On August 10, 2021, an article "Tumor-conditional IL-15 pro-cytokine reactivates anti-tumor immunity with limited toxicity" from Prof. PENG Hua (Institute of Biophysics, Chinese Academy of Sciences) and Prof. FU Yang-Xin (University of Texas Southwestern Medical Center) was published online by Cell Research. This study has developed a new generation IL-15, the pro-IL-15, with low toxicity, tumor restriction, and high anti-tumor efficiency.

Most tumor immunotherapies focus on blocking immune inhibitory signals or activating immune stimulatory pathways. However, several issues hinder clinical application, including severe treatment-associated organ toxicity and poor tumor control due to off-tumor delivery. IL-2, one pleiotropic cytokine which can expand T cells and NK cells, is one of the earliest FDA-approved immunotherapy drugs for metastatic melanoma and renal cell cancer. However, IL-2 has not been widely used in the clinic due to its short half-life, the activation of immune inhibitory regulatory T cells (Tregs), and severe toxicity resulting from the stimulation of vascular endothelium. IL-15 is thought to be superior to IL-2 in the aspects of inducing lower vascular endothelium associated toxicity, much weaker Treg-stimulating activity, strong capacity in expanding NK and CD8⁺ T cells, and no activation-induced cell death (AICD).

IL-15 is a promising cytokine for cancer immunotherapy via expanding NK and CD8⁺ T cells, 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-15Rβ 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 and expand the peripheral NK cells and T cells, thus reducing systemic toxicity, but it still preserves anti-tumor efficacy in TME. In various mouse and human tumor models, the anti-tumor effect of pro-IL-15 depends on intratumoral CD8⁺ T cells and IFN-γ. 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 TKI targeted therapy in a poorly inflamed TUBO tumor model, suggesting pro-IL-15 helps overcome targeted therapy resistance. Our results demonstrate that a next-generation IL-15 cytokine can stimulate potent anti-tumor activity without severe toxicity.

Dr. GUO Jingya (Institute of Biophysics, Chinese Academy of Sciences) and Dr. LIANG Yong (University of Texas Southwestern Medical Center) are the co-first authors of this paper. Prof. PENG Hua (Institute of Biophysics, Chinese Academy of Sciences), Prof. FU Yang-Xin (University of Texas Southwestern Medical Center) and Dr. LIANG Yong (University of Texas Southwestern Medical Center) are the co-corresponding authors of this paper. This work was supported by funding from the National Science Foundation of China.

Related article links: https://www.nature.com/articles/s41422-021-00543-4

Contact: PENG Hua

Institute of Biophysics, Chinese Academy of Sciences

Beijing 100101, China

Email: hpeng@ibp.ac.cn

(Reported by Dr. PENG Hua's group)