肿瘤细胞治疗研究
英文原题：Study of ATLCAR.CD138 Cells for Relapsed/Refractory Multiple Myeloma
这是一项 I 期注册临床试验，评估 T 细胞治疗多发性骨髓瘤的安全性、可行性及初步疗效。当前状态：进行中（不再招募）。计划入组 25 例。试验地点：美国 · 教堂山（共 1 个中心）。登记号：NCT03672318。
不限性别 · ≥ 18 Years
资格标准分为3部分：1) 细胞采集前须满足的资格标准，2) 淋巴细胞清除术前须满足的资格标准，3) CAR138 T细胞输注前须满足的资格标准。 注：在细胞采集和CAR138 T细胞制备期间，如果主治医生认为符合受试者的最佳利益，允许受试者接受额外的标准治疗化疗或放疗以稳定其多发性骨髓瘤。对于在等待CAR138-T细胞制备期间需要桥接化疗和/或放疗的受试者，将收集所给予治疗的相关信息，包括剂量、频率、周期数等。 1. 细胞采集前须满足的资格标准 受试者必须满足以下所有标准方可参加本研究。 签署书面知情同意书以及用于发布个人健康信息的HIPAA授权。受试者必须签署同意书以接受细胞采集。 签署知情同意时年龄 ≥ 18岁。 Karnofsky评分 ≥ 60%。 复发或难治性多发性骨髓瘤的诊断（依据 IMWG 制定的修订版统一疗效标准所定义） 可测量疾病，定义为符合以下一项或多项：1) 血清 M 蛋白 ≥1.0 g/dL（IgA 骨髓瘤为 ≥0.5 g/dL）；2) 尿 M 蛋白 ≥200 mg/24 小时；3) 受累血清游离轻链水平 ≥10 mg/dL 且血清游离轻链比值异常。非分泌型疾病且基线骨髓骨髓瘤负荷至少 30% 的受试者也有资格参加。 既往接受过至少 3 线化疗。既往治疗方案必须包含免疫调节剂（来那度胺或泊马度胺）和蛋白酶体抑制剂（硼替佐米、卡非佐米或伊沙佐米）。 * 如果受试者的疾病对免疫调节剂（来那度胺或泊马度胺）和蛋白酶体抑制剂均难治，则允许接受过 2 线治疗。 曾接受大剂量美法仑治疗后进行自体干细胞移植（ASCT），或不适合该操作或已拒绝该操作。 允许接受异基因干细胞移植，前提是受试者自使用免疫抑制治疗以治疗/预防移植物抗宿主病（GvHD）起已≥ 1年，无活动性移植物抗宿主病（GvHD）的证据，且无活动性感染的证据。 有生育潜力的女性（WOCBP）应愿意在整个研究期间（自样本采集前开始）及研究结束后6个月内采用2种避孕方法、或已手术绝育、或避免异性性行为。WOCBP指未接受手术绝育或停经未超过1年的女性。两种避孕方法可由以下方式组成：两种屏障避孕法，或一种屏障避孕法加一种激素避孕法以防止怀孕。入组试验的WOCBP受试者的男性伴侣应使用避孕套，女性受试者必须负责告知其伴侣需要使用避孕套。 未怀孕或未哺乳（注意：母亲在研究治疗期间不得储存母乳以备将来使用）。 肿瘤所在部位不得因肿瘤增大可能导致气道阻塞。 未诊断出以下任何疾病：淀粉样变性、POEMS 综合征或累及CNS的多发性骨髓瘤。 * 允许浆细胞白血病受试者参加研究。 无活动性炎症性或感染性胃肠道疾病（例如感染性结肠炎、憩室炎或炎症性肠病）。 无妨碍受试者签署知情同意书的精神疾病，或临床医生认为会使CAR-T输注后CNS神经毒性监测复杂化的神经系统疾病。 根据研究者或方案指定人员的判断，受试者愿意并能够遵守研究程序。 经治疗医生判断，无会使本方案对受试者造成不合理风险的医疗状况。 无其他既往或合并恶性肿瘤，以下情况除外： * 非黑色素瘤皮肤癌 * 原位恶性肿瘤 * 根治性治疗后的低危前列腺癌 * 受试者已无病生存 ≥ 3 年的其他癌症。 心功能充分，定义为： * 无急性缺血的ECG证据 * 无ECG证据显示存在活动性、有临床意义的传导系统异常 * 入组研究前，筛选时发现的任何ECG异常，若研究者认为不会使受试者面临风险，须由研究者记录为无医学意义 * 无不受控制的心绞痛或严重室性心律失常 * 无有临床意义的心包疾病 * 登记前6个月内无心肌梗死病史 * 无纽约心脏协会（NYHA）3级或以上的充血性心力衰竭 无活动性感染（真菌、细菌或病毒），包括HIV、HTLV、HBV、HCV（细胞采集时检测可处于待出结果状态；仅确认无活动性感染的样本将用于制备转导细胞）。注意：为符合入组条件，受试者须HIV抗体阴性或HIV病毒载量阴性，HTLV1和2抗体阴性或HTLV1和2 PCR阴性，乙型肝炎表面抗原阴性，且HCV抗体阴性或HCV病毒载量阴性。 在细胞采集前证实器官功能充分，定义如下： * 使用 Cockcroft-Gault 公式计算的肌酐清除率：细胞采集前 60 天内 ≥ 50 mL/min，采集前 24 小时内必须 ≥ 30 mL/min。 * 胆红素：≤ 1.5 × 正常值上限（ULN），除非归因于 Gilbert 综合征 * 天冬氨酸氨基转移酶（AST）：≤ 2.5 × ULN * 丙氨酸氨基转移酶（ALT）：≤ 2.5 × ULN * 血氧饱和度：室内空气下 ≥ 92% * 射血分数：≥ 45% * 血小板：细胞采集前 60 天内 ≥ 50,000 /mm^3; mm3，采集前 24 小时内必须 ≥ 20,000/mm3。 * ANC：细胞采集前 60 天内 ≥ 1000 /mm^3，采集前 24 小时内必须 ≥ 500/mm3（0.5 × 109/L）。 有生育潜力的女性受试者在细胞采集前 72 小时内血清妊娠试验为阴性。注：除非女性已通过手术绝育（已接受子宫切除术、双侧输卵管结扎术或双侧卵巢切除术），或已自然绝经至少连续 12 个月，否则视为具有生育潜力。 既往接受过 CAR-T 治疗的受试者，必须距既往 CAR-T 治疗 ≥9 个月，且经治疗研究者判断，无可用或比本方案更合适的治疗选择。 2. 淋巴细胞清除前须满足的资格标准 __________________________________________________ 必须在淋巴细胞清除前获得参加 CAR-T 细胞治疗试验的书面知情同意。 Karnofsky 评分 ≥ 60%。 有生育潜力的女性（WOCBP）应愿意在整个研究期间（自采集前开始）使用 2 种避孕方法，或已手术绝育，或避免异性性行为，并持续至研究结束后 6 个月。WOCBP 指未接受手术绝育或停经未超过 1 年的女性。这 2 种避孕方法可由以下方式组成：2 种屏障避孕法，或 1 种屏障避孕法加 1 种激素避孕法以防止妊娠。入组本试验的 WOCBP 受试者的男性伴侣应使用避孕套，且女性受试者必须负责告知其伴侣需要使用避孕套。 未怀孕或未处于哺乳期（注意：母亲在接受研究治疗期间，母乳不能储存以备将来使用）。 无位于增大后可能引起气道阻塞部位的肿瘤。 未诊断为以下任何一种疾病：淀粉样变性、POEMS综合征或伴CNS受累的多发性骨髓瘤。 * 患有浆细胞白血病的受试者允许参加。 无活动性炎症性或感染性胃肠道疾病（例如感染性结肠炎、憩室炎或炎症性肠病）。 无会妨碍受试者给予知情同意的精神疾病，或经临床医生判断会使CAR-T输注后CNS神经毒性监测复杂化的神经系统疾病 根据研究者或方案指定人员的判断，受试者愿意并能够遵循研究程序。 无经治医师认为会使本方案对受试者造成不合理危险的医疗状况。 除既往或同时合并恶性肿瘤的病史或治疗不会对试验性方案的安全性或疗效评估产生潜在干扰的受试者外，经研究者判断，无其他既往或同时合并恶性肿瘤者方可入组本试验。 心功能充分定义为： * 无急性心肌缺血的 ECG 证据 * 无活动性、有临床意义的传导系统异常的 ECG 证据 * 入组研究前，筛选时发现的任何不被认为会使受试者面临风险的 ECG 异常，须由研究者记录为无医学意义 * 无不受控的心绞痛或严重室性心律失常 * 无有临床意义的心包疾病 * 登记前 6 个月内无心肌梗死病史 * 无纽约心脏协会（NYHA）3 级或以上的充血性心力衰竭 无活动性感染（真菌、细菌或病毒），包括 HIV、HBV 或 HCV（细胞采集时检测可待出结果；仅确认无活动性感染的样本将用于制备转导细胞）。注：为符合入组条件，受试者须 HIV 抗体或 HIV 病毒载量阴性、乙型肝炎表面抗原阴性，且 HCV 抗体或 HCV 病毒载量阴性。 受试者必须拥有符合分析证书（CofA）接受标准的自体转导激活的 CAR138 T 细胞。 受试者必须在淋巴细胞清除化疗前至少 48 小时停用糖皮质激素；目前未使用剂量 ≥10mg 泼尼松/日或等效剂量的全身性糖皮质激素（接受 <10mg/天泼尼松等效剂量者可由研究者酌情决定入组） 受试者必须在淋巴细胞清除前至少 14 天停止全身化疗 受试者必须在淋巴细胞清除前至少 7 天停止放疗 受试者应在淋巴细胞清除术前7天内重复进行多发性骨髓瘤血清学检查。如果可测量疾病的指标不再符合上述指南（入组资格标准第5条），应联系主要研究者。在这种情况下，如果认为符合受试者的最佳利益，受试者仍可接受淋巴细胞清除和CAR138 T细胞输注。该受试者将不可评估疗效（疾病不可测量），但可评估所有其他安全性和有效性指标。 受试者必须在淋巴细胞清除术前证实器官功能充分，定义如下；所有检查必须在淋巴细胞清除术前72小时内完成。 * 中性粒细胞绝对计数（ANC）：≥ 1000 cells/mm^3；受试者在淋巴细胞清除筛选前1周内未接受G-CSF或GM-CSF，或筛选前2周内未接受聚乙二醇化G-CSF（Neulasta） * 血小板：≥ 50,000 cells/mm^3；受试者在淋巴细胞清除筛选前1周内未接受血小板输注 * 计算的肌酐清除率：采用Cockcroft-Gault公式计算 ≥ 30 mL/min * 胆红素：≤ 1.5 × 正常值上限（ULN），除非归因于Gilbert综合征 * 天冬氨酸氨基转移酶（AST）：≤ AST ≤ 2.5 × ULN * 丙氨酸氨基转移酶（ALT）：≤ AST ≤ 2.5 × ULN * 脉搏血氧饱和度：室内空气下 ≥90% 在淋巴细胞清除前21天内未接受任何研究性药物治疗，或在前六周内未接受任何肿瘤疫苗治疗。 淋巴细胞清除前28天内无重大手术。 有女性伴侣的男性受试者必须已行输精管结扎术，或同意在淋巴细胞清除前至末次研究治疗给药后3个月内使用有效的避孕方法（即双重屏障法：避孕套加杀精剂）。 有生育潜力的女性受试者在淋巴细胞清除治疗前72小时内血清妊娠试验阴性。注意：除非女性受试者已手术绝育（已行子宫切除术、双侧输卵管结扎术或双侧卵巢切除术），或已自然绝经至少连续12个月，否则视为具有生育潜力。 3. CAR138 T细胞输注前需满足的入选标准 _______________________________________________________ Karnofsky评分 ≥ 60%。 有生育潜力的女性（WOCBP）应愿意在整个研究期间（自细胞采集前开始）及研究结束后6个月内采用2种避孕方法、或已手术绝育、或避免异性性行为。WOCBP指未接受手术绝育且未停经超过1年的女性。两种避孕方法可由以下方式组成：两种屏障避孕法，或一种屏障避孕法加一种激素避孕法，以防止妊娠。入组本试验的WOCBP受试者的男性伴侣应使用避孕套，女性受试者必须负责告知其伴侣需要使用避孕套。 无位于增大后可能造成气道梗阻部位的肿瘤。 根据研究者或方案指定人员的判断，受试者愿意并能够遵守研究程序。 经治疗医生判断，无会使本方案对受试者造成不合理风险的医学状况。 心脏功能充足，定义为： * 无ECG急性缺血证据 * 无ECG显示的活动性、有临床意义的传导系统异常证据 * 入组研究前，筛选时发现的任何经判断不会使受试者面临风险的ECG异常，必须由研究者记录为无临床意义 * 无不受控制的心绞痛或严重室性心律失常 * 无有临床意义的心包疾病 * 登记前6个月内无心肌梗死病史 * 无纽约心脏协会3级或以上的充血性心力衰竭 无活动性感染（真菌性、细菌性或病毒性） 无临床医生认为会使CAR-T输注后CNS神经毒性监测复杂化的神经系统疾病 器官功能充足，定义为： * 胆红素≤1.5倍正常值上限（ULN），除非归因于Gilbert综合征 * AST ≤ 5倍ULN * ALT ≤ 5倍ULN * 血清肌酐≤1.5倍ULN * 室内空气环境下脉搏血氧饱和度 > 90% 目前未在使用剂量≥10mg/日 prednisone 或其等效药物的全身性糖皮质激素；每日使用<10mg者可由研究者酌情决定入组。 受试者是接受CAR138 T细胞治疗的合适人选。 主治医师认为受试者无疾病快速进展的临床征象。
Eligibility criteria are divided into 3 sections: 1) eligibility criteria to be fulfilled prior to cell procurement, 2) Eligibility criteria to be met prior to lymphodepletion and 3) Eligibility criteria to be met prior to CAR138 T cell infusion. Note: During the period of cell procurement and CAR138 T-cell production, subjects are allowed to receive additional standard of care chemotherapy or radiation therapy to stabilize their multiple myeloma if the treating physician feels it is in the subject's best interests. For subjects requiring bridging chemotherapy and/or radiation therapy while awaiting manufacture of their CAR138-T cells, details regarding treatment(s) administered including doses, frequency, number of cycles, etc. will be collected. 1. Eligibility criteria to be fulfilled prior to cell procurement Subjects must fulfill all of the following criteria to participate in this study. Written informed consent and HIPAA authorization for release of personal health information. Subjects must sign a consent to undergo cell procurement. Age ≥ 18 years at the time of consent. Karnofsky score of ≥ 60%. Diagnosis of relapsed or refractory multiple myeloma (as defined by the Revised Uniform Response Criteria outlined by the IMWG Measurable disease as defined by one or more of the following: 1) serum M-protein ≥1.0 g/dL (≥0.5 g/dL for IgA myeloma); 2) urine M-protein ≥200 mg/24 hours; 3) involved serum free light chain level ≥10 mg/dL AND an abnormal serum free light chain ratio. Subjects with non-secretory disease and a baseline marrow burden of myeloma of at least 30% will also be eligible to participate. Received at least 3 lines of prior chemotherapy. The prior regimens must have included an immunomodulatory agent (lenalidomide or pomalidomide) and a proteasome inhibitor (bortezomib, carfilzomib or ixazomib). * Two lines of therapy will be allowed if the subject has disease that is refractory to both an immunomodulatory agent (lenalidomide or pomalidomide) and a proteasome inhibitor. Received high dose melphalan followed by autologous stem-cell transplant (ASCT) or is not eligible for or has declined the procedure. Allogeneic stem cell transplantation is allowed provided the subject is ≥ 1 year from immunosuppressive therapy to treat/prevent graft-versus-host disease, has no evidence of active graft-versus-host disease, and has no evidence of active infection. Women of childbearing potential (WOCBP) should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study (starting prior to procurement), and for 6 months after the study is concluded. WOCBP are those who have not been surgically sterilized or have not been free from menses for \> 1 year. The two birth control methods can be composed of: two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. The male partner of WOCBP subjects enrolled into the trial should use a condom and female participants must take the responsibility to inform their partners of the need to use a condom. Not pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study). No tumor in a location where enlargement could cause airway obstruction. No diagnosis of any of the following conditions: amyloidosis, POEMS syndrome or multiple myeloma with CNS involvement. * Subjects with plasma cell leukemia are allowed to participate. No active inflammatory or infectious gastrointestinal disorder (e.g. infectious colitis, diverticulitis or inflammatory bowel disease). No psychiatric illness which would prevent the subject from giving informed consent, or neurological illness that the clinician believes would complicate monitoring for CNS neurotoxicity following CAR-T infusion. Subjects are willing and able to comply with study procedures based on the judgment of the investigator or protocol designee. No medical condition, which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the subject. No other prior or concomitant malignancies with the exception of: * Non-melanoma skin cancer * In-situ malignancy * Low-risk prostate cancer after curative therapy * Other cancer for which the subject has been disease free for ≥ 3 years. Adequate cardiac function, defined as: * No ECG evidence of acute ischemia * No ECG evidence of active, clinically significant conduction system abnormalities * Prior to study entry, any ECG abnormality at screening not felt to put the subject at risk has to be documented by the investigator as not medically significant * No uncontrolled angina or severe ventricular arrhythmias * No clinically significant pericardial disease * No history of myocardial infarction within the last 6 months prior to registration * No Class 3 or higher New York Heart Association Congestive Heart Failure No active infection (fungal, bacterial or viral) including HIV, HTLV, HBV, HCV (tests can be pending at the time of cell procurement; only those samples confirming lack of active infection will be used to generate transduced cells). Note: To meet eligibility, subjects are required to be negative for HIV antibody or HIV viral load, negative for HTLV1 and 2 antibody or PCR negative for HTLV1 and 2, negative for Hepatitis B surface antigen, and negative for HCV antibody or HCV viral load. Demonstrate adequate organ function prior to cell procurement as defined below: * Creatinine Clearance using the Cockcroft-Gault formula: ≥ 50 mL/min within 60 days of cells procurement, must be ≥ 30 mL/min within 24 hours of procurement. * Bilirubin: ≤ 1.5 × upper limit of normal (ULN) unless attributed to Gilbert's syndrome * Aspartate aminotransferase (AST): ≤ 2.5 × ULN * Alanine aminotransferase (ALT): ≤ 2.5 × ULN * Oxygen saturation: ≥ 92% on room air * Ejection fraction: ≥ 45% * Platelets: ≥ 50,000 /mm\^3; mm3 within 60 days of cell procurement, must be ≥ 20,000/mm3 within 24 hours of procurement. * ANC: ≥ 1000 /mm\^3; within 60 days of cell procurement, must be ≥ 500/mm3 (0.5 × 109/L) within 24 hours of procurement. Negative serum pregnancy test within 72 hours prior to cell procurement for female participants of childbearing potential. NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months. Subjects who have received prior CAR-T must be ≥9 months out from prior CAR-T and have no available or more suitable treatment options in the opinion of the treating investigator than this protocol. 2. Eligibility Criteria to be fulfilled prior to lymphodepletion \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ Written informed consent to enroll in the CAR T-cell therapy trial must be obtained prior to lymphodepletion. Karnofsky score of ≥ 60%. Women of childbearing potential (WOCBP) should be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study (starting prior to procurement), and for 6 months after the study is concluded. WOCBP are those who have not been surgically sterilized or have not been free from menses for \> 1 year. The two birth control methods can be composed of: two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. The male partner of WOCBP subjects enrolled into the trial should use a condom and female participants must take the responsibility to inform their partners of the need to use a condom. Not pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study). No tumor in a location where enlargement could cause airway obstruction. No diagnosis of any of the following conditions: amyloidosis, POEMS syndrome or multiple myeloma with CNS involvement. * Subjects with plasma cell leukemia are allowed to participate. No active inflammatory or infectious gastrointestinal disorder (e.g. infectious colitis, diverticulitis or inflammatory bowel disease). No psychiatric illness which would prevent the subject from giving informed consent or neurological illness that clinician believes would complicate monitoring for CNS neurotoxicity following CAR-T infusion Subjects are willing and able to comply with study procedures based on the judgment of the investigator or protocol designee. No medical condition, which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the subject. No other prior or concurrent malignancies with the exception of subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial at the investigator's discretion. Adequate cardiac function is defined as: * No ECG evidence of acute ischemia * No ECG evidence of active, clinically significant conduction system abnormalities * Prior to study entry, any ECG abnormality at screening not felt to put the subject at risk has to be documented by the investigator as not medically significant * No uncontrolled angina or severe ventricular arrhythmias * No clinically significant pericardial disease * No history of myocardial infarction within the last 6 months prior to registration * No Class 3 or higher New York Heart Association Congestive Heart Failure No active infection (fungal, bacterial or viral) including HIV, HBV , or HCV (tests can be pending at the time of cell procurement; only those samples confirming lack of active infection will be used to generate transduced cells). Note: To meet eligibility, subjects are required to be negative for HIV antibody or HIV viral load, negative for Hepatitis B surface antigen, and negative for HCV antibody or HCV viral load. Subjects must have autologous transduced activated CAR138 T-cells that meet the Certificate of Analysis (CofA) acceptance criteria. Subjects must have stopped taking corticosteroids for at least 48 hours prior to lymphodepleting chemotherapy; No current use of systemic corticosteroids at doses ≥10mg prednisone daily or its equivalent (those receiving \<10mg/day prednisone equivalent may be enrolled at discretion of the Investigator) Subjects must have stopped systemic chemotherapy for at least 14 days prior to lymphodepletion Subjects must have stopped radiation therapy for at least 7 days prior to lymphodepletion Subjects should have repeated multiple myeloma serologies performed within 7 days of lymphodepletion. If markers of measurable disease no longer fall within the guidelines outlined above (procurement eligibility criterion #5), the Principal Investigator should be contacted. In such an event, the subject may be allowed to receive lymphodepletion and CAR138 T-cell infusion if it is felt to be in the subject's best interests. The subject would not be evaluable for response (disease not measurable) but would be evaluable for all other safety and efficacy measures. Subjects must demonstrate adequate organ function prior to lymphodepletion as defined below; all tests must be obtained within 72 hours prior to lymphodepletion. * Absolute Neutrophil Count (ANC): ≥ 1000 cells/mm\^3; subjects should not have received G-CSF or GM-CSF within 1 week or pegylated G-CSF (Neulasta) within 2 weeks of screening for lymphodepletion * Platelets: ≥ 50,000 cells/mm\^3; subjects should not have received platelet transfusion within 1 week of screening for lymphodepletion * Calculated creatinine clearance: ≥ 30 mL/min using the Cockcroft-Gault formula * Bilirubin: ≤ 1.5 × upper limit of normal (ULN) unless attributed to Gilbert's syndrome * Aspartate aminotransferase (AST): ≤ AST ≤ 2.5 × ULN * Alanine aminotransferase (ALT): ≤ AST ≤ 2.5 × ULN * Pulse oximetry: ≥90% on room air Has not received treatment with any investigational drug within 21 days or any tumor vaccines within the previous six weeks prior to lymphodepletion. No major surgery within 28 days prior to lymphodepletion. Male subjects with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) prior to lymphodepletion through 3 months after the last dose of study therapy. Negative serum pregnancy test within 72 hours prior to lymphodepleting therapy for female participants of childbearing potential. NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months. 3. Eligibility Criteria to be fulfilled prior to CAR138 T-cell infusion \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ Karnofsky score of ≥ 60%. Women of childbearing potential (WOCBP) should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study (starting prior to procurement), and for 6 months after the study is concluded. WOCBP are those who have not been surgically sterilized or have not been free from menses for \> 1 year. The two birth control methods can be composed of: two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. The male partner of WOCBP subjects enrolled into the trial should use a condom and female participants must take the responsibility to inform their partners of the need to use a condom. No tumor in a location where enlargement could cause airway obstruction. The subject is willing and able to comply with study procedures based on the judgment of the investigator or protocol designee. No medical condition which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the subject. Adequate cardiac function, defined as: * No ECG evidence of acute ischemia * No ECG evidence of active, clinically significant conduction system abnormalities * Prior to study entry, any ECG abnormality at screening not felt to put the subject at risk has to be documented by the Investigator as not clinically significant * No uncontrolled angina or severe ventricular arrhythmias * No clinically significant pericardial disease * No history of myocardial infarction within the last 6 months prior to registration * No Class 3 or higher New York Heart Association Congestive Heart Failure No active infection (fungal, bacterial, or viral) No neurological illness that the clinician believes would complicate monitoring for CNS neurotoxicity following CAR-T infusion Evidence of adequate organ function as defined by: * Bilirubin ≤1.5 times the upper limit of normal (ULN) unless attributed to Gilbert's Syndrome * AST ≤ 5 times ULN * ALT ≤ 5 times ULN * Serum creatinine ≤1.5 time ULN * Pulse oximetry of \> 90% on room air No current use of systemic corticosteroids at doses ≥10mg prednisone daily or its equivalent; those receiving \<10mg daily may be enrolled at the discretion of the Investigator. The subject is a good candidate for treatment with CAR138 T-cells. Subject has no clinical indication of rapidly progressing disease in the opinion of the treating physician.
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：Proportion of participants with dose limiting toxicities as a measure of maximum tolerated dose of CAR138 T cells · The maximum tolerated dose will be determined through assessment of dose limiting toxicity (DLT) experienced during the safety evaluation period. Severity and categorization of adverse events will be determined in accordance with the National Cancer Institute's Common Terminology for Adverse Events (CTCAE, version 5.0). A DLT is defined as any of the following that may, after consultation with the FDA, be considered possibly, probably, or definitely related to the study cellular products: Grade 3 and 4 cytokine release syndrome (CRS) that persists beyond 72 hours, or any Grade 5 CRS event; Grade 4 neutropenia or thrombocytopenia lasting more than 28 days from the time of CAR138 T-cell infusion. Any other ≥ Grade 3 non- hematologic toxicity (exceptions include: alopecia; grade 3 electrolyte abnormalities, hyperglycemia, diarrhea, or nausea and vomiting that can be managed with supportive care and do not persist as Grade 3 toxicities for \> 72 hours)). · 4 weeks from infusion of the CAR138 T cells
次要终点：Survival of CAR138 T cells in vivo as assessed by PCR and flow cytometry；Overall survival after infusion of CAR138 T cells；Progression free survival after infusion of CAR138 T cells；Overall response rate (ORR) as defined as the percentage of subjects achieving a confirmed partial response or better based on the International Myeloma Working Group (IMWG) response criteria.
研究入组的前3名受试者将通过输注接受5x10^6 CAR138 T细胞/m^2。在细胞输注后4周内未观察到剂量限制性毒性（DLT）的前提下，后续每队列3名受试者的输注细胞数量将依次递增至1x10^7 CAR138 T细胞/m^2、2.5x10^7 CAR138 T细胞/m^2、5x10^7 CAR138 T细胞/m^2、1x10^8 CAR138 T细胞/m^2和2x10^8 CAR138 T细胞/m^2。队列入组将交错进行，要求每名受试者按该队列指定剂量水平输注CAR138 T细胞后完成至少2周的安全性监测，之后才允许另一名受试者入组该队列。
人体有多种对抗感染和疾病的方式。似乎没有单一的方式能完美地对抗癌症。这项研究结合了两种不同的抗病方式：抗体和T细胞。抗体是保护身体免受细菌或有毒物质引起的疾病的蛋白质。抗体通过结合这些细菌或物质来发挥作用，从而阻止它们生长并造成不良影响。T细胞，也称为T淋巴细胞，是特殊的抗感染血细胞，能够杀死其他细胞，包括肿瘤细胞或受感染的细胞。抗体和T细胞都已被用于治疗癌症受试者。它们都显示出前景，但单独使用都不足以治愈大多数受试者。本研究旨在将T细胞和抗体结合起来，以创造更有效的治疗方法。正在研究的这种治疗方法称为靶向CD138抗原的自体T淋巴细胞嵌合抗原受体细胞（CAR138 T细胞）。 在先前的研究中，已表明可以将一种新基因导入T细胞，从而增强其识别和杀死癌细胞的能力。基因是DNA的一个单元。基因构成了携带受试者遗传信息的化学结构，这些信息可能决定人类特征（即眼睛颜色、身高和性别）。本研究中导入T细胞的这种新基因可产生一种称为抗CD138的抗体片段。这种抗体在血液中游动，能够检测并粘附到称为多发性骨髓瘤细胞的癌细胞上，因为这些细胞外部有一种称为CD138的物质。抗CD138抗体已被用于治疗多发性骨髓瘤患者，但强度不足以治愈大多数受试者。在本研究中，抗CD138抗体已被改变，使其不再在血液中自由游动，而是其中一部分现在与T细胞连接。只有抗体中粘附多发性骨髓瘤细胞的部分被连接到T细胞上，而不是整个抗体。当抗体以这种方式与T细胞连接时，它被称为嵌合受体。这些CD138嵌合（组合）受体激活的T细胞似乎能杀死部分肿瘤，但它们在体内不能维持很长时间，因此它们对抗癌症的机会尚不明确。
The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancer. This research study combines two different ways of fighting disease: antibodies and T cells. Antibodies are proteins that protect the body from disease caused by bacteria or toxic substances. Antibodies work by binding those bacteria or substances, which stops them from growing and causing bad effects. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including tumor cells or cells that are infected. Both antibodies and T cells have been used to treat subjects with cancers. They both have shown promise, but neither alone has been sufficient to cure most subjects. This study is designed to combine both T cells and antibodies to create a more effective treatment. The treatment that is being researched is called autologous T lymphocyte chimeric antigen receptor cells targeted against the CD138 antigen (CAR138 T cells). In previous studies, it has been shown that a new gene can be put into T cells that will increase their ability to recognize and kill cancer cells. A gene is a unit of DNA. Genes make up the chemical structure carrying the subject's genetic information that may determine human characteristics (i.e., eye color, height and sex). The new gene that is put in the T cells in this study makes a piece of an antibody called anti-CD138. This antibody floats around in the blood and can detect and stick to cancer cells called multiple myeloma cells because they have a substance on the outside of the cells called CD138. Anti-CD138 antibodies have been used to treat people with multiple myeloma, but have not been strong enough to cure most subjects. For this study, the anti-CD138 antibody has been changed so that instead of floating free in the blood part of it is now joined to the T cells. Only the part of the antibody that sticks to the multiple myeloma cells is attached to the T cells instead of the entire antibody. When an antibody is joined to a T cell in this way it is called a chimeric receptor. These CD138 chimeric (combination) receptor-activated T cells seem to kill some of the tumor, but they do not last very long in the body and so their chances of fighting the cancer are unknown.
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