Checkpoint blockade immunotherapy can release the immune suppression on tumor-infiltrating lymphocytes (TILs) but weakly induce TILs proliferation. Although interleukins are potent immune modulators for anti-tumor treatments, severe side effects limit their clinical administration.

Recently, a study published in the Journal of Experimental Medicine and by Prof. FU Yangxin at School of Medicine, Tsinghua University and Prof. PENG Hua at the Institute of Biophysics of the Chinese Academy of Sciences reported their exploration for new cancer immunotherapeutic drugs.

The researchers found that exogenous interleukin 15 (IL-15) greatly expanded TILs and further synergized with anti-PD-L1 therapy, however, systemic delivery of IL-15 resulted in drastic peripheral nature killer (NK) expansion, causing severe toxicity.

To redirect IL-15 to intratumoral PD-1⁺CD8⁺T effector cells instead of NK cells for better tumor control and lower toxicity, researchers engineered an anti-PD-1 fusion to IL-15 and IL-15 receptor α (αPD-1-IL-15-R) with an optimized linker. The IL-15 activity in this fusion protein was geographically concealed by the immunoglobulin Fc region to bypass systemic NK cells.

Systematic administration of αPD-1-IL-15-R elicited extraordinary antitumor efficacy with undetectable toxicity. Mechanistically, cis-delivery of αPD-1-IL-15-R vastly expands tumor-specific CD8⁺T cells for tumor rejection. Additionally, αPD-1-IL-15-R upregulated the levels of PD-1 and IL-15Rβ on T cells to create a feedforward activation loop, thus rejuvenating TILs, resulting in tumor control in situ and suppressing tumor metastasis.

Collectively, αPD-1-IL-15-R elicits effective systemic antitumor immunity by re-navigating IL-15 to tumor-specific PD-1⁺CD8⁺T cells.