Potent immunomodulatory effects of an anti-CEA-IL-2 immunocytokine on tumor therapy and effects of stereotactic radiation
While anti-CEA antibodies have no direct effect on CEA-positive tumors, they can be used to direct potent anti-tumor effects as an antibody-IL-2 fusion protein (immunocytokine, ICK), and at the same time reduce the toxicity of IL-2 as a single agent. Using a fusion protein of humanized anti-CEA with...
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doaj-8d687e3850454660b664629f00e35ad72021-09-24T14:41:23ZengTaylor & Francis GroupOncoImmunology2162-402X2020-01-019110.1080/2162402X.2020.17240521724052Potent immunomodulatory effects of an anti-CEA-IL-2 immunocytokine on tumor therapy and effects of stereotactic radiationMaciej Kujawski0Mark Sherman1Susanta Hui2Darren Zuro3Wen-Hui Lee4Paul Yazaki5Anakim Sherman6Barbara Szpikowska7Junie Chea8Desiree Lasiewski9Kofi Poku10Harry Li11David Colcher12Jeffrey Wong13John E. Shively14City of HopeWest Coast UniversityCity of HopeCity of HopeCity of HopeCity of HopeCity of HopeCity of HopeCity of HopeCity of HopeCity of HopeCity of HopeCity of HopeCity of HopeCity of HopeWhile anti-CEA antibodies have no direct effect on CEA-positive tumors, they can be used to direct potent anti-tumor effects as an antibody-IL-2 fusion protein (immunocytokine, ICK), and at the same time reduce the toxicity of IL-2 as a single agent. Using a fusion protein of humanized anti-CEA with human IL-2 (M5A-IL-2) in a transgenic murine model expressing human CEA, we show high tumor uptake of the ICK to CEA-positive tumors with additional lymph node targeting. ICK treated CEA-positive tumors exhibit significant tumor eradication. Analysis of tumor-infiltrating lymphocytes shows a high frequency of both CD8+ and CD4+ T cells along with CD11b positive myeloid cells in ICK treated mice. The frequency of tumor-infiltrating FoxP3+ CD4+ T cells (Tregs) is significantly reduced vs anti-CEA antibody-treated controls, indicating that ICK did not preferentially stimulate migration or proliferation of Tregs to the tumor. Combination therapy with anti-PD-1 antibody did not improve tumor reduction over ICK therapy alone. Since stereotactic tumor irradiation (SRT), commonly used in cancer therapy has immunomodulatory effects, we tested combination SRT+ICK therapy in two tumor model systems. Use of fractionated vs single high dose SRT in combination with ICK resulted in greater tumor inhibition and immunity to tumor rechallenge. In particular, tumor microenvironment and myeloid cell composition appear to play a significant role in the response rate to ICK+SRT combination therapy.http://dx.doi.org/10.1080/2162402X.2020.1724052il-2immunocytokineceaantibodystereotactic radiationbreast cancer |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Maciej Kujawski Mark Sherman Susanta Hui Darren Zuro Wen-Hui Lee Paul Yazaki Anakim Sherman Barbara Szpikowska Junie Chea Desiree Lasiewski Kofi Poku Harry Li David Colcher Jeffrey Wong John E. Shively |
spellingShingle |
Maciej Kujawski Mark Sherman Susanta Hui Darren Zuro Wen-Hui Lee Paul Yazaki Anakim Sherman Barbara Szpikowska Junie Chea Desiree Lasiewski Kofi Poku Harry Li David Colcher Jeffrey Wong John E. Shively Potent immunomodulatory effects of an anti-CEA-IL-2 immunocytokine on tumor therapy and effects of stereotactic radiation OncoImmunology il-2 immunocytokine cea antibody stereotactic radiation breast cancer |
author_facet |
Maciej Kujawski Mark Sherman Susanta Hui Darren Zuro Wen-Hui Lee Paul Yazaki Anakim Sherman Barbara Szpikowska Junie Chea Desiree Lasiewski Kofi Poku Harry Li David Colcher Jeffrey Wong John E. Shively |
author_sort |
Maciej Kujawski |
title |
Potent immunomodulatory effects of an anti-CEA-IL-2 immunocytokine on tumor therapy and effects of stereotactic radiation |
title_short |
Potent immunomodulatory effects of an anti-CEA-IL-2 immunocytokine on tumor therapy and effects of stereotactic radiation |
title_full |
Potent immunomodulatory effects of an anti-CEA-IL-2 immunocytokine on tumor therapy and effects of stereotactic radiation |
title_fullStr |
Potent immunomodulatory effects of an anti-CEA-IL-2 immunocytokine on tumor therapy and effects of stereotactic radiation |
title_full_unstemmed |
Potent immunomodulatory effects of an anti-CEA-IL-2 immunocytokine on tumor therapy and effects of stereotactic radiation |
title_sort |
potent immunomodulatory effects of an anti-cea-il-2 immunocytokine on tumor therapy and effects of stereotactic radiation |
publisher |
Taylor & Francis Group |
series |
OncoImmunology |
issn |
2162-402X |
publishDate |
2020-01-01 |
description |
While anti-CEA antibodies have no direct effect on CEA-positive tumors, they can be used to direct potent anti-tumor effects as an antibody-IL-2 fusion protein (immunocytokine, ICK), and at the same time reduce the toxicity of IL-2 as a single agent. Using a fusion protein of humanized anti-CEA with human IL-2 (M5A-IL-2) in a transgenic murine model expressing human CEA, we show high tumor uptake of the ICK to CEA-positive tumors with additional lymph node targeting. ICK treated CEA-positive tumors exhibit significant tumor eradication. Analysis of tumor-infiltrating lymphocytes shows a high frequency of both CD8+ and CD4+ T cells along with CD11b positive myeloid cells in ICK treated mice. The frequency of tumor-infiltrating FoxP3+ CD4+ T cells (Tregs) is significantly reduced vs anti-CEA antibody-treated controls, indicating that ICK did not preferentially stimulate migration or proliferation of Tregs to the tumor. Combination therapy with anti-PD-1 antibody did not improve tumor reduction over ICK therapy alone. Since stereotactic tumor irradiation (SRT), commonly used in cancer therapy has immunomodulatory effects, we tested combination SRT+ICK therapy in two tumor model systems. Use of fractionated vs single high dose SRT in combination with ICK resulted in greater tumor inhibition and immunity to tumor rechallenge. In particular, tumor microenvironment and myeloid cell composition appear to play a significant role in the response rate to ICK+SRT combination therapy. |
topic |
il-2 immunocytokine cea antibody stereotactic radiation breast cancer |
url |
http://dx.doi.org/10.1080/2162402X.2020.1724052 |
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