肿瘤细胞治疗研究
英文原题：CD22-targeted chimeric antigen receptor-modified T cells for children and adults with relapse of B-cell acute lymphoblastic leukemia after CD19-directed immunotherapy.
在极度难治性 B-ALL 中良好的安全性特征和高缓解率支持 CART22-65s 的继续开发，但也提示需要将该产品与 HCT 或其他新策略联合使用。
背景：靶向CD19的嵌合抗原受体（CAR）T细胞治疗后，发生CD19抗原丢失的B细胞急性淋巴细胞白血病（B-ALL）复发患者预后极差，亟需开发新的免疫治疗策略。方法：在儿童和成人B-ALL的平行1期研究中，测试一种新型全人源抗CD22/4-1BB CAR-T细胞构建体CART22-65s。淋巴细胞清除后，按3天分次方案输注CART22-65s；若早期出现细胞因子释放综合征（CRS），可省略第2和第3次输注。结果：纳入22例患者，均在既往接受CD19靶向免疫治疗后复发。19例接受输注（儿童17例，成人2例），其中14例（74%）达到完全缓解（CR）；既往对奥加伊妥珠单抗难治者中有4/6例（67%）缓解。14例CR患者中5例接受造血细胞移植（HCT）巩固治疗。中位随访38个月时，12个月无复发生存率为38.4%（95% CI 19.3%–76.5%），总生存率为52.6%（95% CI 34.3%–80.6%）。2例患者因后续CD22阳性复发再次接受CART22-65s治疗，其中1例再次达到CR。首次输注后发生的CRS（17例，89%）和神经毒性（4例，21%）均为1–2级。唯一的3级CRS/神经毒性及唯一的高级别免疫效应细胞相关噬血细胞性淋巴组织细胞增多症样综合征均发生在再次治疗时。体内细胞动力学qPCR数据显示CART22-65s显著增殖，中位峰值出现在输注后20天；一名仅接受CART22-65s并获得长期缓解的患者，细胞持续至第42个月。结论：CART22-65s在极难治B-ALL中安全性良好、缓解率较高，支持继续开发，但也提示需与HCT或其他新型策略联合。试验注册号：NCT02650414和NCT03620058。
BACKGROUND: Relapse of B-cell acute lymphoblastic leukemia (B-ALL) with CD19-antigen loss after CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has a dismal prognosis. Novel immunotherapeutic strategies for this patient population are urgently needed. METHODS: We tested a novel, fully human anti-CD22/4-1BB CAR T-cell construct, CART22-65s, in parallel phase I studies for pediatric and adult B-ALL. After lymphodepletion, CART22-65s was infused using a 3-day fractionated dosing scheme, allowing for omission of the second and third doses in cases of early cytokine release syndrome (CRS). RESULTS: Twenty-two patients, all with relapse after prior CD19-directed immunotherapy, were enrolled. Of 19 infused patients (pediatric, n=17; adult, n=2), 14 (74%) achieved a complete remission (CR), including 4 of 6 (67%) patients refractory to prior inotuzumab. Five of 14 patients in a CR proceeded to consolidative hematopoietic cell transplantation (HCT). With a median follow-up of 38 months, the 12-month relapse-free survival rate was 38.4% (95% CI 19.3% to 76.5%) and overall survival rate was 52.6% (95% CI 34.3% to 80.6%). Two patients received additional CART22-65s treatments for subsequent CD22-positive relapses; one achieved another CR. All CRS (n=17, 89%) and neurotoxicity (n=4, 21%) events after initial infusion were grades 1-2. The only grade 3 CRS/neurotoxicity and the only high-grade immune effector cell-associated hemophagocytic lymphohistocytosis-like syndrome occurred in the retreatment setting. In vivo cellular kinetic data revealed robust CART22-65s proliferation by quantitative PCR peaking at a median of 20 days postinfusion, with the cells persisting out to month 42 in one patient who achieved a long-term remission with CART22-65s alone. CONCLUSIONS: The favorable safety profile and high remission rates in exceedingly refractory B-ALL support the continued development of CART22-65s but also highlight the need to use the product in combination with HCT or other novel strategies. TRIAL REGISTRATION NUMBERS: NCT02650414 and NCT03620058.
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