Targeting the high-affinity IL-2R with high-dose mIL-2/CD25 induces effective antitumor responses

Abstract

Abstract Much interest remains to harness the T cell activating properties of IL-2 to promote antitumor immunity. Current efforts largely utilize approaches directed toward the intermediate-affinity IL-2R to broadly stimulate memory-phenotypic CD8+ T and NK cells while minimizing off-target Tregs. However, this approach does not effectively engage tumor-reactive CD4+ and CD8+ T effector cells that express the high-affinity IL-2R. Recently, we developed a fusion protein where mouse IL-2 was linked to CD25 (mIL-2/CD25 or FP) with selectivity toward the high-affinity IL-2R. At a low dose, the FP is Treg-selective to limit autoimmunity, but at a high dose with a tumor vaccine it expands tumor-reactive T cells to develop antitumor immunity. Here, we assessed the efficacy of high-dose (HD) FP as a cancer monotherapy or with checkpoint blockade. HD FP supports antitumor responses in mice bearing CT26, MC38, or B16.F10 tumors. Although HD FP led to increases in Tregs in immune tissues, Tregs were at a lower frequency in the tumor microenvironment (TME), leading to a high CD8+ T cell:Treg ratio. Further, adding anti-PD-1 to HD FP treatment was more effective in controlling tumors in CT26-bearing mice. Surprisingly, at the doses tested, HD FP supported more robust antitumor responses in each model than IL-2/S4B6 anti-IL-2 complexes (IL2/IC), directed to the intermediate-affinity IL-2R. In the CT26 TME, the number of tumor antigen-specific CD8+ T cells trended upward with HD FP over IL2/IC. These studies indicate that targeting the high-affinity IL-2R on activated tumor-specific T cells with HD FP alone or with PD-1 blockade supports antitumor responses and suggests that this strategy may be more effective than targeting the intermediate-affinity IL-2R. Supported by Bristol Myers Squibb grant support