肿瘤细胞治疗研究
英文原题：CD19/CD22 Bicistronic Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory B Cell Malignancies
这是一项 I/II 期注册临床试验，评估 CD19T 细胞治疗非霍奇金淋巴瘤、白血病、急性淋巴细胞白血病的安全性、可行性及初步疗效。当前状态：招募中。计划入组 130 例。试验地点：美国 · 贝塞斯达（共 1 个中心）。登记号：NCT05442515。
不限性别 · ≥ 3 Years 且 ≤ 39 Years
入选标准 • 病理确诊B细胞ALL（非单纯睾丸或CNS受累）、ALL转化的CML或高级别淋巴瘤（如Burkitt、B淋巴母细胞淋巴瘤、DLBCL，包括惰性淋巴瘤转化为高级别者）；至少一线标准化疗及一线挽救治疗后复发/难治。Ph+ ALL须既往TKI治疗失败。患者不适合/拒绝异基因SCT，或SCT后复发；且无法及时获得、不适合、接受后复发/失败或未应答于市售CD19 CAR-T产品。入组时须有至少MRD或淋巴瘤PET阳性病灶。 • A1b、B1b、C2b队列：免疫组化显示CD19在>15%恶性细胞表达，或流式显示>80%表达，并确认CD22阳性。D1b、2 B-ALL队列：确认CD19或CD22阳性。 • 入组年龄3至39岁。≥16岁者Karnofsky≥50%；<16岁者Lansky≥50%。 • 器官及骨髓功能：白细胞≥750/μL；血小板≥50,000/μL；总胆红素≤2×ULN（有记录Gilbert病且>3×ULN者按方案例外）；AST/ALT≤机构ULN的10倍。肌酐须不超过年龄上限（≤5岁0.8 mg/dL；6至10岁1.0；>10岁1.2）；超出时肌酐清除率须≥60 mL/min/1.73m²。由白血病骨髓受累所致的≥3级全血细胞减少不单独构成排除。 • CNS 1或2级白血病可入组，且无排除标准所列情况。 • 有生育/使他人受孕能力者同意避孕：女性至治疗结束后12个月，男性至结束后4个月。哺乳者或计划哺乳者同意治疗期间停哺乳，且CAR给药后至少1个月继续停哺。 • 心功能：LVEF≥45%或短轴缩短率≥28%。肺功能：静息室内空气血氧>92%。 • 受试者或法定授权代表能理解并签署书面知情同意，并同意共同参加15-C-0028基因治疗迟发不良事件随访研究。 排除标准 • CNS 3级病变、进展性CNS神经体征或影像学活动性CNS淋巴瘤。既往CNS受累残留且稳定/不可逆表现（如失明）不排除。 • 高白细胞血症（原始细胞≥50,000/μL）。 • 筛查血清或尿β-HCG妊娠试验阳性。 • 既往治疗未满足洗脱期：全身化疗、抗肿瘤药或抗体治疗至少2周；氯法拉滨或亚硝基脲至少6周。既往鞘内化疗、类固醇、羟基脲（前2周剂量未增加）或ALL维持治疗（长春新碱、6-巯基嘌呤、口服甲氨蝶呤，Ph+ ALL可含TKI）无固定洗脱期，但急性毒性须恢复。放疗至少3周；骨髓照射体积<10%且照射野外有可评估病灶者无固定间隔。异基因SCT须≥100天、免疫抑制结束≥30天、供者淋巴细胞输注≥6周，且无需全身免疫抑制的活动GVHD。CAR-T或其他过继细胞治疗输注后须>30天再单采。 • HIV抗体阳性提示活动感染；丙肝抗体阳性或乙肝表面抗原阳性提示现症感染。 • 活动性第二恶性肿瘤（宫颈原位癌除外），除非至少2年前已根治且目前缓解。 • 对研究药物或细胞制备所用相似化学/生物成分曾有严重即刻超敏反应。 • 未控制的有症状并发疾病或社会情况会妨碍依从，或主要研究者认为会对受试者造成不可接受风险。
* INCLUSION CRITERIA:
* Diagnosis
* Participant must:
* Have pathology confirmed B cell ALL (not isolated to the testis or CNS), CML with ALL transformation, or high-grade lymphoma (e.g., Burkitt's lymphoma, B-lymphoblastic lymphoma, diffuse large B-cell lymphoma, inclusive of low-grade lymphoma that has transformed to high grade disease); and
* Have relapsed or been refractory after at least one standard chemotherapy regimen and at least one salvage treatment. Participants with Philadelphia chromosome + ALL must have failed prior tyrosine kinase inhibitor; and
* Be ineligible for allogeneic stem cell transplant (SCT), have refused SCT, or have recurred after SCT; and
* Be unable to access (in a timely manner), ineligible for, or have relapsed/failed after or not responded to a commercially available CD19 CAR T-cell construct; and
* Have evidence of at least minimal residual disease or PET-avid disease (lymphoma) at the time of enrollment.
* CD22/CD19 expression
* Cohorts A1b, B1b, C2b
* CD19 must be detected on \>15% of the malignant cells by immunohistochemistry or \> 80% by flow cytometry.
* CD22 positivity must be confirmed.
* Cohorts D1b, 2 B-ALL
* CD19 or CD22 positivity must be confirmed
* Age \>= 3 years of age and \<=39 years of age at time of enrollment.
* Clinical Performance status: Participants \>= 16 years of age: Karnofsky \>= 50%; Participants \< 16 years of age: Lansky scale \>= 50%.
* Participants must have adequate organ and marrow function as defined below:
* leukocytes \>= 750/mcL\*
* platelets \>= 50,000/mcL\*
* total bilirubin \<=2 X ULN (except in the case of participants with documented Gilbert's disease \> 3x ULN)
* AST(SGOT)/ALT(SGPT) \<=10 X institutional upper limit of normal
* creatinine \<= the maximum for age listed in the table below OR
* measured creatinine clearance \>=60 mL/min/1.73 m\^2 for participants with creatinine levels above the max listed below per age.
* Age (Years) \<= 5 / Maximum Serum Creatinine (mg/dL) \<= 0.8
* Age (Years) 6 to \<= 10 / Maximum Serum Creatinine (mg/dL) \<= 1.0
* Age (Years) \>10 / Maximum Serum Creatinine (mg/dL) \<= 1.2
* a participant will not be excluded because of pancytopenia \>= Grade 3 if it is due to underlying bone marrow involvement by leukemia
* Central nervous system (CNS) Status
* Participants with leukemia with CNS 1 and 2 disease are eligible in the absence of exclusion criteria
* Participants of child-bearing or child-fathering potential must be willing to practice effective birth control from the time of enrollment until 12 months following completion of study treatment for women and for 4 months following completion of study treatment for men.
* Participants who are breastfeeding or plan to breastfeed must agree to discontinue/postpone breastfeeding while on study therapy and until 1 month after the administration of CAR.
* Cardiac function: Left ventricular ejection fraction \>= 45% or fractional shortening \>=28%
* Pulmonary Function
* Baseline oxygen saturation \>92% on room air at rest
* Ability of participant or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document.
* Ability and willingness of participant or Legally Authorized Representative (LAR) to co- enroll on 15-C-0028: Follow-up Evaluation for Gene-Therapy Related Delayed Adverse Events after Participation in Pediatric Oncology Branch Clinical Trials.
EXCLUSION CRITERIA:
Participants meeting any of the following criteria are not eligible for participation in the study:
* Participants with CNS3 disease, progressing neurologic signs\* of CNS disease, radiologically detected active CNS lymphoma (\*resolving manifestation or persistent and/or irreversible findings from prior CNS involvement (e.g., blindness) is not exclusionary)
* Hyperleukocytosis (\>= 50,000 blasts/microL)
* Positive serum or urine beta-HCG pregnancy test performed at screening.
* Participants will be excluded based on prior therapy if they fail to meet following washout criteria:
* Therapy: Systemic Chemotherapy, anti-neoplastic agents, antibody- based therapies
* Washout\*: \>=2 weeks
* Exceptions: 6 weeks for clofarabine or nitrosoureas; No washout for prior intrathecal chemotherapy, steroid therapy, hydroxyurea (no dose increases within prior 2 weeks) or ALL maintenance-type chemotherapy (vincristine, 6-mercaptopurine, oral methotrexate, or a tyrosine kinase inhibitor for participants with Ph+ ALL) provided there is recovery from any acute toxic effects
* Therapy: Radiation
* Washout\*: \>=3 weeks
* Exceptions: No time restriction with radiation therapy if the volume of bone marrow treated is less than 10% and the participant has measurable/evaluable disease outside the radiation window
* Therapy: Allogeneic Stem Cell Transplant
* Washout\*: \>= 100 days since SCT; \>= 30 days since completion of immunosuppression; \>= 6 weeks since donor lymphocyte infusion (DLI)
* Exceptions: Cannot have evidence of active graft-versus-host disease (GVHD) requiring systemic immunosuppression
* Therapy: CAR T-Cell Therapy or other Adoptive Cell Therapy
* Washout\*: \> 30 days post infusion
* Washout: Time between therapy and apheresis
* Positive HIV antibodies consistent with active HIV.
* Positive hepatitis C antibodies or positive Hepatitis B surface antigen (HbsAG) indicative of current/active HCV/HBV.
* Active second malignancy other than in situ carcinoma of the cervix, unless the tumor was treated with curative intent at least two years previously and participant is in remission.
* History of severe, immediate hypersensitivity reaction attributed to compounds of similar chemical or biologic composition to any agents used in study or in the manufacturing of the cells.
* Uncontrolled, symptomatic, intercurrent illness or social situations that would limit compliance with study requirements or in the opinion of the PI would pose an unacceptable risk to the participant.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：Safety · Assess the safety of administering escalating doses of autologous CD19/CD22-CAR engineered T cells in children and young adult with B cell ALL or lymphoma following a cyclophosphamide/fludarabine LD. · 30 days post CAR T infusion；Efficacy · Determine the efficacy of CD19/CD22 therapy in participants with B-ALL/B-LBL. · Monthly until 3 months post CAR T infusion and then at 6 months and every 6 months after that, for 2 years post-infusion for each participant, up to 2 years after the entry date of the last participant.
次要终点：Assess response and toxicity (CRS grade)；Overall response rate；Progression free survival (PFS) and Overall survival (OS)；Persistence and expansion；Adverse Events；Feasibility
逐步增加CD19/CD22 CAR转导T细胞剂量，联合标准淋巴清除（氟达拉滨75 mg/m²及环磷酰胺900 mg/m²）。
输注CD19/CD22 CAR转导T细胞。
逐步增加CD19/CD22 CAR转导T细胞剂量，联合强化淋巴清除（氟达拉滨120 mg/m²及环磷酰胺1,200 mg/m²）。
输注CD19/CD22 CAR转导T细胞。
以最大耐受剂量或已给出的最高剂量输注CD19/CD22 CAR转导T细胞并联合淋巴清除。
输注CD19/CD22 CAR转导T细胞，适用于CD19或CD22任一阳性者。
以最大耐受剂量或已给出的最高剂量输注CD19/CD22 CAR转导T细胞并采用方案2淋巴清除。
以II期推荐剂量输注CD19/CD22 CAR转导T细胞。
本研究评估CD19/CD22双靶点嵌合抗原受体T细胞治疗复发/难治性B细胞恶性肿瘤儿童及青年患者的安全性和疗效。受试者接受筛查、白细胞单采和T细胞基因改造，随后接受化疗及CAR-T输注；治疗后密集随访28天，并继续长期随访。
Background: Acute lymphoblastic leukemia (ALL) is the most common cancer in children. About 90% of children and young adults who are treated for ALL can now be cured. But if the disease comes back, the survival rate drops to less than 50%. Better treatments are needed for ALL relapses. Objective: To test chimeric antigen receptor (CAR) therapy. CARs are genetically modified cells created from each patient s own blood cells. his trial will use a new type of CAR T-cell that is targeting both CD19 and CD22 at the same time. CD19 and CD22 are proteins found on the surface of most types of ALL. Eligibility: People aged 3 to 39 with ALL or related B-cell lymphoma that has not been cured by standard therapy. Design: Participants will be screened. This will include: Physical exam Blood and urine tests Tests of their lung and heart function Imaging scans Bone marrow biopsy. A large needle will be inserted into the body to draw some tissues from the interior of a bone. Lumbar puncture. A needle will be inserted into the lower back to draw fluid from the area around the spinal cord. Participants will undergo apheresis. Their blood will circulate through a machine that separates blood into different parts. The portion containing T cells will be collected; the remaining cells and fluids will be returned to the body. The T cells will be changed in a laboratory to make them better at fighting cancer cells. Participants will receive chemotherapy starting 4 or 5 days before the CAR treatment. Participants will be admitted to the hospital. Their own modified T cells will be returned to their body. Participants will visit the clinic 2 times a week for 28 days after treatment. Follow-up will continue for 15 years....
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