人正交 IL-2 与 IL-2Rβ 系统增强白血病小鼠模型中 CAR-T 细胞的扩增与抗肿瘤活性

Interleukin-2 (IL-2) is a central T cell cytokine that promotes T cell proliferation and effector function; however, toxicity due to its pluripotency limits its application to enhance CAR T cell immunotherapy. Previously, mouse IL-2 and its cognate receptor were engineered to create an orthogonal ( ortho ) cytokine-cytokine receptor pair capable of delivering an IL-2 signal without toxicity.

Here, we engineered a human orthogonal IL-2 ( ortho- hIL-2) and human orthogonal IL-2R ( ortho- hIL-2R ) pair, containing human-specific mutations. Ortho- hIL-2 is selective toward ortho- hIL-2R expressing cells with no appreciable signaling on wild-type T cells. Ortho- hIL-2 induces IL-2 receptor signaling and supports proliferation of both an IL-2 dependent cell line and primary T cells transduced to express the ortho- hIL-2R .

Using CD19-specific chimeric antigen receptor (CAR) T cells, we show that ortho -hIL-2 induces a dose-dependent increase in ortho -hIL-2R + CAR T cell expansion in vivo by as much as 1000-fold at 2 weeks after adoptive transfer into immunodeficient mice bearing CD19 + Nalm6 leukemia xenografts. Ortho -hIL-2 can rescue the antileukemic effect of an otherwise suboptimal CAR T cell dose.

In addition, ortho -hIL-2 administration initiated at the time of leukemic relapse after CAR T cell therapy can rescue an otherwise failed antileukemic response. These data highlight the potential of combining an orthogonal cytokine approach with T cell based immunotherapies to augment the antitumor efficacy of engineered T cells.