肿瘤细胞治疗研究
英文原题：Kappa-CD28 T Lymphocytes, Chronic Lymphocytic Leukemia, B-cell Lymphoma or Multiple Myeloma, CHARKALL
Kappa-CD28 T Lymphocytes, Chronic Lymphocytic Leukemia, B-cell Lymphoma or Multiple Myeloma, CHARKALL
这是一项 I 期注册临床试验，评估 T 细胞治疗淋巴瘤、骨髓瘤、白血病的安全性、可行性及初步疗效。当前状态：进行中（不再招募）。计划入组 54 例。试验地点：美国 · 休斯顿（共 2 个中心）。登记号：NCT00881920。
不限性别 · ≥ 18 Years
纳入标准：
血液采集阶段：
* B细胞慢性淋巴细胞白血病（B-CLL）、复发或难治性B细胞淋巴瘤（或其他B细胞肿瘤）或多发性骨髓瘤，且为κ轻链单克隆。
* 预期生存期至少12周。
* 无其他癌症病史（非黑色素瘤皮肤癌、乳腺原位癌或宫颈原位癌除外），除非该肿瘤已在入组前至少2年接受根治性治疗并成功治愈。
* 如需通过单采采集血液，肌酐（Cre）和AST须低于正常值上限的1.5倍。
* 如需通过单采采集血液，PT和PTTK须低于正常值上限的1.5倍。
T细胞治疗阶段：
诊断为以下疾病之一：
1. κ轻链单克隆B-CLL，且符合以下任一条件：
1）出现进行性骨髓衰竭证据，表现为贫血和/或血小板减少新发或加重；
2）巨大脾肿大（即脾脏超出左肋缘至少6 cm）、进行性脾肿大或有症状的脾肿大；
3）巨大淋巴结（即最长径至少10 cm）、进行性淋巴结肿大或有症状的淋巴结肿大；
4）淋巴细胞进行性增多，2个月内增加超过50%，或淋巴细胞倍增时间（LDT）<6个月；
5）有全身症状，定义为以下一种或多种与疾病相关的症状或体征：
1. 过去6个月内非故意体重下降≥10%；
2. 明显疲劳（即ECOG体能状态≥2级，无法工作或进行日常活动）；
3. 无其他感染证据时，体温>100.5°F或38.0°C持续至少2周；
4. 无感染证据时，盗汗持续超过1个月；
5. 一线治疗后疾病耐药；
6. 首次治疗后短时间内进展（<2年）。
或
2. κ轻链单克隆的惰性或侵袭性B细胞淋巴瘤（或其他B细胞肿瘤），存在可测量疾病，且至少接受过一种含利妥昔单抗或等效单克隆抗体的化疗方案。
或
3. κ轻链单克隆多发性骨髓瘤，存在可测量疾病，且至少接受过一种化疗方案。
* 预期生存期至少12周。
* 入组前已从所有既往化疗毒性中恢复。若有医学指征，可使用PD-1/PD-L1抑制剂。
* 中性粒细胞绝对计数（ANC）>500；血红蛋白≥7.0。
* 胆红素<正常值上限的3倍。
* AST<正常值上限的5倍。
* 估算肾小球滤过率（GFR）>50 mL/min。
* 室内空气下脉搏血氧饱和度>90%。
* Karnofsky评分>60%。
* HIV血清学阴性。
* 有可用的自体转导外周血T细胞，流式细胞术测得CAR-κ表达≥15%。
* 患者须签署知情同意书，确认知晓本研究为研究性试验，已被告知可能获益及毒副作用，并将获得同意书副本。
* 有性生活的患者须同意在研究期间及研究结束后3个月内采用一种较高效的避孕方法；男性伴侣应使用避孕套。
* CLL患者的Coombs试验须为阴性。
排除标准：
血液采集阶段：
* 存在需要抗生素治疗的活动性感染。
* 活动性自身免疫性疾病。
T细胞治疗阶段：
* 有症状的心脏病。
* 对含鼠源蛋白产品有超敏反应史；目前正在接受研究性药物，或过去6周内接受过研究性药物；过去6周内接受过任何肿瘤疫苗。
* 肿瘤位于增大后可能导致气道阻塞的部位。
* 妊娠或哺乳期。
INCLUSION CRITERIA:
BLOOD PROCUREMENT:
* B-CLL or recurrent or refractory B-cell lymphoma (or other B-cell neoplasm) or multiple myeloma monoclonal for Kappa-light chain
* Life expectancy of at least 12 weeks or greater.
* No history of other cancer (except non-melanoma skin cancer or in situ breast cancer or cervix cancer) unless the tumor was successfully treated with curative intent at least 2 years before trial entry
* If requires pheresis to collect blood, Cre and AST less than 1.5 upper limit of normal
* If requires pheresis to collect blood, PT and PTTK less than 1.5 upper limit normal
T CELL TREATMENT:
Diagnosis of:
1. B-CLL monoclonal for Kappa light chain with one of the following criteria:
1. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia
2. Massive (ie, at least 6 cm below the left costal margin) or progressive or symptomatic splenomegaly
3. Massive nodes (ie, at least 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy
4. Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of less than 6 months.
5. Constitutional symptoms, defined as any one or more of the following disease-related symptoms or signs:
1. Unintentional weight loss of 10% or more within the previous 6 months;
2. Significant fatigue (ie, ECOG PS 2 or worse; inability to work or perform usual activities);
3. Fevers higher than 100.5°F or 38.0°C for 2 or more weeks without other evidence of infection; or
4. Night sweats for more than 1 month without evidence of infection.
5. Patients who have resistant disease after primary treatment
6. Patients who have a short time to progression after the first treatment (less than 2 years)
OR
2. Indolent or aggressive B-cell lymphoma (or other B-cell neoplasm) monoclonal for Kappa-light chain with measurable disease after receiving at least one chemotherapy regimen that includes Rituximab or an equivalent monoclonal antibody
OR
3. Multiple myeloma monoclonal for Kappa-light chain with measurable disease after receiving at least one chemotherapy regimen
* Life expectancy of at least 12 weeks or greater.
* Recovered from the toxic effects of all prior chemotherapy before entering this study. PD1/PDL1 inhibitors will be allowed if medically indicated
* ANC \> 500, Hgb greater than or equal to 7.0.
* Bilirubin less than 3 times the upper limit of normal.
* AST less than 5 times the upper limit of normal.
* Estimated GFR \> 50mL/min
* Pulse oximetry of \> 90% on room air
* Karnofsky score of \> 60%.
* Negative serology for HIV.
* Available autologous transduced peripheral blood T-cells with 15% or more expression of CAR-Kappa determined by flow-cytometry.
* Patients must sign an informed consent indicating that they are aware this is a research study and have been told of its possible benefits and toxic side effects. Patients will be given a copy of the consent form.
* Sexually active patients must be willing to utilize one of the more effective birth control methods during the study and for 3 months after the study is concluded. The male partner should use a condom.
* If patient has CLL, must have negative Coombs test.
EXCLUSION CRITERIA:
BLOOD PROCUREMENT:
* Active infection requiring antibiotics
* Active autoimmune disease
T CELL TREATMENT:
* Symptomatic cardiac disease.
* History of hypersensitivity reactions to murine protein-containing products. Currently receiving any investigational agents within the previous six weeks or received any tumor vaccines within the previous 6 weeks.
* Tumor in a location where enlargement could cause airway obstruction.
* Pregnant or lactating.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：Number of Patients with Dose-Limiting Toxicities (DLT) · DLT will be defined as any grade 3-5 toxicity that is NOT (1) pre-existing, or (2) due to infection (to which patients with CLL and NHL are so predisposed), or (3) due to underlying malignancy, and that is considered to be possibly, probably, or definitely related to the study drug. Toxicity will be evaluated using NCI criteria version 4.X. · 6 weeks
次要终点：To measure the anti-tumor effects of CAR-K+ T lymphocytes.
化疗后至少24小时输注T细胞。将评估3个剂量水平，每个剂量水平纳入2人队列。每名患者接受一次注射，体积2–30 mL，输注时长1至20分钟。
化疗后至少24小时输注T细胞。将评估3个剂量水平，每个剂量水平纳入2人队列。每名患者接受一次注射，体积2–30 mL，输注时长1至20分钟。
化疗后至少24小时输注T细胞。将评估3个剂量水平，每个剂量水平纳入2人队列。每名患者接受一次注射，体积2–30 mL，输注时长1至20分钟。
患者患有称为非霍奇金淋巴瘤（NHL）、多发性骨髓瘤（MM）或慢性淋巴细胞白血病（CLL）的癌症，且疾病经治疗后复发或未消退。目前尚无针对这类癌症的标准治疗，或现有治疗无法使所有此类病例获得完全缓解。这是一项使用特殊免疫细胞的基因转移研究。 人体有多种对抗感染和疾病的方式，但没有一种方式能完美地对抗癌症。本研究将研究人员希望能协同作用的两种抗病方式结合起来：抗体和T细胞。抗体是一类可保护人体免受细菌及其他疾病侵害的蛋白质。T细胞（又称T淋巴细胞）是能够抵抗感染的特殊血细胞，可杀伤其他细胞，包括肿瘤细胞。抗体和T细胞均已用于癌症治疗并显示出潜力，但目前尚不足以治愈大多数患者。 本研究使用的抗体可识别淋巴瘤、多发性骨髓瘤或CLL细胞上的κ免疫球蛋白。该抗体识别肿瘤细胞上的κ分子后即可结合肿瘤细胞。本研究对κ抗体进行了改造，使其不再游离于血液中，而是与T细胞连接。这种与T细胞连接的抗体称为嵌合受体。嵌合受体T细胞似乎能够杀伤部分肿瘤，但在体内存留时间不长，因此抗癌作用有限。 研究人员在实验室发现，若加入一种称为CD28、可刺激T细胞生长的蛋白质，T细胞的作用会更好。研究人员将抗κ抗体与T细胞连接并加入CD28，期望制备出能在体内存留更久、效果更好的细胞。 此前参加本研究的患者被分配接受三个不同剂量水平之一的κ-CD28 T细胞。研究发现这三个剂量水平均安全。目前计划为患者使用已测试的最高剂量。 κ-CD28嵌合T细胞为尚未获美国食品药品监督管理局（FDA）批准的研究性产品。
Patients have a type of cancer called NHL, Multiple Myeloma (MM) or CLL that has come back or has not gone away after treatment. There is no standard treatment for the cancer at this time or the currently used treatments do not work completely in all cases like these. This is a gene transfer research study using special immune cells. The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting disease, antibodies and T cells, that investigators hope will work together. Antibodies are types of proteins that protect the body from bacterial and other diseases. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including tumor cells. Both antibodies and T cells have been used to treat patients with cancers; they have shown promise, but have not been strong enough to cure most patients. The antibody used in this study recognizes a protein on the lymphoma, MM or CLL cells called kappa immunoglobulin. Antibodies can stick to lymphoma, MM or CLL cells when it recognizes the kappa molecules present on the tumor cells. For this study, the kappa antibody has been changed so that instead of floating free in the blood it is now joined to the T cells. When an antibody is joined to a T cell in this way it is called a chimeric receptor. These chimeric receptor-T cells seem to kill some of the tumor, but they don't last very long and so their chances of fighting the cancer are limited. In the laboratory, investigators found that T cells work better if they also add a protein that stimulates T cells to grow called CD28. By joining the anti-kappa antibody to the T cells and adding the CD28, the investigators expect to be able to make cells that will last for a longer time in the body (because of the presence of the CD28). They are hoping this will make the cells work better. Previously, when patients enrolled on this study, they were assigned to one of three different doses of the kappa-CD28 T cells. We found that all three dose levels are safe. Now, the plan is to give patients the highest dose that we tested. These chimeric T cells (kappa-CD28) are an investigational product not approved by the FDA.
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