CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia.
CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia.
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DOI：
10.1126/scitranslmed.3005930
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发表时间：
2013-03-20
影响因子：
17.1
通讯作者：
Sadelain M
中科院分区：
文献类型：
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作者：
Brentjens RJ;Davila ML;Riviere I;Park J;Wang X;Cowell LG;Bartido S;Stefanski J;Taylor C;Olszewska M;Borquez-Ojeda O;Qu J;Wasielewska T;He Q;Bernal Y;Rijo IV;Hedvat C;Kobos R;Curran K;Steinherz P;Jurcic J;Rosenblat T;Maslak P;Frattini M;Sadelain M
成人复发性B-急性淋巴细胞性白血病(ALL)预后很差。只有那些能够在没有微小残留病的情况下实现二次缓解(mrd-−)的患者才有希望在随后的异基因造血干细胞移植(allo-hsct)中长期存活。我们对5例复发的B-ALL患者进行了自体T细胞治疗，T细胞表达CD19二代双信号嵌合抗原受体(ζ)，命名为19-28Z。所有接受T细胞输注的持续性形态疾病或MRD+疾病的患者均显示肿瘤迅速根除，并通过深度测序PCR评估获得MRD阴性的完全缓解。治疗耐受性良好，尽管显著的细胞因子升高，尤其是在治疗时有疾病形态证据的患者中观察到的，需要淋巴毒性类固醇治疗来减轻细胞因子介导的毒性。值得注意的是，细胞因子升高与CAR修饰T细胞输注时的肿瘤负荷直接相关。1例经CAR修饰的T细胞治疗后复发的患者的肿瘤细胞不能接受额外的allo-HSCT治疗，显示CD19持续表达和对自体19-28Z T细胞介导的细胞毒敏感，提示额外的CAR修饰的T细胞输注具有潜在的临床益处。这些结果证明了19-28Z CAR修饰的T细胞在复发性/难治性B-ALL患者中的显著抗肿瘤效果，以及这种新疗法诱导分子显著缓解的可靠性，是通往随后allo-HSCT潜在治愈疗法的理想桥梁。
Adults with relapsed B-acute lymphoblastic leukemia (ALL) have a dismal prognosis. Only those patients able to achieve a second remission with no minimal residual disease (MRD−) have a hope for long-term survival in the context of a subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have treated 5 relapsed B-ALL subjects with autologous T cells expressing a CD19-specific CD28/CD3ζ second generation dual-signaling chimeric antigen receptor (CAR) termed 19-28z. All patients with persistent morphological disease or MRD+ disease upon T cell infusion demonstrated rapid tumor eradication and achieved MRD-negative complete remissions as assessed by deep sequencing PCR. Therapy was well tolerated although significant cytokine elevations, specifically observed in those patients with morphologic evidence of disease at the time of treatment, required lymphotoxic steroid therapy to ameliorate cytokine-mediated toxicities. Significantly, cytokine elevations directly correlated to tumor burden at the time of CAR modified T cell infusions. Tumor cells from one patient with relapsed disease after CAR modified T cell therapy, ineligible for additional allo-HSCT therapy, exhibited persistent expression of CD19 and sensitivity to autologous 19-28z T cell mediated cytotoxicity suggesting potential clinical benefit of additional CAR modified T cell infusions. These results demonstrate the marked anti-tumor efficacy of 19-28z CAR modified T cells in patients with relapsed/refractory B-ALL and the reliability of this novel therapy to induce profound molecular remissions, an ideal bridge to potentially curative therapy with subsequent allo-HSCT.
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DOI：
10.1097/cji.0b013e318194a6e8
发表时间：
2009-02
期刊：
Journal of immunotherapy (Hagerstown, Md. : 1997)
影响因子：
--
作者：
Hollyman D;Stefanski J;Przybylowski M;Bartido S;Borquez-Ojeda O;Taylor C;Yeh R;Capacio V;Olszewska M;Hosey J;Sadelain M;Brentjens RJ;Rivière I
通讯作者：
Rivière I
影响因子：
51.1
作者：
Kantarjian, Hagop;Thomas, Deborah;O'Brien, Susan
通讯作者：
O'Brien, Susan
影响因子：
20.3
作者：
Kochenderfer, James N.;Wilson, Wyndham H.;Rosenberg, Steven A.
通讯作者：
Rosenberg, Steven A.
影响因子：
12.4
作者：
Zhong, Xiao-Song;Matsushita, Maiko;Sadelain, Michel
通讯作者：
Sadelain, Michel
带有嵌合抗原受体的T细胞具有有效的抗肿瘤作用，可以在晚期白血病患者中建立记忆。
影响因子：
17.1
作者：
Kalos M;Levine BL;Porter DL;Katz S;Grupp SA;Bagg A;June CH
通讯作者：
June CH