Genetic Inactivation of CD33 in Hematopoietic Stem Cells to Enable CAR T Cell Immunotherapy for Acute Myeloid Leukemia.
Genetic Inactivation of CD33 in Hematopoietic Stem Cells to Enable CAR T Cell Immunotherapy for Acute Myeloid Leukemia.
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CD33在造血干细胞中的遗传失活，使CAR T细胞免疫疗法患有急性髓样白血病。
DOI：
10.1016/j.cell.2018.05.013
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发表时间：
2018-05-31
期刊：
影响因子：
64.5
通讯作者：
Gill S
中科院分区：
文献类型：
--
作者：
Kim MY;Yu KR;Kenderian SS;Ruella M;Chen S;Shin TH;Aljanahi AA;Schreeder D;Klichinsky M;Shestova O;Kozlowski MS;Cummins KD;Shan X;Shestov M;Bagg A;Morrissette JJD;Sekhri P;Lazzarotto CR;Calvo KR;Kuhns DB;Donahue RE;Behbehani GK;Tsai SQ;Dunbar CE;Gill S
缺乏癌症限制性表面标志物是使用嵌合抗原受体（CAR）T细胞进行抗原特异性免疫治疗的主要障碍。例如，靶向急性髓性白血病（AML）中的典型髓性标志物CD 33导致来自正常髓性细胞破坏的毒性。我们假设白血病特异性抗原可以通过从正常造血干细胞和祖细胞（HSPC）中删除CD 33来产生，从而产生对CD 33靶向治疗具有抗性的造血系统，并使CAR T细胞能够特异性靶向AML。我们产生了CD 33缺陷型人HSPC，并在免疫缺陷小鼠中证明了正常的植入和分化。恒河猴中的自体CD 33 KO HSPC移植显示了基因编辑细胞的长期多谱系植入，具有正常的骨髓功能。CD 33缺陷细胞对靶向CD 33的CAR T细胞不敏感，从而允许有效消除白血病而不产生骨髓毒性。这些研究阐明了一种新的抗原特异性免疫治疗方法，通过遗传工程改造宿主，以避免靶向，脱肿瘤毒性。用CD 33阴性人造血干细胞重建免疫系统使得抗CD 33 CAR-T细胞能够杀死急性髓性白血病，同时保留髓样发育和功能。
The absence of cancer-restricted surface markers is a major impediment to antigen-specific immunotherapy using chimeric antigen receptor (CAR) T cells. For example, targeting the canonical myeloid marker CD33 in acute myeloid leukemia (AML) results in toxicity from destruction of normal myeloid cells. We hypothesized that a leukemia-specific antigen could be created by deleting CD33 from normal hematopoietic stem and progenitor cells (HSPC), thereby generating a hematopoietic system resistant to CD33-targeted therapy and enabling specific targeting of AML with CAR T cells. We generated CD33-deficient human HSPC and demonstrated normal engraftment and differentiation in immunodeficient mice. Autologous CD33 KO HSPC transplantation in rhesus macaques demonstrated long-term multilineage engraftment of gene-edited cells, with normal myeloid function. CD33-deficient cells were impervious to CD33-targeting CAR T cells, allowing for efficient elimination of leukemia without myelotoxicity. These studies illuminate a novel approach to antigen-specific immunotherapy by genetically engineering the host to avoid on-target, off-tumor toxicity. Reconstitution of the immune system with CD33 negative human hematopoietic stem cells enables anti-CD33 CAR-T cell killing of acute myeloid leukemia while sparing myeloid development and function.
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影响因子：
11.4
作者：
Kenderian SS;Ruella M;Shestova O;Klichinsky M;Aikawa V;Morrissette JJ;Scholler J;Song D;Porter DL;Carroll M;June CH;Gill S
通讯作者：
Gill S
影响因子：
64.5
作者：
Levine JH;Simonds EF;Bendall SC;Davis KL;Amir el-AD;Tadmor MD;Litvin O;Fienberg HG;Jager A;Zunder ER;Finck R;Gedman AL;Radtke I;Downing JR;Pe'er D;Nolan GP
通讯作者：
Nolan GP
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
64.8
作者：
Genovese, Pietro;Schiroli, Giulia;Escobar, Giulia;Di Tomaso, Tiziano;Firrito, Claudia;Calabria, Andrea;Moi, Davide;Mazzieri, Roberta;Bonini, Chiara;Holmes, Michael C.;Gregory, Philip D.;van der Burg, Mirjam;Gentner, Bernhard;Montini, Eugenio;Lombardo, Angelo;Naldini, Luigi
通讯作者：
Naldini, Luigi
影响因子：
20.3
作者：
Appelbaum, Frederick R.;Bernstein, Irwin D.
通讯作者：
Bernstein, Irwin D.