Preclinical Evaluation of Recombinant Human IL15 Protein Fused with Albumin Binding Domain on Anti-PD-L1 Immunotherapy Efficiency and Anti-Tumor Immunity in Colon Cancer and Melanoma.

Fei-Ting Hsu,Chang-Liang Tsai,Keng-Li Lan,Po-Fu Yueh,Yu-Chang Liu,Chih-Hsien Chang

doi:10.3390/cancers13081789

Abstract

Simple SummaryIn this manuscript, we reported that a newly developed recombinant human IL15 fused with albumin binding domain (hIL15-ABD) showed superior biological half-life, pharmacokinetic and anti-tumor immunity than wild-type (WT) hIL15. Our hIL-15-ABD can effectively enhance anti-tumor efficacy of anti-PD-L1 on colon cancer and melanoma animal models. The anti-tumor potential of hIL-15-ABD was associated with tumor microenvironment (TME) regulation, including the activation of NK cells and CD8+ T cells, the reduction of immunosuppressive cells (MDSCs and Tregs) and the suppression of immunosuppressive factors (IDO, FOXP3 and VEGF). In conclusion, our new hIL15-ABD combined with anti-PD-L1 antibody increased the activity of anti-tumor effector cells involved in both innate and adaptive immunities, decreased the TME’s immunosuppressive cells, and showed greater anti-tumor effect than that of either monotherapy. We suggested hIL15-ABD as the potential complementary agent may effectively augment the therapeutic efficacy of anti-PD-L1 antibody in colon cancer and melanoma model.Anti-PD-L1 antibody monotherapy shows limited efficacy in a significant proportion of the patients. A common explanation for the inefficacy is a lack of anti-tumor effector cells in the tumor microenvironment (TME). Recombinant human interleukin-15 (hIL15), a potent immune stimulant, has been investigated in clinical trial with encouraging results. However, hIL15 is constrained by the short half-life of hIL15 and a relatively unfavorable pharmacokinetics profile. We developed a recombinant fusion IL15 protein composed of human IL15 (hIL15) and albumin binding domain (hIL15-ABD) and explored the therapeutic efficacy and immune regulation of hIL-15, hIL15-ABD and/or combination with anti-PD-L1 on CT26 murine colon cancer (CC) and B16-F10 murine melanoma models. We demonstrated that hIL15-ABD has significant inhibitory effect on the CT26 and B16-F10 tumor growths as compared to hIL-15. hIL-15-ABD not only showed superior half-life and pharmacokinetics data than hIL-15, but also enhance anti-tumor efficacy of antibody against PD-L1 via suppressive effect on accumulation of Tregs and MDSCs and activation of NK and CD8+T cells. Immune suppressive factors including VEGF and IDO were also decreased by combination treatment. hIL15-ABD combined with anti-PD-L1 antibody increased the activity of anti-tumor effector cells involved in both innate and adaptive immunities, decreased the TME’s immunosuppressive cells, and showed greater anti-tumor effect than that of either monotherapy.

Highlights

Active immune system possesses fighting ability against tumor development and progression
We present that human interleukin-15 (hIL15)-albumin binding domain (ABD) significantly increased percentage of CD8+ T and natural killer (NK) cells (Figure 3J–O), and effectively reduced population of Tregs and myeloid-derived suppressor cells (MDSCs) compared to hIL-15 treatment (Figure 3D–I)
HIL15-ABD may suppress the accumulation of MDSCs and Treg at the site of the tumor

Summary

Introduction

Active immune system possesses fighting ability against tumor development and progression. An example of this is cytotoxic T lymphocytes (CD8+ T cells) and natural killer (NK) cells attacking tumor cells that can be elicited by antitumor immune signaling, resulting in tumor destruction [1,2]. Tumors can escape immune surveillance through immunosuppressive tumor microenvironment (TME), restricting antitumor immunity. (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) modulate inactivation of CD8+ T and nature killer (NK) cells, resulting in tumor immune evasion in TME. Evasion of immune surveillance is conductive to tumor survival and progression [3,4,5]. Increased expression of PD-1/PD-L1 pathway is linked to T cell exhaustion and poor survival in multiple types of cancers. Many preclinical and clinical studies have demonstrated that the therapeutic efficacy of PD-1/PD-L1 blocking antibodies can be enhanced with immunologic or non-immunologic agents [4]

Methods

Results

Discussion

Conclusion