A human orthogonal IL-2 and IL-2Rβ system enhances CAR T cell expansion and antitumor activity in a murine model of leukemia

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 CART 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 beta (ortho-hIL-2R beta) pair, containing human-specific mutations. Ortho-hIL-2 is selective toward ortho-hIL-2R beta-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 beta. Using CD19-specific chimeric antigen receptor (CAR) T cells, we show that ortho-hIL-2 induces a dose-dependent increase in ortho-hIL-2R beta(+) CART 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 CART cell dose. In addition, ortho-hIL-2 administration initiated at the time of leukemic relapse after CART 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.

Automated summary

Researchers have successfully created a pair of human orthogonal IL-2 and orthogonal IL-2 receptor through engineering, which can deliver IL-2 signal without toxicity, and demonstrated that this approach can enhance the antitumor efficacy of engineered T cells.