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Radiation Dose Escalation Is Crucial in Anti-CTLA-4 Antibody Therapy to Enhance Local and Distant Antitumor Effect in Murine Osteosarcoma

We previously reported that a combination of 10 Gy of X-ray irradiation and dual immune checkpoint blockade with anti-CTLA-4 (C4) and anti-PD-L1 antibodies produced a significant shrinkage of irradiated and unirradiated tumors (abscopal effect) and prolonged overall survival. However, the optimal ra...

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Autores principales: Takenaka, Wataru, Takahashi, Yutaka, Tamari, Keisuke, Minami, Kazumasa, Katsuki, Shohei, Seo, Yuji, Isohashi, Fumiaki, Koizumi, Masahiko, Ogawa, Kazuhiko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352693/
https://www.ncbi.nlm.nih.gov/pubmed/32545427
http://dx.doi.org/10.3390/cancers12061546
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author Takenaka, Wataru
Takahashi, Yutaka
Tamari, Keisuke
Minami, Kazumasa
Katsuki, Shohei
Seo, Yuji
Isohashi, Fumiaki
Koizumi, Masahiko
Ogawa, Kazuhiko
author_facet Takenaka, Wataru
Takahashi, Yutaka
Tamari, Keisuke
Minami, Kazumasa
Katsuki, Shohei
Seo, Yuji
Isohashi, Fumiaki
Koizumi, Masahiko
Ogawa, Kazuhiko
author_sort Takenaka, Wataru
collection PubMed
description We previously reported that a combination of 10 Gy of X-ray irradiation and dual immune checkpoint blockade with anti-CTLA-4 (C4) and anti-PD-L1 antibodies produced a significant shrinkage of irradiated and unirradiated tumors (abscopal effect) and prolonged overall survival. However, the optimal radiation delivery regimen combined with single immune checkpoint blockade of C4 for inducing a maximum systemic antitumor response still remains unclear, particularly for patients with osteosarcoma. We used syngeneic C3H mice that were subcutaneously injected with LM8 osteosarcoma cells into both legs. C4 was administered three times, and one side of the tumor was irradiated by X-ray beams. The optimal radiation dose required to induce the abscopal effect was explored with a focus on the induction of the type-I interferon pathway. Radiation delivered in a single fraction of 10 Gy, 4.5 Gy × 3 fractions (fx), and 2 Gy × 8 fx with C4 failed to produce significant inhibition of unirradiated tumor growth compared with monotherapy with C4. Dose escalation to 16 Gy in a single fraction, or the equivalent hypofractionated dose of 8 Gy × 3 fx, which significantly increased secretion of IFN-β in vitro, produced a dramatic regression of both irradiated and unirradiated tumors and prolonged overall survival in combination with C4. Furthermore, irradiation at 16 Gy in both a single fraction and 8 Gy × 3 fx diminished regulatory T cells in the unirradiated tumor microenvironment. These results suggest that total dose escalation of radiation is crucial in C4 therapy to enhance the antitumor response in both local and distant tumors and prolonged overall survival regardless of fractionation for osteosarcoma.
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spelling pubmed-73526932020-07-21 Radiation Dose Escalation Is Crucial in Anti-CTLA-4 Antibody Therapy to Enhance Local and Distant Antitumor Effect in Murine Osteosarcoma Takenaka, Wataru Takahashi, Yutaka Tamari, Keisuke Minami, Kazumasa Katsuki, Shohei Seo, Yuji Isohashi, Fumiaki Koizumi, Masahiko Ogawa, Kazuhiko Cancers (Basel) Article We previously reported that a combination of 10 Gy of X-ray irradiation and dual immune checkpoint blockade with anti-CTLA-4 (C4) and anti-PD-L1 antibodies produced a significant shrinkage of irradiated and unirradiated tumors (abscopal effect) and prolonged overall survival. However, the optimal radiation delivery regimen combined with single immune checkpoint blockade of C4 for inducing a maximum systemic antitumor response still remains unclear, particularly for patients with osteosarcoma. We used syngeneic C3H mice that were subcutaneously injected with LM8 osteosarcoma cells into both legs. C4 was administered three times, and one side of the tumor was irradiated by X-ray beams. The optimal radiation dose required to induce the abscopal effect was explored with a focus on the induction of the type-I interferon pathway. Radiation delivered in a single fraction of 10 Gy, 4.5 Gy × 3 fractions (fx), and 2 Gy × 8 fx with C4 failed to produce significant inhibition of unirradiated tumor growth compared with monotherapy with C4. Dose escalation to 16 Gy in a single fraction, or the equivalent hypofractionated dose of 8 Gy × 3 fx, which significantly increased secretion of IFN-β in vitro, produced a dramatic regression of both irradiated and unirradiated tumors and prolonged overall survival in combination with C4. Furthermore, irradiation at 16 Gy in both a single fraction and 8 Gy × 3 fx diminished regulatory T cells in the unirradiated tumor microenvironment. These results suggest that total dose escalation of radiation is crucial in C4 therapy to enhance the antitumor response in both local and distant tumors and prolonged overall survival regardless of fractionation for osteosarcoma. MDPI 2020-06-12 /pmc/articles/PMC7352693/ /pubmed/32545427 http://dx.doi.org/10.3390/cancers12061546 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Takenaka, Wataru
Takahashi, Yutaka
Tamari, Keisuke
Minami, Kazumasa
Katsuki, Shohei
Seo, Yuji
Isohashi, Fumiaki
Koizumi, Masahiko
Ogawa, Kazuhiko
Radiation Dose Escalation Is Crucial in Anti-CTLA-4 Antibody Therapy to Enhance Local and Distant Antitumor Effect in Murine Osteosarcoma
title Radiation Dose Escalation Is Crucial in Anti-CTLA-4 Antibody Therapy to Enhance Local and Distant Antitumor Effect in Murine Osteosarcoma
title_full Radiation Dose Escalation Is Crucial in Anti-CTLA-4 Antibody Therapy to Enhance Local and Distant Antitumor Effect in Murine Osteosarcoma
title_fullStr Radiation Dose Escalation Is Crucial in Anti-CTLA-4 Antibody Therapy to Enhance Local and Distant Antitumor Effect in Murine Osteosarcoma
title_full_unstemmed Radiation Dose Escalation Is Crucial in Anti-CTLA-4 Antibody Therapy to Enhance Local and Distant Antitumor Effect in Murine Osteosarcoma
title_short Radiation Dose Escalation Is Crucial in Anti-CTLA-4 Antibody Therapy to Enhance Local and Distant Antitumor Effect in Murine Osteosarcoma
title_sort radiation dose escalation is crucial in anti-ctla-4 antibody therapy to enhance local and distant antitumor effect in murine osteosarcoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352693/
https://www.ncbi.nlm.nih.gov/pubmed/32545427
http://dx.doi.org/10.3390/cancers12061546
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