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

• Published in: Cancers Vol. 13; no. 8; p. 1789
• Main Authors: Hsu, Fei-Ting, Liu, Yu-Chang, Tsai, Chang-Liang, Yueh, Po-Fu, Chang, Chih-Hsien, Lan, Keng-Li
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 09.04.2021; MDPI
• Subjects: Albumin; Animal models; Antibodies; CD8 antigen; Cell activation; Colon cancer; Colorectal cancer; Cytotoxicity; E coli; Effector cells; Foxp3 protein; Fusion protein; IL15; Immunity; Immunoregulation; Immunotherapy; Interleukin 1; Interleukin 15; Lung cancer; Lymphocytes T; Melanoma; Metastasis; PD-L1; PD-L1 protein; Pharmacokinetics; Phosphorylation; Proteins; Tumor microenvironment; Tumors; Vascular endothelial growth factor; United States > US; PD-L1; melanoma; tumor microenvironment; IL15; colon cancer
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers13081789

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.