Murine allogeneic CD19 CAR T cells harbor potent antileukemic activity but have the potential to mediate lethal GVHD
Murine allogeneic CD19 CAR T cells harbor potent antileukemic activity but have the potential to mediate lethal GVHD
复制标题
DOI：
10.1182/blood-2015-08-664250
复制
发表时间：
2016-03-10
期刊：
影响因子：
20.3
通讯作者：
Fry, Terry J.
中科院分区：
文献类型：
--
作者：
Jacoby, Elad;Yang, Yinmeng;Fry, Terry J.
急性淋巴细胞性白血病(ALL)在骨髓移植(BMT)后持续或复发，预后很差。嵌合抗原受体(CAR)T细胞的成功为用白血病重定向供者来源的T细胞治疗这些患者提供了机会，这种T细胞可能比来自白血病患者的T细胞功能更好，但有可能介导移植物抗宿主病(GVHD)。我们和其他人一起，以前已经证明了在同种异体环境中肿瘤特异性T细胞功能障碍。在这里，我们研究了骨髓移植后的CAR T细胞功能，使用的是免疫活性的小鼠不相合的同种异体移植模型，然后是供者来源的CD19-CAR T细胞。异基因供者来源的CD19-CAR T细胞消除残留的ALL的效力与同基因骨髓移植后给予的相同。令人惊讶的是，同种异体CAR T细胞介导了致死性急性移植物抗宿主病(GVHD)并导致早期死亡，这在这个微小的错配模型中是不典型的。我们证明了同种异体和同基因CAR T细胞都表现出作为效应T细胞的初始扩增，同种异体CAR T细胞的峰值较高，但很快就被删除了。有趣的是，CAR介导的急性GVHD只有在白血病存在的情况下才能看到，这表明CAR与靶细胞的相互作用导致了GVHD。事实上，只有在白血病和CAR T细胞同时存在的情况下，血清IL-6才会升高，在延迟的供者淋巴细胞输注模型中，IL-6中和可以改善GVHD的严重程度。最后，异基因的CD4(+)CAR T细胞与GVHD有关，这与它们在CAR刺激下产生IL-6的能力有关。总之，我们证明了供者来源的同种异体CAR T细胞是活跃的，但具有驱动GVHD的能力。
Acute lymphoblastic leukemia (ALL) persisting or relapsing following 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, which may be more functional than T cells derived from patients with leukemia but have the potential to mediate graft-versus-host disease (GVHD). We, together with others, have previously demonstrated tumor-specific T-cell dysfunction in the allogeneic environment. Here, we studied CAR T-cell function following BMT using an 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, which is 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 induced GVHD. Indeed, serum interleukin (IL)-6 was elevated only in the presence of both leukemia and CAR T cells, and IL-6 neutralization ameliorated the severity of GVHD in a delayed donor lymphocyte infusion 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 donor-derived allogeneic CAR T cells are active but have the capacity to drive GVHD.