标题: 小鼠同种异基因CD19 CAR-T细胞抗白血病的能力及其导致致命GVHD的潜力 [打印本页] 作者: icartab 时间: 2016-1-9 12:09 标题: 小鼠同种异基因CD19 CAR-T细胞抗白血病的能力及其导致致命GVHD的潜力 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 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,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.