Leveraging long-acting IL-15 agonists for intratumoral delivery and enhanced antimetastatic activity.

INTRODUCTION

IL-15 agonists hold promise as immunotherapeutics due to their ability to induce the proliferation and expansion of cytotoxic immune cells including natural killer (NK) and CD8 T cells. However, they generally have short half-lives that necessitate frequent administration to achieve efficacy. To address this limitation, we have developed a half-life extension technology using hydrogel microspheres (MS). Here, the therapeutic is tethered to MSs by a releasable linker with pre-programed cleavage rates. We previously showed the MS conjugate of single-chain IL-15, MS~IL-15, effectively increased the half-life of IL-15 to approximately 1 week and enhanced the pharmacodynamics. We sought to determine whether the same would be true with a MS conjugate of the IL-15 agonist, receptor-linker IL-15 (RLI).

METHODS

We prepared a long acting MS conjugate of RLI, MSRLI. The pharmacokinetics and pharmacodynamics of MSRLI were measured in C57BL/6J mice and compared to MSIL-15. The antitumor efficacy of MSRLI was measured when delivered subcutaneously or intratumorally in the CT26 tumor model and intratumorally in the orthotopic EO771 tumor model.

RESULTS

MSRLI exhibited a half-life of 30 h, longer than most IL-15 agonists but shorter than MSIL-15. The shorter than expected half-life of MSRLI was shown to be due to target-mediated-disposition caused by an IL-15 induced cytokine sink. MSRLI resulted in very potent stimulation of NK and CD44CD8 T cells, but also caused significant injection-site toxicity that may preclude subcutaneous administration. We thus pivoted our efforts toward studying the MSRLI for long-acting intra-tumoral therapy, where some degree of necrosis might be beneficial. When delivered intra- tumorally, both MSIL-15 and MS~RLI had modest anti-tumor efficacy, but high anti- metastatic activity.

CONCLUSION

Intra-tumoral MSRLI and MSRLI combined with systemic treatment with other agents could provide beneficial antitumor and anti-metastatic effects without the toxic effects of systemic IL-15 agonists. Our findings demonstrate that intra-tumorally administered long-acting IL-15 agonists counter two criticisms of loco-regional therapy: the necessity for frequent injections and the challenge of managing metastases.