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Functional and mechanistic advantage of the use of a bifunctional anti-PD-L1/IL-15 superagonist
BACKGROUND: Anti(α)-programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) monotherapy fails to provide durable clinical benefit for most patients with carcinoma. Recent studies suggested that strategies to reduce immunosuppressive cells, promote systemic T-cell responses and lymphocyte tr...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204804/ https://www.ncbi.nlm.nih.gov/pubmed/32303618 http://dx.doi.org/10.1136/jitc-2019-000493 |
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author | Knudson, Karin M Hicks, Kristin C Ozawa, Yohei Schlom, Jeffrey Gameiro, Sofia R |
author_facet | Knudson, Karin M Hicks, Kristin C Ozawa, Yohei Schlom, Jeffrey Gameiro, Sofia R |
author_sort | Knudson, Karin M |
collection | PubMed |
description | BACKGROUND: Anti(α)-programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) monotherapy fails to provide durable clinical benefit for most patients with carcinoma. Recent studies suggested that strategies to reduce immunosuppressive cells, promote systemic T-cell responses and lymphocyte trafficking to the tumor microenvironment (TME) may improve efficacy. N-809 is a first-in-class bifunctional agent comprising the interleukin (IL)-15 superagonist N-803 fused to two αPD-L1 domains. Thus, N-809 can potentially stimulate effector immune cells through IL-15 and block immunosuppressive PD-L1. Here, we examined the antitumor efficacy and immunomodulatory effects of N-809 versus N-803+αPD-L1 combination. METHODS: The ability of N-809 to block PD-L1 and induce IL-15-dependent immune effects was examined in vitro and in vivo. Antitumor efficacy of N-809 or N-803+αPD-L1 was evaluated in two murine carcinoma models and an extensive analysis of immune correlates was performed in the tumor and tumor-draining lymph node (dLN). RESULTS: We demonstrate that N-809 blocks PD-L1 and induces IL-15-dependent immune effects. N-809 was well-tolerated and reduced 4T1 lung metastasis, decreased MC38 tumor burden and increased survival versus N-803+αPD-L1. Compared with N-803+αPD-L1, N-809 enhanced natural killer (NK) and CD8(+) T-cell activation and function in the dLN and TME, relating to increased gene expression associated with interferon and cytokine signaling, lymphoid compartment, costimulation and cytotoxicity. The higher number of TME CD8(+) T cells was attributed to enhanced infiltration, not in situ expansion. Increased TME NK and CD8(+) T-cell numbers correlated with augmented chemokine ligands and receptors. Moreover, in contrast to N-803+αPD-L1, N-809 reduced immunosuppressive regulatory T cells (T(reg)), monocytic myeloid-derived suppressor cells (M-MDSC) and M2-like macrophages in the TME. CONCLUSIONS: Our results suggest that N-809 functions by a novel immune mechanism to promote antitumor efficacy. Foremost, N-809 enhances intratumoral lymphocyte numbers by increasing trafficking via altered chemokine levels in the TME and chemokine receptor expression on CD8(+) T cells and NK cells. In addition, N-809 reduces immunosuppressive and pro-tumorigenic immune cells in the TME, including T(reg), M2-like macrophages and M-MDSC. Overall, these novel effects of N-809 promote an inflamed TME, leading to lower tumor burden and increased survival. These results provide mechanistic insight and rationale supporting the potential clinical study of N-809 in patients with carcinoma. |
format | Online Article Text |
id | pubmed-7204804 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-72048042020-05-12 Functional and mechanistic advantage of the use of a bifunctional anti-PD-L1/IL-15 superagonist Knudson, Karin M Hicks, Kristin C Ozawa, Yohei Schlom, Jeffrey Gameiro, Sofia R J Immunother Cancer Clinical/Translational Cancer Immunotherapy BACKGROUND: Anti(α)-programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) monotherapy fails to provide durable clinical benefit for most patients with carcinoma. Recent studies suggested that strategies to reduce immunosuppressive cells, promote systemic T-cell responses and lymphocyte trafficking to the tumor microenvironment (TME) may improve efficacy. N-809 is a first-in-class bifunctional agent comprising the interleukin (IL)-15 superagonist N-803 fused to two αPD-L1 domains. Thus, N-809 can potentially stimulate effector immune cells through IL-15 and block immunosuppressive PD-L1. Here, we examined the antitumor efficacy and immunomodulatory effects of N-809 versus N-803+αPD-L1 combination. METHODS: The ability of N-809 to block PD-L1 and induce IL-15-dependent immune effects was examined in vitro and in vivo. Antitumor efficacy of N-809 or N-803+αPD-L1 was evaluated in two murine carcinoma models and an extensive analysis of immune correlates was performed in the tumor and tumor-draining lymph node (dLN). RESULTS: We demonstrate that N-809 blocks PD-L1 and induces IL-15-dependent immune effects. N-809 was well-tolerated and reduced 4T1 lung metastasis, decreased MC38 tumor burden and increased survival versus N-803+αPD-L1. Compared with N-803+αPD-L1, N-809 enhanced natural killer (NK) and CD8(+) T-cell activation and function in the dLN and TME, relating to increased gene expression associated with interferon and cytokine signaling, lymphoid compartment, costimulation and cytotoxicity. The higher number of TME CD8(+) T cells was attributed to enhanced infiltration, not in situ expansion. Increased TME NK and CD8(+) T-cell numbers correlated with augmented chemokine ligands and receptors. Moreover, in contrast to N-803+αPD-L1, N-809 reduced immunosuppressive regulatory T cells (T(reg)), monocytic myeloid-derived suppressor cells (M-MDSC) and M2-like macrophages in the TME. CONCLUSIONS: Our results suggest that N-809 functions by a novel immune mechanism to promote antitumor efficacy. Foremost, N-809 enhances intratumoral lymphocyte numbers by increasing trafficking via altered chemokine levels in the TME and chemokine receptor expression on CD8(+) T cells and NK cells. In addition, N-809 reduces immunosuppressive and pro-tumorigenic immune cells in the TME, including T(reg), M2-like macrophages and M-MDSC. Overall, these novel effects of N-809 promote an inflamed TME, leading to lower tumor burden and increased survival. These results provide mechanistic insight and rationale supporting the potential clinical study of N-809 in patients with carcinoma. BMJ Publishing Group 2020-04-16 /pmc/articles/PMC7204804/ /pubmed/32303618 http://dx.doi.org/10.1136/jitc-2019-000493 Text en © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Clinical/Translational Cancer Immunotherapy Knudson, Karin M Hicks, Kristin C Ozawa, Yohei Schlom, Jeffrey Gameiro, Sofia R Functional and mechanistic advantage of the use of a bifunctional anti-PD-L1/IL-15 superagonist |
title | Functional and mechanistic advantage of the use of a bifunctional anti-PD-L1/IL-15 superagonist |
title_full | Functional and mechanistic advantage of the use of a bifunctional anti-PD-L1/IL-15 superagonist |
title_fullStr | Functional and mechanistic advantage of the use of a bifunctional anti-PD-L1/IL-15 superagonist |
title_full_unstemmed | Functional and mechanistic advantage of the use of a bifunctional anti-PD-L1/IL-15 superagonist |
title_short | Functional and mechanistic advantage of the use of a bifunctional anti-PD-L1/IL-15 superagonist |
title_sort | functional and mechanistic advantage of the use of a bifunctional anti-pd-l1/il-15 superagonist |
topic | Clinical/Translational Cancer Immunotherapy |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204804/ https://www.ncbi.nlm.nih.gov/pubmed/32303618 http://dx.doi.org/10.1136/jitc-2019-000493 |
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