肿瘤细胞治疗研究
英文原题：Genetically Modified T-cells (CMV-Specific CD19-CAR T-cells) Plus a Vaccine (CMV-MVA Triplex) for the Treatment of Intermediate or High Grade B-Cell Non-Hodgkin Lymphoma
Genetically Modified T-cells (CMV-Specific CD19-CAR T-cells) Plus a Vaccine (CMV-MVA Triplex) for the Treatment of Intermediate or High Grade B-Cell Non-Hodgkin Lymphoma
分数与星级只用于站内排序 —— 不代表疗效、安全性或个人适用性。
这是一项 I 期注册临床试验，评估抗 CD19 细胞治疗用于淋巴瘤、非霍奇金淋巴瘤的安全性、可行性及初步疗效。当前状态：招募中。计划入组 15 例。试验地点：美国 · 杜阿尔特（共 1 个中心）。登记号：NCT05801913。
不限性别 · ≥ 18 Years
纳入标准： • 受试者和/或法定授权代表提供书面知情同意；适当时按机构规定取得受试者赞同。 • 同意使用诊断性肿瘤活检存档组织；若无可用组织，可由主要研究者批准例外。非英语受试者可在City of Hope认证口译/笔译人员协助下使用简式同意书开始筛选和白细胞单采，同时申请完整译文。 • 年龄≥18岁；Karnofsky体能状态≥70；入组时预期生存期≥16周。 • 复发/难治性中高等级B细胞非霍奇金淋巴瘤（如弥漫大B细胞淋巴瘤、套细胞淋巴瘤或转化型淋巴瘤），需要治疗且不适合、拒绝或既往已接受自体造血细胞移植。City of Hope病理复核须确认诊断材料与既往中高等级CD19阳性恶性肿瘤一致。 • 无白细胞单采、淋巴清除化疗、糖皮质激素、托珠单抗、天花疫苗或其他MVA疫苗的已知禁忌。 • CMV血清学阳性。 • 总血清胆红素≤2.0 mg/dL；Gilbert综合征患者总胆红素≤3.0 mg/dL可入组。AST、ALT均<2.5×ULN。 • 血清肌酐≤2.5×ULN，或按Cockcroft-Gault公式估算肌酐清除率≥40 mL/min；且未接受血液透析。 • ANC≥1,000/μL；初筛时不得通过输血或生长因子达到该标准。血红蛋白≥8 g/dL；初筛时不得通过输血或生长因子达到该标准。血小板≥50,000/μL；若骨髓浆细胞占细胞总量≥50%，须≥30,000/μL；初筛时不得通过输血或生长因子达到该标准。 • 入组前8周内LVEF≥45%。无需吸氧时血氧饱和度>92%。 • 有生育能力女性妊娠试验阴性；如尿检阳性或无法确认阴性，须进行血清妊娠检测。 • 有生育能力的男女同意在整个研究期间及方案治疗末次给药后至少6个月采取有效避孕措施或避免异性性行为。有生育能力指未经手术绝育（男女均适用），或女性停经不超过1年。 排除标准： • 既往异基因干细胞移植；若已从移植中恢复且无活动性移植物抗宿主病（GVHD），则不排除。 • 入组前14天内使用生长因子；入组前7天内输注血小板。 • 同时使用全身性糖皮质激素或长期使用免疫抑制药物。标准剂量近期/当前吸入或外用激素不排除；允许生理替代剂量激素（泼尼松≤5 mg/日或其他糖皮质激素等效剂量）。 • 活动性自身免疫病且需全身免疫抑制治疗。 • 正在接受其他研究药物、其他生物治疗、化疗或放疗。 • 按City of Hope常规诊疗标准存在淋巴清除化疗和/或CAR-T 治疗的禁忌。 • 筛选前2周内有临床显著心律失常，或心律失常经药物治疗仍不稳定。 • 既往视神经炎，或其他累及中枢神经系统的免疫/炎症性疾病（包括癫痫、任何可测量的中枢神经系统占位或其他活动性CNS疾病）。既往CNS疾病经有效治疗达完全缓解（脑脊液白细胞<5/mm³且无原始细胞）者可入组。 • 对与研究药物或西妥昔单抗化学/生物组成相似的化合物有过敏反应史。 • 已知出血性疾病（如血管性血友病）或血友病。 • 筛选前6个月内卒中或颅内出血。 • 其他恶性肿瘤史，但经手术或其他治疗达到根治目的者、皮肤基底细胞癌或局限性皮肤鳞状细胞癌、非肌层浸润性膀胱癌，或根治治疗后至少3年无活动性疾病者除外。 • 临床显著且未控制的疾病；需抗生素治疗的活动性感染；HIV阳性；活动性病毒性肝炎。 • 女性妊娠或哺乳。 • 研究者认为因安全原因禁忌参加研究程序的其他情况；或研究者认为受试者可能无法遵守所有研究程序（包括可行性/后勤方面的依从问题）。
Inclusion Criteria: * Documented informed consent of the participant and/or legally authorized representative * Assent, when appropriate, will be obtained per institutional guidelines * Agreement to allow the use of archival tissue from diagnostic tumor biopsies * If unavailable, exceptions may be granted with study principal investigator (PI) approval * Note: For research participants who do not speak English, a short form consent may be used with a City of Hope (COH) certified interpreter/translator to proceed with screening and leukapheresis, while the request for a translated full consent is processed * Age: \>= 18 years * Karnofsky Performance Status (KPS) \>= 70 * Life expectancy \>= 16 weeks at the time of enrollment * Patients requiring treatment for relapsed or refractory intermediate or high-grade B cell NHL (e.g., diffuse large B-cell lymphoma \[DLBCL\], mantle cell lymphoma \[MCL\], or transformed NHL) who are not eligible for, or who refuse, or have previously received autologous hematopoietic cell transplantation (autoHCT) * Note: COH pathology review should confirm that research participant's diagnostic material is consistent with history of intermediate or high-grade CD19+ malignancy * No known contraindications to leukapheresis, lymphodepleting chemotherapy, steroids or tocilizumab, smallpox vaccine and any other MVA-based vaccines * Patient must be CMV seropositive * Total serum bilirubin =\< 2.0 mg/dL * Participants with Gilbert syndrome may be included if their total bilirubin is =\< 3.0 * Aspartate aminotransferase (AST) \< 2.5 x upper limit of normal (ULN) * Alanine aminotransferase (ALT) \< 2.5 x ULN * Serum creatinine =\< 2.5 x ULN or estimated creatinine clearance of \>= 40 mL/min per the Cockcroft-Gault formula, and the participant is not on hemodialysis * Absolute neutrophil count \>= 1000/uL (Transfusions and growth factors must not be used to meet these requirements at initial screening) * Hemoglobin (Hb) \>= 8 g/dl (Transfusions and growth factors must not be used to meet these requirements at initial screening) * Platelet count \>= 50,000/uL (\>= 30,000/uL if bone marrow plasma cells are \>= 50% of cellularity) (Transfusions and growth factors must not be used to meet these requirements at initial screening) * Left ventricular ejection fraction \>= 45% within 8 weeks before enrollment * Oxygen (O2) saturation \> 92% without requiring supplemental oxygen * Women of childbearing potential (WOCBP): negative urine or serum pregnancy test * If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required * Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of protocol therapy * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only) Exclusion Criteria: * Prior allogeneic stem cell transplant unless the participant has recovered from transplantation and does not have active graft versus host disease (GVHD) * Growth factors within 14 days of enrollment * Platelet transfusions within 7 days of enrollment * Concurrent use of systemic steroids or chronic use of immunosuppressant medications. Recent or current use of inhaled or topical steroids in standard doses is not exclusionary. Physiologic replacement of steroids (prednisone =\< 5 mg/day, or equivalent doses of other corticosteroids) is allowed * Patients with active autoimmune disease requiring systemic immune suppressive therapy are not allowed * Participants may not be receiving any other investigational agents or concurrent biological therapy, chemotherapy, or radiation therapy * Any standard contraindications to lymphodepleting chemotherapy and/or CAR T-cell therapy per standard of care practices at COH * Subjects with clinically significant arrhythmia or arrhythmias not stable on medical management within two weeks of screening * Subjects with a known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the central nervous system (CNS), including seizure disorder, any measurable masses of CNS, or any other active CNS disease * Note: Research participants with a history of CNS disease that has been effectively treated to complete remission (\< 5 white blood cell \[WBC\]/mm\^3 and no blasts in cerebral spinal fluid \[CSF\]) will be eligible * History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agents or cetuximab * Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia * History of stroke or intracranial hemorrhage within 6 months prior to screening * History of other malignancies, except for malignancy surgically resected (or treated with other modalities) with curative intent, basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; non-muscle invasive bladder cancer; malignancy treated with curative intent with no known active disease present for \>= 3 years * Clinically significant uncontrolled illness * Active infection requiring antibiotics * Immunodeficiency virus (human immunodeficiency virus \[HIV\]) positive * Active viral hepatitis * Females only: Pregnant or breastfeeding * Any other condition that would, in the investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns with clinical study procedures * Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
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 toxicity · Toxicities will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0, and the revised American Society for Transplantation and Cellular Therapy (ASTCT) cytokine release syndrome (CRS) grading systems. Will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome. · Up to 28 days；Incidence of adverse events · Will be assessed and graded according to the NCI CTCAE v5.0, and the ASTCT consensus grading for CRS and neurotoxicity associated with immune effector cells. · Up to 15 years
次要终点：Feasibility as assessed by the ability to meet the required cell dose and product release requirement；Short- and long-term cytomegalovirus (CMV)-specific CD19-chimeric antigen receptor (CAR) T cell expansion and persistence；Clinically significant CMV reactivation；Disease response (complete response/minor response/partial response/disease progression/stable disease)；Progression-free survival；Overall survival
第-30天进行白细胞单采，研究期间按标准治疗于第-10至-3天接受淋巴清除化疗。随后第0天静脉输注CMV特异性CD19 CAR-T 细胞；若无不可接受毒性，于第28天及第56天肌内注射CMV-MVA Triplex疫苗。研究期间及随访期间进行X线、PET、CT、MRI检查，并采集血样和进行骨髓活检。
本Ⅰ期研究评估巨细胞病毒（CMV）特异性CD19CAR-T 细胞联合CMV改良痘苗病毒安卡拉（MVA）Triplex疫苗，经淋巴清除后治疗复发/难治性中高等级B细胞非霍奇金淋巴瘤的安全性和可行性。CAR-T 细胞由患者自身T细胞在实验室进行基因修饰，使其识别癌细胞表面蛋白，再扩增并回输。CMV-MVA Triplex疫苗由基因修饰病毒制成，可能增强机体杀伤癌细胞的免疫应答，从而帮助预防肿瘤复发。
This phase I trial studies the safety and feasibility of cytomegalovirus (CMV) specific CD19-chimeric antigen receptor (CAR) T cells in combination with the CMV-modified vaccinia Ankara (MVA) triplex vaccine following lymphodepletion in treating patients with intermediate or high grade B-cell non-Hodgkin lymphoma (NHL) that has come back after a period of improvement (relapsed) or that does not respond to treatment (refectory). CAR T cells are a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added in the laboratory. The special receptor is called CAR. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion. Vaccines such as CMV-MVA triplex are made from gene-modified viruses and may help the body build an effective immune response to kill cancer cells. Giving CMV-specific CD19-CAR T-cells plus the CMV-MVA triplex vaccine may help prevent the cancer from coming back.
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