治疗。 细胞输注条件 输注当日存在以下任一情况时，给药延迟24小时；若问题持续超过24小时，则不进行细胞输注：药物治疗无法控制的心律失常；需血管加压药支持的低血压；疑似或活动性未控制感染。 排除标准 1. 淋巴清除开始时和/或细胞输注时存在活动性或未控制感染。 2. 合并有神经系统受累的自身免疫病，如多发性硬化症。 3. 入组前30天内接种过任何活疫苗。 4. 任何需全身抗生素治疗的活动性感染。 5. 筛选前2年内存在其他恶性肿瘤，且未以根治为目的治疗；原位非黑色素瘤皮肤癌、宫颈原位癌，或经与医学监查员讨论认定为低风险的其他情况除外。 6. 淋巴清除前28天内接受重大手术、前14天内接受小手术，或研究者认为可能危及患者安全的任何计划中医疗/手术操作。
Inclusion criteria: 1\. Patients with multiple myeloma with an expression of NY-ESO-1 by immunohistochemistry in the pre-screening or screening tumor sample or PCR NY-ESO-1 testing by Pathology. CD138 by immunostains will be performed to identify plasma cells before testing for NY-ESO-1 2. Patients are HLA-A\*02:01, HLA-A\*2:05, or HLA-A\*2:06 positive on human leukocyte antigen (HLA) typing at any time. 3\. Patients with relapsed or refractory multiple myeloma (MM) (patients with solitary plasmacytoma are not eligible) who meet the following criteria: 1. \> or = 2 prior lines of therapy (including exposure to at least one proteasome inhibitor, immunomodulatory imide drug \[ImiD\], and anti-cd38 antibody and refractory to the last line of therapy) 2. Have measurable disease (serum monoclonal \[M\] protein level ≥ 0.5 g/dL, and/or urine M protein level ≥ 200 mg/24hrs, and/or involved serum free light chain \[FLC\] level ≥10 mg/dL provided the serum-free light-chain ratio is abnormal) \*\* Refractory is defined as a documented progressive disease during or within 60 days (measured from the last dose of any drug within the regimen) of completing treatment with the last anti-myeloma regimen before study entry 4. No anti-myeloma therapy within 7 days of lymphodepleting therapy. Note: Steroids are allowed at any time up until lymphodepletion. Localized radiation for palliation is allowed at any time up until NK cell infusion 5. Prior autologous/allogeneic transplants are allowed. 6. Prior cell therapy is allowed against targets other than NY-ESO-1. 7. Patients must have recovered from systemic toxicity of prior anti-myeloma therapy at the start of lymphodepletion 8. Eastern Cooperative Oncology Group (ECOG) performance status \<= 2 9. Estimated glomerular filtration rate (eGFR using the Chronic Kidney Disease Epidemiology Collaboration \[CKI-EPI\] equation) \>= 30 ml/min/1.73 m\^2 10. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =\< 2.5 x upper limit of normal (ULN) or =\< 5 x ULN if documented liver metastases 11. Total bilirubin =\< 1.5 mg/dL, except in subjects with Gilbert's syndrome in whom total bilirubin must be =\< 3.0 mg/dL 12. No history of liver cirrhosis 13. No ascites 14. Cardiac ejection fraction \>= 50% 15. No clinically significant pericardial effusion as determined by an ECHO or MUGA 16. No uncontrolled arrhythmias or symptomatic cardiac disease 17. No clinically significant pleural effusion (per principal investigator \[PI\] discretion) 18. Baseline oxygen saturation \> 92% on room air 19. Able to provide written informed consent 20. 18-80 years of age 21. Weight ≥ 40 kg 22. Absolute neutrophil count (ANC) ≥ 1000 / * Note: Growth factor support is allowed prior to lymphodepletion chemotherapy (LD chemo). Transfusion support is allowed at any time. If cytopenias are related to multiple myeloma, the patient may proceed without meeting above hematologic parameters only if bone marrow plasma cells are \>= 50% 19. Hemoglobin ≥ 8 g/dL * Note: Growth factor support is allowed prior to LD chemo. Transfusion support is allowed at any time. If cytopenias are related to multiple myeloma, the patient may proceed without meeting above hematologic parameters only if bone marrow plasma cells are \>= 50% 20. Platelet count \>= 25,000 /uL * Note: Growth factor support is allowed prior to LD chemo. Transfusion support is allowed at any time. If cytopenias are related to multiple myeloma, the patient may proceed without meeting above hematologic parameters only if bone marrow plasma cells are \>= 50% 21. All participants who are able to have children must practice effective birth control while on study and up to 3 months post completion of study therapy. Acceptable forms of birth control for female patients include: hormonal birth control, intrauterine device, diaphragm with spermicide, condom with spermicide, or abstinence, for the length of the study. If the participant is a female and becomes pregnant or suspects pregnancy, she must immediately notify her doctor. If the participant becomes pregnant during this study, she will be taken off this study. The study team will ask for information about the pregnancy 22. Men who are able to have children must use effective birth control while on the study. If the male participant fathers a child or suspects that he has fathered a child while on the study, he must immediately notify his doctor 23. Signed consent to long-term follow-up protocol PA17-0483 to fulfill the institutional responsibilities to various regulatory agencies 24. Patients with relapsed or refractory plasma cell leukemia who have received at least two previous regimens CRITERIA FOR LYMPHODEPLETION: Patient should continue to meet eligibility criteria above with the following exceptions: \* Platelet count \>/= 25,000 /μL \*\* Note: Growth factor support is allowed prior to LD chemo. Transfusion support is allowed at any time. If cytopenias are related to multiple myeloma, the patient may proceed without meeting above hematologic parameters only if bone marrow plasma cells are \>= 50% CRITERIA FOR CELL INFUSION: Patients who meet one of the following criteria on the day of infusion will have their administration delayed for 24 hours. If these problems persist beyond 24 hours, patients will not receive their cell infusion. 1. Cardiac arrhythmias not controlled with medical management 2. Hypotension requiring vasopressor support 3. Suspected or active uncontrolled infection Exclusion Criteria 1. Active or uncontrolled infection at the start of lymphodepletion and/or cell infusion 2. Patients with concurrent autoimmune diseases with neurologic involvement, such as multiple sclerosis 3. Participants who have received any live vaccines within 30 days prior to study entry 4. Any active infection requiring systematic antibiotics 5. Any evidence of another malignancy within the last 2 years prior to screening that has not been treated with curative intent (except in situ non-melanoma skin cell cancers and/or carcinoma in-situ of the cervix or other conditions that are deemed low-risk after discussion with the medical monitor) 6. Any major surgery within 28 days of lymphodepletion, minor surgery within 14 days of lymphodepletion, or any planned medical or surgical procedure that in the opinion of the investigator, might jeopardize the patient's safety
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：Incidence of dose-limiting toxicities (Part A) · Characterized by stringent complete response + complete response + very good partial response + partial response. Will provide an estimate of the objective response rate along with a 95% exact confidence interval. · Within 28 days of the natural killer (NK) cell infusion；Overall response rate (Part B) · Characterized by stringent complete response + complete response + very good partial response + partial response. Will provide an estimate of the objective response rate along with a 95% exact confidence interval. · At day 30 following NK cell infusion
次要终点：Progression free survival (PFS) rate；NY-ESO-1 T-cell receptor (TCR)/IL-15 NK cell number；Lymphocyte populations；Patient Reported Outcomes Measurement Information System-29 quality of life questionnaire score；Duration of response
第-5、-4、-3天分别静脉输注氟达拉滨（1小时）和环磷酰胺（3小时）；第0天静脉输注NY-ESO-1 TCR/IL-15 NK细胞（1至40分钟）。若输注后未达到完全缓解（CR），且无疾病进展或不可接受毒性，可每12至16周重复淋巴清除化疗及细胞输注，最多额外输注3次，直至达到CR或共完成4个周期。筛选时进行胸部X线及超声心动图或MUGA；研究期间采集血样、进行PET/CT和骨髓穿刺/活检。
本研究旨在确定复发/难治性多发性骨髓瘤患者可接受的NY-ESO-1 TCR/IL-15 NK细胞推荐剂量，并评估A部分确定的剂量能否帮助控制疾病。
To find the recommended dose of NY-ESO-1 TCR/IL-15 NK cells that can be given to patients with relapsed or refractory MM. To learn if the dose of NY-ESO-1 TCR/IL-15 NK cells found in Part A can help to control the disease.
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