Interleukin-21 combined with PD-1 or CTLA-4 blockade enhances antitumor immunity in mouse tumor models
Recent advances in cancer treatment with checkpoint blockade of receptors such as CTLA-4 and PD-1 have demonstrated that combinations of agents with complementary immunomodulatory effects have the potential to enhance antitumor activity as compared to single agents. We investigated the efficacy of i...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2018-01-01
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| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/2162402X.2017.1377873 |
| _version_ | 1818133277037297664 |
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| author | Katherine E. Lewis Mark J. Selby Gregg Masters Jose Valle Gennaro Dito Wendy R. Curtis Richard Garcia Kathy A. Mink Kimberly S. Waggie Matthew S. Holdren Joseph F. Grosso Alan J. Korman Maria Jure-Kunkel Stacey R. Dillon |
| author_facet | Katherine E. Lewis Mark J. Selby Gregg Masters Jose Valle Gennaro Dito Wendy R. Curtis Richard Garcia Kathy A. Mink Kimberly S. Waggie Matthew S. Holdren Joseph F. Grosso Alan J. Korman Maria Jure-Kunkel Stacey R. Dillon |
| author_sort | Katherine E. Lewis |
| collection | DOAJ |
| description | Recent advances in cancer treatment with checkpoint blockade of receptors such as CTLA-4 and PD-1 have demonstrated that combinations of agents with complementary immunomodulatory effects have the potential to enhance antitumor activity as compared to single agents. We investigated the efficacy of immune-modulatory interleukin-21 (IL-21) combined with checkpoint blockade in several syngeneic mouse tumor models. After tumor establishment, mice were administered recombinant mouse IL-21 (mIL-21) alone or in combination with blocking monoclonal antibodies against mouse PD-1 or CTLA-4. In contrast to monotherapy, IL-21 enhanced antitumor activity of mCTLA-4 mAb in four models and anti-PD-1 mAb in two models, with evidence of synergy for one or both of the combination treatments in the EMT-6 and MC38 models. The enhanced efficacy was associated with increased intratumoral CD8+ T cell infiltrates, CD8+ T cell proliferation, and increased effector memory T cells, along with decreased frequency of central memory CD8+ T cells. In vivo depletion of CD8+ T cells abolished the antitumor activities observed for both combination and monotherapy treatments, further supporting a beneficial role for CD8+ T cells. In all studies, the combination therapies were well tolerated. These results support the hypothesis that the combination of recombinant human IL-21 with CTLA-4 or PD-1 monoclonal antibodies could lead to improved outcomes in cancer patients. |
| first_indexed | 2024-12-11T08:50:10Z |
| format | Article |
| id | doaj.art-54e3b8070e6e4ea1b4254c709405e4a3 |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-12-11T08:50:10Z |
| publishDate | 2018-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-54e3b8070e6e4ea1b4254c709405e4a32022-12-22T01:14:01ZengTaylor & Francis GroupOncoImmunology2162-402X2018-01-017110.1080/2162402X.2017.13778731377873Interleukin-21 combined with PD-1 or CTLA-4 blockade enhances antitumor immunity in mouse tumor modelsKatherine E. Lewis0Mark J. Selby1Gregg Masters2Jose Valle3Gennaro Dito4Wendy R. Curtis5Richard Garcia6Kathy A. Mink7Kimberly S. Waggie8Matthew S. Holdren9Joseph F. Grosso10Alan J. Korman11Maria Jure-Kunkel12Stacey R. Dillon13Bristol-Myers SquibbBristol-Myers SquibbBristol-Myers SquibbBristol-Myers SquibbBristol-Myers SquibbBristol-Myers SquibbBristol-Myers SquibbBristol-Myers SquibbBristol-Myers SquibbBristol-Myers SquibbBristol-Myers SquibbBristol-Myers SquibbBristol-Myers SquibbBristol-Myers SquibbRecent advances in cancer treatment with checkpoint blockade of receptors such as CTLA-4 and PD-1 have demonstrated that combinations of agents with complementary immunomodulatory effects have the potential to enhance antitumor activity as compared to single agents. We investigated the efficacy of immune-modulatory interleukin-21 (IL-21) combined with checkpoint blockade in several syngeneic mouse tumor models. After tumor establishment, mice were administered recombinant mouse IL-21 (mIL-21) alone or in combination with blocking monoclonal antibodies against mouse PD-1 or CTLA-4. In contrast to monotherapy, IL-21 enhanced antitumor activity of mCTLA-4 mAb in four models and anti-PD-1 mAb in two models, with evidence of synergy for one or both of the combination treatments in the EMT-6 and MC38 models. The enhanced efficacy was associated with increased intratumoral CD8+ T cell infiltrates, CD8+ T cell proliferation, and increased effector memory T cells, along with decreased frequency of central memory CD8+ T cells. In vivo depletion of CD8+ T cells abolished the antitumor activities observed for both combination and monotherapy treatments, further supporting a beneficial role for CD8+ T cells. In all studies, the combination therapies were well tolerated. These results support the hypothesis that the combination of recombinant human IL-21 with CTLA-4 or PD-1 monoclonal antibodies could lead to improved outcomes in cancer patients.http://dx.doi.org/10.1080/2162402X.2017.1377873interleukin 21il-21pd-1ctla-4mc38ct26emt-6b16-f10mouse tumor models |
| spellingShingle | Katherine E. Lewis Mark J. Selby Gregg Masters Jose Valle Gennaro Dito Wendy R. Curtis Richard Garcia Kathy A. Mink Kimberly S. Waggie Matthew S. Holdren Joseph F. Grosso Alan J. Korman Maria Jure-Kunkel Stacey R. Dillon Interleukin-21 combined with PD-1 or CTLA-4 blockade enhances antitumor immunity in mouse tumor models OncoImmunology interleukin 21 il-21 pd-1 ctla-4 mc38 ct26 emt-6 b16-f10 mouse tumor models |
| title | Interleukin-21 combined with PD-1 or CTLA-4 blockade enhances antitumor immunity in mouse tumor models |
| title_full | Interleukin-21 combined with PD-1 or CTLA-4 blockade enhances antitumor immunity in mouse tumor models |
| title_fullStr | Interleukin-21 combined with PD-1 or CTLA-4 blockade enhances antitumor immunity in mouse tumor models |
| title_full_unstemmed | Interleukin-21 combined with PD-1 or CTLA-4 blockade enhances antitumor immunity in mouse tumor models |
| title_short | Interleukin-21 combined with PD-1 or CTLA-4 blockade enhances antitumor immunity in mouse tumor models |
| title_sort | interleukin 21 combined with pd 1 or ctla 4 blockade enhances antitumor immunity in mouse tumor models |
| topic | interleukin 21 il-21 pd-1 ctla-4 mc38 ct26 emt-6 b16-f10 mouse tumor models |
| url | http://dx.doi.org/10.1080/2162402X.2017.1377873 |
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