肿瘤细胞治疗研究
英文原题：CARPALL: Immunotherapy With CD19+CD22 CAR T-cells for CD19+ and CD22+ Acute Lymphoblastic Leukaemia
这是一项 I 期注册临床试验，评估 CD19CAR-T 细胞治疗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 50 例。试验地点：欧洲 · 伦敦、曼彻斯特（共 3 个中心）。登记号：NCT02443831。
不限性别 · ≤ 24 Years
纳入标准 1. 年龄≤24岁的儿童和年轻成人，患高危或复发性CD19阳性、CD22阳性急性淋巴细胞白血病（ALL），并符合以下至少一项： 1）ALLTogether-1方案或等效诱导治疗结束时疾病耐药（原始细胞>5%）。 2）一线国家方案第2个时间点仍有较高水平微小残留病（MRD）（目前定义为ALLTogether-1方案第9周MRD>10⁻⁴或等效标准）。 3）高危婴儿ALL：诊断时年龄<6个月，伴MLL基因重排，且初诊白细胞计数>300×10⁹/L，或早期激素应答不佳（即按国家指南或等效方案完成7天诱导前激素治疗后，循环原始细胞计数>1×10⁹/L）。 4）任何携带t(17;19) TCF3-HLF重排的患者。 5）高危首次复发，包括极早期复发（诊断后18个月内）、早期复发（治疗期间或治疗结束后6个月内复发），以及伴高危遗传学特征的任何复发；高危遗传学特征包括KMT2A（MLL）重排、低二倍体／近单倍体、t(17;19)(q22;p13)/TCF3-HLF、iAMP21、t(1;19)(q21;p13)/TCF3-PBX1或t(9;22)(34.1 q11.2)/BCR-ABL1。 6）16～24岁患者在治疗期间复发。 7）婴儿ALL任何复发。 8）ALL第二次或以上复发。 9）任何难治性ALL复发（定义为至少接受1个标准化疗周期后，流式细胞术检测原始细胞>1%）。 10）计划进行干细胞移植前MRD>10⁻⁴。 11）复发性ALL患者符合干细胞移植条件，但无可用HLA相合供者或存在其他移植禁忌。 12）干细胞移植后ALL复发，且计划输注CD19+CD22 CAR-T细胞的时间距移植>4个月。 13）接受tisagenlecleucel抗CD19 CAR-T治疗后早期（定义为输注后<6个月）B细胞再生障碍消失，或出现任何CD19+CD22+复发。 注：符合上述一项或多项条件的单纯CNS复发患者可参加本研究。 2. 同意接受妊娠检测，并在适用时采取充分避孕措施。 3. 签署书面知情同意书。 登记阶段排除标准 1. 活动性乙型肝炎、丙型肝炎或HIV感染。 2. 未吸氧时血氧饱和度≤90%。 3. 胆红素>正常上限的3倍。 4. 肌酐>正常上限的3倍。 5. 妊娠或哺乳期。 6. 仅适用于干细胞移植患者：存在活动性显著急性移植物抗宿主病（GVHD；西雅图标准总体≥Ⅱ级）或需要全身激素治疗的中重度慢性GVHD（NIH共识标准）。 7. 无法耐受白细胞单采。 8. Karnofsky评分（年龄≥10岁）或Lansky评分（年龄<10岁）≤50%。 9. 既往存在显著神经系统疾病（基础血液系统恶性肿瘤CNS受累除外）。 10. 疾病为CD19阴性或CD22阴性。 CD19+CD22 CAR-T细胞输注阶段排除标准 1. 计划输注CD19+CD22 CAR-T细胞时存在严重并发感染。 2. 计划输注时需要补充氧气，或存在活动性肺部浸润。 3. 异基因移植受者在计划输注时存在活动性显著急性GVHD（总体≥Ⅱ级）或需要全身激素治疗的中重度慢性GVHD。注：在GVHD消退且停用激素前，此类患者不符合入组条件。
Inclusion Criteria: 1. Children and young adults (age 24 years or younger) with high risk/relapsed CD19+ and CD22+ acute lymphoblastic leukaemia with: 1. Resistant disease (\>5% blasts) at end of ALLTogether-1 protocol or equivalent induction 2. ALL with persisting high level MRD at 2nd time point of frontline national protocol (currently MRD \>10-4 at week 9 ALLTogether-1 Protocol or equivalent). 3. High risk infant ALL (age \< 6 months at diagnosis with MLL gene rearrangement and either presenting white cell count \> 300 x 10\^9/L or poor steroid early response (i.e. circulating blast count \>1x10\^9/L following 7 day steroid pre-phase of induction as per national guidelines or equivalent) 4. Any patient with t(17,19) TCF3-HLF rearrangement 5. High risk 1st relapse (defined as very early (relapse within 18 months of diagnosis) and early relapses (any patient relapsing on therapy or within 6 months of completing treatment) and any relapse with high risk genetics, namely (KMT2A (MLL) rearrangements, low hypodiploidy/near haploidy, t(17;19)(q22;p13)/TCF3-HLF, iAMP21 and t(1;19)(q21;p13)/TCF3- PBX1, t(9;22)(34.1 q11.2)/BCR-ABL1 6. Any on therapy relapse in patients age 16-24 7. Any relapse of infant ALL 8. ALL post ≥ 2nd relapse 9. Any refractory relapse of ALL (defined as \> 1% blasts by flow cytometry after a at least 1 cycle of standard chemotherapy) 10. ALL with MRD \>10-4 prior to planned stem cell transplant 11. Any relapse of ALL eligible for stem cell transplant but no available HLA matched donor or other contraindication to transplant 12. Any relapse of ALL after stem cell transplant as long as planned time of CD19+CD22CAR T cell infusion is \> 4 months post-transplant 13. Early (defined as \< 6 months post-infusion) loss of B cell aplasia or any CD19+CD22+ relapse following CD19CAR T cell therapy with Tisagenlecleucel Note patients with isolated CNS relapse meeting one or more of the criteria above are eligible for the study 2. Agreement to have a pregnancy test, use adequate contraception (if applicable) 3. Written informed consent Exclusion Criteria: Exclusion Criteria for registration: 1. Active Hepatitis B, C or HIV infection 2. Oxygen saturation ≤ 90% on air 3. Bilirubin \> 3 x upper limit of normal 4. Creatinine \> 3 x upper limit of normal 5. Women who are pregnant or breastfeeding 6. Stem Cell Transplant patients only: active significant (overall Grade ≥ II, Seattle criteria) acute GVHD or moderate/ severe chronic GVHD (NIH consensus criteria) requiring systemic steroids. 7. Inability to tolerate leucapheresis 8. Karnofsky (age ≥ 10 years) or Lansky (age \< 10) score ≤ 50% 9. Pre-existing significant neurological disorder (other than CNS involvement of underlying haematological malignancy) 10. CD19 negative or CD22 negative disease Exclusion criteria for CD19+CD22CAR T-cell infusion: 1. Severe intercurrent infection at the time of scheduled CD19+CD22 CAR T-cell infusion 2. Requirement for supplementary oxygen or active pulmonary infiltrates at the time of scheduled CD19+CD22 CAR T-cell infusion 3. Allogeneic transplant recipients with active significant acute GVHD overall grade ≥II or moderate/severe chronic GVHD requiring systemic steroids at the time of scheduled CD19+CD22 CAR T-cell infusion. Note: Such patients will be excluded until the patient is GVHD free and off steroids
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 unacceptable toxicity following CD19+CD22 CAR T-cell infusion · The incidence of unacceptable toxicity occurring within 28 days of CD19+CD22CAR T-cell infusion. · 28 days；Molecular remission · Efficacy will be assessed by determining Minimal Residual Disease in the bone marrow aspirate using immunoglobulin heavy chain (IgH) quantitative polymerase chain reaction (qPCR) and/or Next Generation Sequencing in all patients. The proportion of patients achieving molecular remission at 28 days post CD19+CD22CAR T-cell infusion will be determined. · 28 days
次要终点：Feasibility of Generation of CD19+CD22 CAR T-cells；Molecular Remission；Long-Term Molecular Remission；Duration of Response；Safety and Tolerability of the CAR T-cells；Incidence of B Aplasia；Incidence of Hypogammaglobulinaemia；Frequency of Circulating CD19+CD22 CAR T-cells
符合入组标准的患者将接受白细胞单采，以分离用于制备CD19+CD22 CAR-T细胞的血液免疫细胞。患者将在输注CD19+CD22 CAR-T细胞前接受低剂量全身照射、氟达拉滨和环磷酰胺淋巴清除治疗。
本研究旨在评估CD19+CD22嵌合抗原受体（CAR）重定向自体T细胞用于高危、复发性CD19+和CD22+儿童急性淋巴细胞白血病的安全性、疗效和缓解持续时间。
This study aims to evaluate the safety, efficacy and duration of response of CD19+CD22 Chimeric Antigen Receptor (CAR) redirected autologous T-cells in children with high risk, relapsed CD19+ and CD22+ acute lymphoblastic leukaemia
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