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小鼠异基因CD19 CAR-T细胞治疗具有强大的抗白血病活性但是可能会导致致命的GVHD

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发表于 2015-12-16 21:41:38 | 显示全部楼层 |阅读模式
Murine allogeneic CD19 CAR T-cells harbor potent anti-leukemic activity but have the potential to mediate lethal GVHD.
Acute lymphoblastic leukemia (ALL) persisting or relapsing following a bone marrow transplantation (BMT) has a dismal prognosis. Success with chimeric-antigen-receptor (CAR) T-cells offers an opportunity to treat these patients with leukemia-redirected donor-derived T-cells, that may be more functional than T-cells derived from patients with leukemia but have the potential to mediate graft versus host disease (GVHD). We and others have previously demonstrated tumor-specific cell dysfunction in the allogeneic environment. Here, we studied CAR T-cell function following BMT using a T-n immunocompetent murine model of minor mismatched allogeneic transplantation followed by donor-derived CD19-CAR T-cells. Allogeneic donor-derived CD19-CAR T-cells eliminated residual ALL with equal potency to those administered after syngeneic BMT. Surprisingly, allogeneic CAR T-cells mediated lethal acute GVHD with early mortality, atypical for this minor mismatch model. We demonstrated that both allogeneic and syngeneic CAR T-cells show initial expansion as effector T-cells, with a higher peak but rapid deletion of allogeneic CAR T-cells. Interestingly, CAR mediated acute GVHD was only seen in the presence of leukemia, suggesting CAR-target interactions inducing GVHD. Indeed, serum interleukin-6 (IL-6) was elevated only in the presence of both leukemia and CAR T-cells, and IL-6 neutralization ameliorated severity of GVHD in a delayed-DLI model. Finally, allogeneic CD4+ CAR T-cells were responsible for GVHD, which correlated with their ability to produce IL-6 upon CAR stimulation. Altogether, we demonstrate that allogeneic CAR T-cells have the capacity to drive GVHD, with significant expansion and later deletion.
小鼠异基因CD19 CAR-T细胞治疗具有强大的抗白血病活性但是可能会导致致命的GVHD
急性淋巴细胞白血病(ALL)在骨髓移植之后会出现持续发病和复发,有一个令人沮丧的预后。使用CAR-T细胞治疗提供了一个成功治疗这些患者的机会,这也许比使用病人来源的T细胞更加有效果,但是会有一个潜在的导致GVHD的可能性。我们事先论证了肿瘤特异性细胞在异体环境下会出现功能障碍。我们利用一个T-N免疫小鼠模型,在骨髓移植之后使用CD 19CAR-T细胞处理,然后研究CAR-T细胞的功能。异基因来源的CD 19 CAR-T细胞消除残余的ALL细胞的能力与同基因骨髓移植具有同等效果。奇怪的是,在轻微不匹配的小鼠模型中,异基因CAR-T细胞治疗会导致严重的急性GVHD,会导致早期死亡。我们发现,同基因和异基因的CAR-T细胞移植在初始阶段,作为效应T细胞都会有一个增长和峰值,但是异基因CAR-T细胞治疗中会迅速出现细胞衰减。有趣的是,CAR介导的急性GVHD只会在白血病中出现,暗示了CAR靶向的目标包括了GVHD事实上,血清白细胞介素-6IL-6)只在白血病和CAR-T存在时升高。最后,异体CD4+CAR T细胞是导致GVHD的原因,这与他们能刺激产生IL-6的能力相关。总之,我们表明,同种异体CAR T细胞治疗对移植物抗宿主病有驱动力,会出现显著的数量扩增扩张和后来的缺失。
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