Point mutation in CD19 facilitates immune escape of B cell lymphoma from CAR-T cell therapy.
Point mutation in CD19 facilitates immune escape of B cell lymphoma from CAR-T cell therapy.
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CD19点突变促进B细胞淋巴瘤逃避CAR-T细胞治疗
DOI：
10.1136/jitc-2020-001150
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发表时间：
2020-10
影响因子：
10.9
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Zhang Z;Chen X;Tian Y;Li F;Zhao X;Liu J;Yao C;Zhang Y
背景由于CD 19突变导致的肿瘤复发会阻碍嵌合抗原受体（CAR）-T细胞治疗的疗效。在此，我们关注的是在CAR-T细胞输注后B细胞在B细胞的CD 19中表现出点突变的淋巴瘤患者。方法采用流式细胞术检测外周血和骨髓中的CAR-T和CD 19 + B细胞。进行基因组测序以鉴定复发前和复发后样本中CAR-T和CD 19 + B细胞的分子特征。构建汽车中的CD 19，其包含具有FMC 63或21 D4的单链可变片段（scFV）抗体。还通过体外和体内实验评估了CAR-T细胞的细胞毒性功效。结果1例高级别B细胞淋巴瘤患者在接受CD 19 CAR（FMC 63）-T细胞输注后6个月，淋巴瘤完全缓解，但左侧乳腺复发。在CD 19的外显子3中发现突变（p.163. R-L）在患者的恶性B细胞中。在2例对CAR-T细胞治疗表现出耐药性的淋巴瘤患者中，在CD 19的外显子3中检测到突变（第174页）。L-V）。功能分析显示，FMC 63 CAR-T细胞对野生型CD 19+细胞表现出抗肿瘤能力，但无法根除这两种类型的突变CD 19+细胞。有趣的是，21 D4 CAR-T细胞有可能根除这些突变的CD 19+细胞，并对缺失外显子1、2或3的CD 19+细胞表现出高抗肿瘤能力。结论点突变可促进CAR-T细胞治疗的免疫逃逸，替代CAR-T细胞可有效清除突变的B细胞，为复发淋巴瘤患者提供个体化治疗方法。
Background Tumor relapse due to mutation in CD19 can hinder the efficacy of chimeric antigen receptor (CAR)-T cell therapy. Herein, we focused on lymphoma patients whose B cells exhibited a point mutation in CD19 of B cells after CAR-T cell infusion. Methods The CAR-T and CD19+ B cells from peripheral blood or bone marrow were assessed using flow cytometry. Genome sequencing was conducted to identify the molecular characteristics of CAR-T and CD19+ B cells from pre-relapse and postrelapse samples. CD19 in CARs comprising single chain fragments variable (scFV) antibody with FMC63 or 21D4 was constructed. The cytotoxic efficacy of CAR-T cells was also evaluated via in vitro and in vivo experiments. Results A patient with high-grade B cell lymphoma exhibited complete response, but the lymphoma relapsed in her left breast at 6 months after CD19 CAR (FMC63)-T cell infusion. A mutation was found in exon 3 of CD19 (p.163. R-L) in malignant B cells of the patient. In two lymphoma patients who exhibited resistance to CAR-T cell therapy, a mutation was detected in exon 3 of CD19 (p.174. L-V). Functional analysis revealed that FMC63 CAR-T cells exhibited antitumor ability against wild-type CD19+ cells but were unable to eradicate these two types of mutated CD19+ cells. Interestingly, 21D4 CAR-T cells were potentially capable of eradicating these mutated CD19+ cells and exhibiting high antitumor capacity against CD19+ cells with loss of exon 1, 2, or 3. Conclusions These findings suggest that point mutation can facilitate immune escape from CAR-T cell therapy and that alternative CAR-T cells can effectively eradicate the mutated B cells, providing an individualized therapeutic approach for lymphoma patients showing relapse.
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影响因子：
28.5
作者：
Kasakovski D;Xu L;Li Y
通讯作者：
Li Y
DOI：
10.1158/1078-0432.ccr-18-3784
发表时间：
2019-09-01
期刊：
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Fry TJ
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DOI：
10.1097/cji.0000000000000243
发表时间：
2018
期刊：
Journal of immunotherapy (Hagerstown, Md. : 1997)
影响因子：
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作者：
Liu Y;Chen X;Wang D;Li H;Huang J;Zhang Z;Qiao Y;Zhang H;Zeng Y;Tang C;Yang S;Wan X;Chen YH;Zhang Y
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Zhang Y
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影响因子：
82.9
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