Pegram H J, Purdon T J, van Leeuwen D G, Curran K J, Giralt S A, Barker J N, Brentjens R J
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Leukemia. 2015 Feb;29(2):415-22. doi: 10.1038/leu.2014.215. Epub 2014 Jul 9.
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.
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）患者接受脐带血（UCB）移植（UCBT）后死亡的主要原因。过继转移经改造以表达肿瘤靶向嵌合抗原受体（CAR）的供体来源T细胞，可能会根除移植后持续存在的疾病。然而，由于可用的UCB T细胞数量少以及体外溶细胞性细胞扩增能力有限，UCBT受者无法获得这种治疗。我们开发了一种新策略，可在外源性细胞因子的作用下将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来源T细胞可产生>150倍的扩增，并具有独特的中央记忆/效应细胞表型。此外，UCB T细胞经改造后既表达CD19特异性CAR（1928z），又分泌IL-12。1928z/IL-12 UCB T细胞保留了中央记忆效应细胞表型，并且在体外具有增强的抗肿瘤功效。此外，过继转移1928z/IL-12 UCB T细胞可显著提高携带CD19(+)肿瘤的SCID-Beige小鼠的存活率。CAR改造的UCB T细胞的临床转化可能会增强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。
