肿瘤细胞治疗研究
英文原题：BAFF CAR-T Cells (LMY-922) for Treatment of Refractory Hematologic Malignancies
这是一项 I 期注册临床试验，评估细胞治疗用于非霍奇金淋巴瘤、慢性淋巴细胞白血病、白血病的安全性、可行性及初步疗效。当前状态：尚未开始招募。计划入组 27 例。试验地点：美国 · 克利夫兰（共 1 个中心）。登记号：NCT07679919。
不限性别 · ≥ 18 Years 且 ≤ 75 Years
纳入标准：
1. 男性或女性，年龄18-75岁。 2. 患者需符合：
a. NHL：组织学确诊的B细胞NHL（包括但不限于弥漫性大B细胞淋巴瘤（DLBCL）、滤泡性淋巴瘤、MCL、边缘区淋巴瘤（MZL）） i. 经过2线或以上治疗后复发，或 ii. 对既往化疗难治（定义为对最近一次化疗方案的最佳反应为疾病进展或稳定疾病持续≤6个月；或既往自体干细胞移植（ASCT）后疾病进展或复发≤12个月），且 iii. 根据Lugano恶性淋巴瘤修订版疗效标准存在可测量病灶
或
b. CLL：组织学确诊的CLL i. 经过2线或以上治疗后复发 ii. 既往处方治疗必须包含Bruton酪氨酸激酶（BTK）抑制剂和B细胞淋巴瘤2（BCL2）抑制剂， iii. 存在可测量病灶和活动性疾病：活动性疾病根据iwCLL标准定义，至少符合以下标准之一：
1. 进行性骨髓衰竭的证据，表现为贫血和/或血小板减少的发生或加重。Hb <10 g/dL或血小板计数<100 × 10^9/L的临界水平通常被视为治疗指征。
2. 巨脾（即左肋缘下≥6 cm）或进行性或症状性脾肿大。
3. 巨块型淋巴结（即最长径≥10 cm）或进行性或症状性淋巴结肿大。
4. 症状性或功能性结外受累（如皮肤、肾脏、肺、脊柱等）。
5. 疾病相关症状，定义为以下任何一项：
1. 过去6个月内非自愿体重下降≥10%。
2. 显著疲劳（即东部肿瘤协作组（ECOG）体能状态评分2或更差；无法工作或无法进行日常活动）。
3. 发热≥38.0°C持续2周或以上，无感染证据。
4. 盗汗≥1个月，无感染证据。
或
c. HCL：组织学确诊的HCL i. 经过至少1线治疗后复发，该治疗必须包含嘌呤核苷（如氟达拉滨、克拉屈滨或喷司他丁）和moxetumomab pasudotox。
ii. 需要治疗，表现为以下任何一项：中性粒细胞绝对计数（ANC）<1 × 10^3/mcL，Hb <10g/dL，血小板计数<100 × 10^3/mcL，白血病细胞计数>5 × 10^3/mcL，症状性脾肿大，或HCL肿块短轴增大>2 cm。
或
d. MM：组织学确诊的MM i. 经过3线或以上治疗后复发或难治，包括免疫调节剂、蛋白酶体抑制剂和抗CD38抗体。
ii. 根据IMWG统一疗效标准存在可测量病灶 3. 器官功能充分，定义为：
1. 根据Cockcroft-Gault公式计算的肌酐清除率大于或等于45 ml/min
2. 受试者必须具有足够的心脏功能，定义为最近一次超声心动图左心室射血分数 ≥ 45%，且无临床显著的心律失常、心包积液、瓣膜性或缺血性心脏病。
3. 肺功能充分，室内空气下脉搏血氧饱和度 ≥ 92%。
4. 总胆红素 < 1.5×机构正常值上限（若由基线癌症引起以及 Gilbert 综合征患者，则 <2.5×）。
5. 丙氨酸氨基转移酶（ALT（血清谷丙转氨酶（SGPT）））和天冬氨酸氨基转移酶（AST（血清谷草转氨酶（SGOT））< 2.5×机构正常值上限。
4. 受试者（或法定监护人）必须能够理解并愿意签署书面知情同意文件。
5. 对于有生育能力的女性：同意在治疗期间及 CAR-T 细胞输注后至少 1 年内保持禁欲（避免异性性交）或使用年失败率 < 1% 的避孕方法。
女性若已月经初潮、尚未达到绝经后状态（< 12 个月连续闭经且除绝经外无其他已确定原因），且未接受过手术绝育（切除卵巢和/或子宫），则被认为有生育能力。
年失败率 < 1% 的避孕方法示例包括双侧输卵管结扎、男性绝育、抑制排卵的激素避孕药、释放激素的宫内节育器和铜质宫内节育器。
性禁欲的可靠性应根据临床试验的持续时间
以及患者偏好和惯常的生活方式进行评估。周期性禁欲（例如日历法、排卵法、症状体温法或排卵后法）和体外射精是不可接受的避孕方法。
6. 对于男性：同意保持禁欲（避免异性性交）或使用避孕措施，并同意避免捐献精子，定义如下：对于有生育能力的女性伴侣，男性必须在治疗期间及 CAR-T 细胞输注后至少 1 年内保持禁欲或使用避孕套加另一种避孕方法，两者合计年失败率 < 1%。男性在此期间必须避免捐献精子。对于怀孕的女性伴侣，男性必须在治疗期间及 CAR-T 细胞输注后至少 1 年内保持禁欲或使用避孕套，以避免潜在的胚胎或胎儿暴露。
性禁欲的可靠性应根据临床试验的持续时间以及患者偏好和惯常的生活方式进行评估。周期性禁欲（例如日历法、排卵法、症状体温法或排卵后法）和体外射精是不可接受的避孕方法。
7. 在剂量水平3（450 × 百万 BAFF+ CAR细胞）接受治疗的患者体重至少55kg，所有其他剂量水平的患者体重至少37kg。
排除标准：
1. 除非黑色素瘤皮肤癌或原位癌（如宫颈、膀胱、乳腺）外，存在第二种活动性（即当前需要抗肿瘤治疗）非B细胞系恶性肿瘤。
2. 需要定期透析的肾衰竭。
3. 未控制的肺部疾病或感染。
4. 心血管疾病，包括症状性充血性心力衰竭、不稳定型心绞痛、具有临床意义的心律失常、心肌梗死或卒中（包括短暂性脑缺血发作或其他缺血性事件），且发生于入组前6个月内。
5. 需要全身治疗的活动性感染。
6. HIV血清阳性，且在入组前12个月内有获得性免疫缺陷综合征（AIDS）定义的机会性感染史，或未接受已确立的抗逆转录病毒治疗（ART）至少四周且HIV病毒载量低于400拷贝/mL。
7. 妊娠或哺乳期女性被排除在本研究之外（应停止哺乳），因为母体接受LMY-922和淋巴细胞清除性化疗对胎儿和哺乳婴儿存在未知但潜在的不良事件风险。有生育潜力的女性必须血清妊娠试验阴性。
8. 血清学状态反映活动性乙型或丙型肝炎感染。乙型肝炎核心抗体、乙型肝炎表面抗原（HBsAg）或丙型肝炎抗体阳性的患者，入组前必须聚合酶链反应（PCR）阴性。（PCR阳性患者将被排除。）
9. 有临床相关中枢神经系统（CNS）病变史的患者，如未控制的癫痫、瘫痪、失语、未控制的脑血管疾病、严重脑损伤、痴呆和帕金森病。
10. 存在未控制的并发或精神疾病/社会状况，会限制对研究要求的依从性的受试者。
11. 筛选前2周内接种活疫苗的患者。
12. 同时使用高剂量全身性类固醇和/或免疫抑制治疗。
1. CAR-T细胞输注前，类固醇剂量必须减至≤10 mg/天泼尼松等效剂量。
2. 免疫抑制药物必须在CAR-T细胞输注前至少5个半衰期停止使用。
Inclusion Criteria:
1\. Male or female 18-75 years of age. 2. Patient with:
a. NHL: Histologically confirmed B cell NHL (including but not limited to diffuse large B cell lymphoma (DLBCL), follicular lymphoma, MCL, marginal zone lymphoma (MZL)) i. Relapsed after 2 or more lines of therapy, or ii. Have disease refractory to prior chemotherapy (defined as progressive disease or stable disease lasting ≤ 6 months, as best response to most recent chemotherapy regimen; or disease progression, or recurrence ≤ 12 months after prior autologous stem cell transplantation (ASCT), and iii. Measurable disease per Lugano Revised Response Criteria for Malignant Lymphoma
or
b. CLL: histologically confirmed CLL i. Relapsed after 2 or more lines of therapy ii. Previous therapies prescribed must have included a Bruton's tyrosine kinase (BTK) inhibitor and a B-cell lymphoma 2 (BCL2) inhibitor, iii. Measurable disease and active disease: Active disease as defined by the iwCLL criteria, meeting at least one of the following criteria:
1. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia. Cutoff levels of Hb \<10 g/dL or platelet counts \<100 × 10\^9/L are generally regarded as indication for treatment.
2. Massive (i.e., ≥6 cm below the left costal margin) or progressive or symptomatic splenomegaly.
3. Massive nodes (i.e., ≥10 cm in longest diameter) or progressive or symptomatic lymphadenopathy.
4. Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, spine, etc.).
5. Disease-related symptoms as defined by any of the following:
1. Unintentional weight loss ≥10% within the previous 6 months.
2. Significant fatigue (i.e., Eastern Cooperative Oncology Group (ECOG) performance scale 2 or worse; cannot work or unable to perform usual activities).
3. Fevers ≥ 38.0°C for 2 or more weeks without evidence of infection.
4. Night sweats for ≥1 month without evidence of infection.
or
c. HCL: histologically confirmed HCL i. Relapsed after at least one line of therapy, which must have included a purine nucleoside (eg. fludarabine, cladribine or pentostatin) and moxetumomab pasudotox.
ii. Need for treatment as evidenced by any one of the following: Absolute Neutrophil Count (ANC) \<1 × 10\^3/mcL, Hb \<10g/dL, platelet count \<100 × 10\^3/mcL, leukemia cell count \>5 × 10\^3/mcL, symptomatic splenomegaly, or enlarging HCL mass \>2 cm in short axis.
or
d. MM: histologically confirmed MM i. Relapsed or refractory after 3 or more lines of therapy including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody.
ii. Measurable disease per IMWG uniform response criteria 3. Adequate organ function as defined by:
1. Creatinine clearance more than or equal to 45 ml/min calculated by the Cockcroft - Gault formula
2. Subjects must have adequate cardiac function as defined as left ventricular ejection fraction ≥ 45% on the most recent echocardiogram and no clinically significant arrhythmias, pericardial effusion, valvular, or ischemic heart disease.
3. Adequate pulmonary function with pulse oximetry ≥ 92% on room air.
4. Total Bilirubin \< 1.5× the institutional upper limit of normal (\<2.5× if caused by the baseline cancer and in patients with Gilbert's syndrome).
5. Alanine aminotransferase (ALT (Serum Glutamic-Pyruvic Transaminase (SGPT))) and Aspartate Aminotransferase (AST (Serum Glutamic-Oxaloacetic Transaminase (SGOT) \< 2.5× the institutional upper limit of normal.
4\. Subjects (or legal guardians) must have the ability to understand and the willingness to sign a written informed consent document.
5\. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of \< 1% per year during the treatment period and for at least 1 year after CAR-T cell infusion.
A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (\< 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of \< 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration
of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
6\. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below: With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of \< 1% per year during the treatment period and for at least 1 year after CAR-T cell infusion. Men must refrain from donating sperm during this same period. With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 1 year after CAR-T cell infusion to avoid potential embryonal or fetal exposure.
The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
7\. Body weight of at least 55kg for patients treated at dose level 3 (450 × million BAFF+ CAR cells) and at least 37kg for all other dose levels.
Exclusion Criteria:
1. Second active (i.e., currently requires antineoplastic therapy) non-B cell lineage malignancy, other than non-melanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast).
2. Renal failure requiring regular dialysis.
3. Uncontrolled pulmonary disease or infection.
4. Cardiovascular disorders including symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmias, myocardial infarction or stroke (including transient ischemic attack, or other ischemic event) within 6 months prior to registration.
5. Active infection requiring systemic treatment.
6. HIV seropositive with a history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections within 12 months of enrollment, or has not been on an established antiretroviral therapy (ART) for at least four weeks with an HIV viral load less than 400 copies/mL.
7. Pregnant or breastfeeding women are excluded from this study (breastfeeding should be discontinued), because there is an unknown, but potential risk for adverse events in fetuses and nursing infants secondary to treatment of the mother with LMY-922 and lymphodepleting chemotherapy. Women of childbearing potential must have a negative serum pregnancy test.
8. Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded.)
9. Patients with history of clinically relevant central nervous system (CNS) pathology such as uncontrolled epilepsy, paresis, aphasia, uncontrolled cerebrovascular disease, severe brain injuries, dementia, and Parkinson's disease.
10. Subjects with uncontrolled intercurrent or psychiatric illness/social situations that would limit compliance with study requirements.
11. Patients receiving a live vaccine within 2 weeks prior to screening.
12. Concurrent use of high dose systemic steroids and/or immunosuppressive therapies.
1. Steroid dose must be weaned to ≤10 mg/day prednisone equivalent prior to CAR-T cell infusion.
2. Immunosuppressive medications must be stopped at least 5 half-lives prior to CAR-T cell infusion.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：To assess the safety profile of LMY-922 in patients with refractory hematologic malignancies. · Incidence and severity of treatment-emergent adverse events · 12 Months；To determine the Recommended Phase II Dose of LMY-922 in patients with refractory hematologic malignancies. · Incidence of dose limiting toxicities (DLT) · 12 Months
次要终点：Response rates for each malignancy；Progression free survival (PFS) for each malignancy；Duration of response for each malignancy；Overall survival (OS) for each malignancy
非霍奇金淋巴瘤组的 LMY-922 剂量水平 -1，为 7500 万个 BAFF+ CAR 细胞，这是一项开放标签、剂量递增研究，最多包含四个 LMY-922 剂量水平。LMY-922 的最大耐受剂量将通过剂量递增 3+3 设计确定。
非霍奇金淋巴瘤组的 LMY-922 剂量水平 1，为 1.5 亿个 BAFF+ CAR 细胞，这是一项开放标签、剂量递增研究，最多包含四个 LMY-922 剂量水平。LMY-922 的最大耐受剂量将通过剂量递增 3+3 设计确定。
非霍奇金淋巴瘤组的 LMY-922 剂量水平 2，为 3 亿个 BAFF+ CAR 细胞，这是一项开放标签、剂量递增研究，最多包含四个 LMY-922 剂量水平。LMY-922 的最大耐受剂量将通过剂量递增 3+3 设计确定。
非霍奇金淋巴瘤组的 LMY-922 剂量水平 3，为 4.5 亿个 BAFF+ CAR 细胞，这是一项开放标签、剂量递增研究，最多包含四个 LMY-922 剂量水平。LMY-922 的最大耐受剂量将通过剂量递增 3+3 设计确定。
慢性淋巴细胞白血病 / 毛细胞白血病组的 LMY-922 剂量水平 -1，为 7500 万个 BAFF+ CAR 细胞，这是一项开放标签、剂量递增研究，最多包含四个 LMY-922 剂量水平。LMY-922 的最大耐受剂量将通过剂量递增 3+3 设计确定。
慢性淋巴细胞白血病 / 毛细胞白血病组的 LMY-922 剂量水平 1，为 1.5 亿个 BAFF+ CAR 细胞，这是一项开放标签、剂量递增研究，最多包含四个 LMY-922 剂量水平。LMY-922 的最大耐受剂量将通过剂量递增 3+3 设计确定。
慢性淋巴细胞白血病 / 毛细胞白血病组的 LMY-922 剂量水平 2，为 3 亿个 BAFF+ CAR 细胞，这是一项开放标签、剂量递增研究，最多包含四个 LMY-922 剂量水平。LMY-922 的最大耐受剂量将通过剂量递增 3+3 设计确定。
慢性淋巴细胞白血病 / 毛细胞白血病组的 LMY-922 剂量水平 3，为 4.5 亿个 BAFF+ CAR 细胞，这是一项开放标签、剂量递增研究，最多包含四个 LMY-922 剂量水平。LMY-922 的最大耐受剂量将通过剂量递增 3+3 设计确定。
嵌合抗原受体T（CAR-T）细胞治疗已显示出对难治性血液系统恶性肿瘤的活性，然而并非所有肿瘤都对CD19靶向CAR-T细胞有反应或持续保持反应。我们假设表达BAFF的CAR-T细胞（BAFF CAR-T细胞）可以成为治疗难治性血液系统恶性肿瘤的另一种策略，即使在靶向分化簇抗原19（CD19）的CAR-T治疗后复发后也是如此。这项1期研究将评估安全剂量，并使用单一淋巴细胞清除方案和BAFF CAR-T细胞生产工艺，提供BAFF CAR-T细胞对难治性血液系统恶性肿瘤活性的初步信号。
Therapy with chimeric antigen receptor T (CAR-T) cells has demonstrated activity against refractory hematologic malignancies, however not all tumors respond or remain in response to CD19 targeted CAR-T cells. We posit that CAR-T cells expressing BAFF (BAFF CAR-T cells) can become another strategy to treat refractory hematologic malignancies, even after relapse following cluster of differentiation antigen 19 (CD19) targeting CAR-T treatment. This phase 1 study will evaluate safe dose and provide initial signal of the activity of BAFF CAR-T cells against refractory hematologic malignancies using a single lymphodepletion regimen and using a BAFF CAR-T cell manufacturing process.
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