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Bempegaldesleukin (BEMPEG; NKTR‐214) efficacy as a single agent and in combination with checkpoint‐inhibitor therapy in mouse models of osteosarcoma
Survival of patients with relapsed/refractory osteosarcoma has not improved in the last 30 years. Several immunotherapeutic approaches have shown benefit in murine osteosarcoma models, including the anti‐programmed death‐1 (anti‐PD‐1) and anti‐cytotoxic T‐lymphocyte antigen‐4 (anti‐CTLA‐4) immune ch...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley & Sons, Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984260/ https://www.ncbi.nlm.nih.gov/pubmed/33152115 http://dx.doi.org/10.1002/ijc.33382 |
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author | Hennessy, Marlene Wahba, Andrew Felix, Kumar Cabrera, Mariella Segura, Maria Gabriela Kundra, Vikas Ravoori, Murali K. Stewart, John Kleinerman, Eugenie S. Jensen, Vanessa Behrana Gopalakrishnan, Vidya Pena, Rhoneil Quach, Phi Kim, Grace Kivimäe, Saul Madakamutil, Loui Overwijk, Willem W. Zalevsky, Jonathan Gordon, Nancy |
author_facet | Hennessy, Marlene Wahba, Andrew Felix, Kumar Cabrera, Mariella Segura, Maria Gabriela Kundra, Vikas Ravoori, Murali K. Stewart, John Kleinerman, Eugenie S. Jensen, Vanessa Behrana Gopalakrishnan, Vidya Pena, Rhoneil Quach, Phi Kim, Grace Kivimäe, Saul Madakamutil, Loui Overwijk, Willem W. Zalevsky, Jonathan Gordon, Nancy |
author_sort | Hennessy, Marlene |
collection | PubMed |
description | Survival of patients with relapsed/refractory osteosarcoma has not improved in the last 30 years. Several immunotherapeutic approaches have shown benefit in murine osteosarcoma models, including the anti‐programmed death‐1 (anti‐PD‐1) and anti‐cytotoxic T‐lymphocyte antigen‐4 (anti‐CTLA‐4) immune checkpoint inhibitors. Treatment with the T‐cell growth factor interleukin‐2 (IL‐2) has shown some clinical benefit but has limitations due to poor tolerability. Therefore, we evaluated the efficacy of bempegaldesleukin (BEMPEG; NKTR‐214), a first‐in‐class CD122‐preferential IL‐2 pathway agonist, alone and in combination with anti‐PD‐1 or anti‐CTLA‐4 immune checkpoint inhibitors in metastatic and orthotopic murine models of osteosarcoma. Treatment with BEMPEG delayed tumor growth and increased overall survival of mice with K7M2‐WT osteosarcoma pulmonary metastases. BEMPEG also inhibited primary tumor growth and metastatic relapse in lungs and bone in the K7M3 orthotopic osteosarcoma mouse model. In addition, it enhanced therapeutic activity of anti‐CTLA‐4 and anti‐PD‐1 checkpoint blockade in the DLM8 subcutaneous murine osteosarcoma model. Finally, BEMPEG strongly increased accumulation of intratumoral effector T cells and natural killer cells, but not T‐regulatory cells, resulting in improved effector:inhibitory cell ratios. Collectively, these data in multiple murine models of osteosarcoma provide a path toward clinical evaluation of BEMPEG‐based regimens in human osteosarcoma. |
format | Online Article Text |
id | pubmed-7984260 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley & Sons, Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-79842602021-03-24 Bempegaldesleukin (BEMPEG; NKTR‐214) efficacy as a single agent and in combination with checkpoint‐inhibitor therapy in mouse models of osteosarcoma Hennessy, Marlene Wahba, Andrew Felix, Kumar Cabrera, Mariella Segura, Maria Gabriela Kundra, Vikas Ravoori, Murali K. Stewart, John Kleinerman, Eugenie S. Jensen, Vanessa Behrana Gopalakrishnan, Vidya Pena, Rhoneil Quach, Phi Kim, Grace Kivimäe, Saul Madakamutil, Loui Overwijk, Willem W. Zalevsky, Jonathan Gordon, Nancy Int J Cancer Cancer Therapy and Prevention Survival of patients with relapsed/refractory osteosarcoma has not improved in the last 30 years. Several immunotherapeutic approaches have shown benefit in murine osteosarcoma models, including the anti‐programmed death‐1 (anti‐PD‐1) and anti‐cytotoxic T‐lymphocyte antigen‐4 (anti‐CTLA‐4) immune checkpoint inhibitors. Treatment with the T‐cell growth factor interleukin‐2 (IL‐2) has shown some clinical benefit but has limitations due to poor tolerability. Therefore, we evaluated the efficacy of bempegaldesleukin (BEMPEG; NKTR‐214), a first‐in‐class CD122‐preferential IL‐2 pathway agonist, alone and in combination with anti‐PD‐1 or anti‐CTLA‐4 immune checkpoint inhibitors in metastatic and orthotopic murine models of osteosarcoma. Treatment with BEMPEG delayed tumor growth and increased overall survival of mice with K7M2‐WT osteosarcoma pulmonary metastases. BEMPEG also inhibited primary tumor growth and metastatic relapse in lungs and bone in the K7M3 orthotopic osteosarcoma mouse model. In addition, it enhanced therapeutic activity of anti‐CTLA‐4 and anti‐PD‐1 checkpoint blockade in the DLM8 subcutaneous murine osteosarcoma model. Finally, BEMPEG strongly increased accumulation of intratumoral effector T cells and natural killer cells, but not T‐regulatory cells, resulting in improved effector:inhibitory cell ratios. Collectively, these data in multiple murine models of osteosarcoma provide a path toward clinical evaluation of BEMPEG‐based regimens in human osteosarcoma. John Wiley & Sons, Inc. 2020-11-25 2021-04-15 /pmc/articles/PMC7984260/ /pubmed/33152115 http://dx.doi.org/10.1002/ijc.33382 Text en © 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Cancer Therapy and Prevention Hennessy, Marlene Wahba, Andrew Felix, Kumar Cabrera, Mariella Segura, Maria Gabriela Kundra, Vikas Ravoori, Murali K. Stewart, John Kleinerman, Eugenie S. Jensen, Vanessa Behrana Gopalakrishnan, Vidya Pena, Rhoneil Quach, Phi Kim, Grace Kivimäe, Saul Madakamutil, Loui Overwijk, Willem W. Zalevsky, Jonathan Gordon, Nancy Bempegaldesleukin (BEMPEG; NKTR‐214) efficacy as a single agent and in combination with checkpoint‐inhibitor therapy in mouse models of osteosarcoma |
title | Bempegaldesleukin (BEMPEG; NKTR‐214) efficacy as a single agent and in combination with checkpoint‐inhibitor therapy in mouse models of osteosarcoma |
title_full | Bempegaldesleukin (BEMPEG; NKTR‐214) efficacy as a single agent and in combination with checkpoint‐inhibitor therapy in mouse models of osteosarcoma |
title_fullStr | Bempegaldesleukin (BEMPEG; NKTR‐214) efficacy as a single agent and in combination with checkpoint‐inhibitor therapy in mouse models of osteosarcoma |
title_full_unstemmed | Bempegaldesleukin (BEMPEG; NKTR‐214) efficacy as a single agent and in combination with checkpoint‐inhibitor therapy in mouse models of osteosarcoma |
title_short | Bempegaldesleukin (BEMPEG; NKTR‐214) efficacy as a single agent and in combination with checkpoint‐inhibitor therapy in mouse models of osteosarcoma |
title_sort | bempegaldesleukin (bempeg; nktr‐214) efficacy as a single agent and in combination with checkpoint‐inhibitor therapy in mouse models of osteosarcoma |
topic | Cancer Therapy and Prevention |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984260/ https://www.ncbi.nlm.nih.gov/pubmed/33152115 http://dx.doi.org/10.1002/ijc.33382 |
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