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
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 invest...
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MDPI AG
2021-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/8/1789 |
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| author | Fei-Ting Hsu Yu-Chang Liu Chang-Liang Tsai Po-Fu Yueh Chih-Hsien Chang Keng-Li Lan |
| author_facet | Fei-Ting Hsu Yu-Chang Liu Chang-Liang Tsai Po-Fu Yueh Chih-Hsien Chang Keng-Li Lan |
| author_sort | Fei-Ting Hsu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T12:29:21Z |
| format | Article |
| id | doaj.art-d422c15096cd444896d1ac809a1acb54 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T12:29:21Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-d422c15096cd444896d1ac809a1acb542023-11-21T14:49:07ZengMDPI AGCancers2072-66942021-04-01138178910.3390/cancers13081789Preclinical 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 MelanomaFei-Ting Hsu0Yu-Chang Liu1Chang-Liang Tsai2Po-Fu Yueh3Chih-Hsien Chang4Keng-Li Lan5Department of Biological Science and Technology, China Medical University, Taichung 406, TaiwanDepartment of Radiation Oncology, Chang Bing Show Chwan Memorial Hospital, Lukang, Changhua 505, TaiwanDepartment of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei 112, TaiwanDepartment of Biological Science and Technology, China Medical University, Taichung 406, TaiwanDepartment of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei 112, TaiwanInstitute of Traditional Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, TaiwanAnti-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.https://www.mdpi.com/2072-6694/13/8/1789PD-L1IL15colon cancermelanomatumor microenvironment |
| spellingShingle | Fei-Ting Hsu Yu-Chang Liu Chang-Liang Tsai Po-Fu Yueh Chih-Hsien Chang Keng-Li Lan 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 Cancers PD-L1 IL15 colon cancer melanoma tumor microenvironment |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | PD-L1 IL15 colon cancer melanoma tumor microenvironment |
| url | https://www.mdpi.com/2072-6694/13/8/1789 |
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