Combination of CD19 and CD22 CAR-T cell therapy in relapsed B-cell acute lymphoblastic leukemia after allogeneic transplantation
Combination of CD19 and CD22 CAR-T cell therapy in relapsed B-cell acute lymphoblastic leukemia after allogeneic transplantation
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DOI：
10.1002/ajh.26160
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发表时间：
2021-03-29
影响因子：
12.8
通讯作者：
Tong, Chunrong
中科院分区：
文献类型：
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作者：
Liu, Shuangyou;Deng, Biping;Tong, Chunrong
异基因移植后复发的急性淋巴细胞白血病（ALL）的预后是令人沮丧的，当用常规方法治疗时。虽然单靶点CD 19或CD 22嵌合抗原受体（CAR）T细胞疗法在难治性/复发性B-ALL中实现了较高的完全缓解（CR）率，但在大多数患者中无法维持持久缓解。为了延长无复发生存期，我们依次组合了CD 19和CD 22 CAR-T细胞，以治疗淋巴母细胞上同时表达CD 19/CD 22抗原的移植后复发B-ALL患者。收集患者来源的供体细胞以产生CAR-T细胞，所述CAR-T细胞被编码由CD 3 ζ和4-1BB组成的第二代汽车的慢病毒载体转染。第二次T细胞输注安排在第一次CAR-T治疗后至少1个月，通常在6个月内。27例成人和儿童患者，包括11例（41%）髓外疾病（EMD）患者，接受了第一次CD 19 CAR-T治疗，23例（85%）达到CR。随后，27名患者中的21名接受了第二次CD 22 CAR-T，并随访了中位数为19.7（范围5.6-27.3）个月，14例CR，7例复发，2例因疾病进展死亡; Kaplan-Meier生存分析显示，12个月和18个月时的总生存率和无事件生存率分别为88.5%和67.5%。23%的患者发生了CAR-T相关的移植物抗宿主病（GVHD），其中8%新发急性GVHD，15%在CAR-T之前存在持续或恶化的cGVHD。这种CD 19和CD 22 CAR-T序贯治疗的联合策略显著改善了移植后复发的B-ALL患者的长期生存率。
The prognosis of relapsed acute lymphoblastic leukemia (ALL) after allogeneic transplantation is dismal when treated with conventional approaches. While single-target CD19 or CD22 chimeric antigen receptor (CAR) T-cell therapy has achieved high complete remission (CR) rates in refractory/relapsed B-ALL, it could not maintain a durable remission in most patients. To prolong relapse-free survival, we sequentially combined CD19 and CD22 CAR-T cells to treat post-transplant relapsed B-ALL patients with both CD19/CD22 antigen expression on lymphoblasts. Patient-derived donor cells were collected to produce CAR-T cells that were transfected by lentiviral vectors encoding second generation CARs composed of CD3 zeta and 4-1BB. The second T-cell infusion was scheduled at least 1 month, and usually within 6 months after the first CAR-T treatment. Twenty-seven adult and pediatric patients, including 11 (41%) with extramedullary diseases (EMD), received the first CD19 CAR-T and 23 (85%) achieved CR. Subsequently, 21 out of 27 patients received the second CD22 CAR-T and were followed-up for a median of 19.7 (range, 5.6-27.3) months; 14 cases remained in CR, seven relapsed and two of them died from disease progression; Kaplan-Meier survival analysis showed overall survival and event-free survival rates of 88.5% and 67.5%, respectively, at both 12 months and 18 months. CAR-T associated graft-versus-host disease (GVHD) occurred in 23% of patients, with 8% new-onset acute GVHD and 15% persistent or worsened pre-existing cGVHD before CAR-T. This combination strategy of sequential CD19 and CD22 CAR-T therapy significantly improved the long-term survival in B-ALL patients who relapsed after transplantation.