Tumor-conditional IL-15 pro-cytokine reactivates anti-tumor immunity with limited toxicity

IL-15 is a promising cytokine to expand NK and CD8(+) T cells for cancer immunotherapy, but its application is limited by dose-limiting, on-target off-tumor toxicity. Here, we have developed a next-generation IL-15 that is activated inside the tumor microenvironment (TME). This pro-IL-15 has the extracellular domain of IL-15R beta fused to the N-terminus of sIL-15-Fc through a tumor-enriched Matrix Metalloproteinase (MMP) cleavable peptide linker to block its activity. Unlike sIL-15-Fc, pro-IL-15 does not activate the peripheral expansion of NK cells and T cells, thus reducing systemic toxicity, but it still preserves efficient anti-tumor abilities. In various mouse tumors, the anti-tumor effect of pro-IL-15 depends on intratumoral CD8(+) T cells and IFN-gamma. Pro-IL-15 increases the stem-like TCF1(+)Tim-3(-)CD8(+) T cells within tumor tissue and helps overcome immune checkpoint blockade (ICB) resistance. Moreover, pro-IL-15 synergizes with current tyrosine kinase inhibitor (TKI) targeted-therapy in a poorly inflamed TUBO tumor model, suggesting that pro-IL-15 helps overcome targeted-therapy resistance. Our results demonstrate a next-generation IL-15 cytokine that can stimulate potent anti-tumor activity without severe toxicity.

Automated summary

A next-generation IL-15 cytokine has been developed in this study, which can be activated inside the tumor microenvironment without causing systemic toxicity by avoiding peripheral expansion of NK and T cells. The anti-tumor effect of pro-IL-15 depends on intratumoral CD8(+) T cells and IFN-gamma, and it helps overcome immune checkpoint blockade resistance and synergizes with current targeted-therapy. This novel IL-15 cytokine shows potent anti-tumor activity while minimizing severe toxicity.