IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia.
IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia.
复制标题
作者：
疾病复发或进展是高危、复发或难治性急性淋巴细胞白血病（ALL）患者脐带血（UCB）移植（UCBT）后死亡的主要原因。连续转移经修饰以表达肿瘤靶向嵌合抗原受体（CAR）的供体来源的T细胞可以根除移植后的持续性疾病。然而，由于可用的UCB T细胞数量少以及溶细胞细胞的离体扩增能力有限，UCBT接受者无法获得这种治疗。我们已经开发了一种新的策略，在外源性细胞因子的背景下将UCB T细胞扩增至临床相关数量。用白细胞介素（IL）-12和IL-15培养的UCB衍生的T细胞产生>150倍的扩增，具有独特的中枢记忆/效应表型。此外，UCB T细胞经修饰以表达CD 19特异性CAR 1928 z并分泌IL-12。1928 z/IL-12 UCB T细胞保留了中枢记忆效应表型，并在体外具有增加的抗肿瘤功效。此外，1928 z/IL-12 UCB T细胞的过继转移导致携带CD 19+肿瘤的SCID-米色小鼠的存活率显著提高。CAR修饰的UCB T细胞的临床翻译可以增强UCBT后的移植物抗白血病效应，从而进一步提高B细胞ALL移植患者的无病生存率。
Disease relapse or progression is a major cause of death following umbilical cord blood (UCB) transplantation (UCBT) in patients with high-risk, relapsed or refractory acute lymphoblastic leukemia (ALL). Adoptive transfer of donor-derived T cells modified to express a tumor-targeted chimeric antigen receptor (CAR) may eradicate persistent disease after transplantation. Such therapy has not been available to UCBT recipients, however, due to the low numbers of available UCB T cells and the limited capacity for ex vivo expansion of cytolytic cells. We have developed a novel strategy to expand UCB T cells to clinically relevant numbers in the context of exogenous cytokines. UCB-derived T cells cultured with interleukin (IL)-12 and IL-15 generated >150-fold expansion with a unique central memory/effector phenotype. Moreover, UCB T cells were modified to both express the CD19-specific CAR, 1928z, and secrete IL-12. 1928z/IL-12 UCB T cells retained a central memory-effector phenotype and had increased antitumor efficacy in vitro. Furthermore, adoptive transfer of 1928z/IL-12 UCB T cells resulted in significantly enhanced survival of CD19+ tumor-bearing SCID-Beige mice. Clinical translation of CAR-modified UCB T cells could augment the graft-versus-leukemia effect after UCBT and thus further improve disease-free survival of transplant patients with B-cell ALL.
登录
查看更多内容
影响因子：
20.3
作者：
Smith, Brenden W.;Rozelle, Sarah S.;Murphy, George J.
通讯作者：
Murphy, George J.
影响因子：
17.1
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
通讯作者：
Sadelain M
影响因子：
20.3
作者：
Verneris, Michael R.;Brunstein, Claudio G.;Wagner, John E.
通讯作者：
Wagner, John E.
影响因子：
20.3
作者：
Serrano, LM;Pfeiffer, T;Cooper, LJN
通讯作者：
Cooper, LJN
影响因子：
11.2
作者：
Wang, Leanne X. J.;Westwood, Jennifer A.;Darcy, Phillip K.
通讯作者：
Darcy, Phillip K.