IL-15 Trans-Signaling with the Superagonist RLI Promotes Effector/Memory CD8+ T Cell Responses and Enhances Antitumor Activity of PD-1 Antagonists

Abstract

Tumors with the help of the surrounding environment facilitate the immune suppression in patients, and immunotherapy can counteract this inhibition. Among immunotherapeutic strategies, the immunostimulatory cytokine IL-15 could represent a serious candidate for the reactivation of antitumor immunity. However, exogenous IL-15 may have a limited impact on patients with cancer due to its dependency on IL-15Rα frequently downregulated in cancer patients. In this work, we studied the antitumor activity of the IL-15 superagonist receptor-linker–IL-15 (RLI), designed to bypass the need of endogenous IL-15Rα. RLI consists of human IL-15 covalently linked to the human IL-15Rα sushi+ domain. In a mouse model of colorectal carcinoma, RLI as a stand-alone treatment could limit tumor outgrowth only when initiated at an early time of tumor development. At a later time, RLI was not effective, coinciding with the strong accumulation of terminally exhausted programmed cell death-1 (PD-1)high T cell Ig mucin-3+ CD8+ T cells, suggesting that RLI was not able to reactivate terminally exhausted CD8+ T cells. Combination with PD-1 blocking Ab showed synergistic activity with RLI, but not with IL-15. RLI could induce a greater accumulation of memory CD8+ T cells and a stronger effector function in comparison with IL-15. Ex vivo stimulation of tumor-infiltrated lymphocytes from 16 patients with renal cell carcinoma demonstrated 56% of a strong tumor-infiltrated lymphocyte reactivation with the combination anti–PD-1/RLI compared with 43 and 6% with RLI or anti–PD-1, respectively. Altogether, this work provides evidence that the sushi–IL-15Rα/IL-15 fusion protein RLI enhances antitumor activity of anti–PD-1 treatment and is a promising approach to stimulate host immunity.

The potential and promise of IL-15 in immuno-oncogenic therapies

“…Overall, in multiple models systems, regardless of formation, the sIL-15/IL-15Rα complexes have been shown to be significantly more potent than native IL-15 in both in vitro and in vivo studies [18,55,19,54]. Furthermore, these IL-15 agonists can also be applied to ex vivo stimulation of tumor-specific lymphocytes (TILs) and NK cells [67] or be engineered for cellular expression and viral vector expression but are not discussed herein for space consideration.…”

“…Whereas IL-15 alone increases IFN-γ production and PD-1 expression by CD8 T cells, the addition of IL-15 plus αPD-L1 decreased PD-1 expression and further increased IFN-γ secretion [47]. Combination therapy with IL-15 superagonists (RLI and ALT-803) and blocking antibodies against PD-L1 and CTLA-4 have also been shown to increase survival and reduce tumor growth in colon and glioblastoma murine tumor models, as compared to one of the treatments alone [67,61,62]. While αPD-L1 mAb alone was able to delay growth of colon carcinomas and rarely induced remission, combined treatment with αPD-L1 mAb plus RLI resulted in reduced tumor growth, longer survival, and tumor regression in 40% of mice [67,61,62].…”

“…Combination therapy with IL-15 superagonists (RLI and ALT-803) and blocking antibodies against PD-L1 and CTLA-4 have also been shown to increase survival and reduce tumor growth in colon and glioblastoma murine tumor models, as compared to one of the treatments alone [67,61,62]. While αPD-L1 mAb alone was able to delay growth of colon carcinomas and rarely induced remission, combined treatment with αPD-L1 mAb plus RLI resulted in reduced tumor growth, longer survival, and tumor regression in 40% of mice [67,61,62]. Among the combination-treated tumor-free mice, all mice remained tumor free after second inoculation demonstrating the induction of an efficient adaptive memory immune response.…”

“…IL-15 superagonist ALT-803 also has an additive effect in combination with αPD-L1 mAb on survival of glioblastoma tumor-bearing mice [62]. In the pulmonary metastasis model of CT26 colon carcinoma cells, administration of ALT-803 plus αCTLA-4, but not αPD-L1, synergistically increased the survival of CT26-bearing mice [67,61,62]. However, αPD-L1 in conjunction with both ALT-803 and αCTLA-4 further improved the survival of CT26 mice.…”

ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial

“…Preclinical studies have shown benefit of combining these two classes of drugs. 15 In this trial, we assess the safety of the combination of ALT-803 and nivolumab immunotherapy, and the anti-tumour activity of cytokine treatment in the treatment of NSCLC.…”