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Takenaka W, Takahashi Y, Tamari K, et al. Radiation Dose Escalation is Crucial in Anti-CTLA-4 Antibody Therapy to Enhance Local and Distant Antitumor Effect in Murine Osteosarcoma. Cancers (Basel). 2020;12(6)doi: 10.3390/cancers12061546.
Takenaka, W., Takahashi, Y., Tamari, K., Minami, K., Katsuki, S., Seo, Y., Isohashi, F., Koizumi, M., & Ogawa, K. (2020). Radiation Dose Escalation is Crucial in Anti-CTLA-4 Antibody Therapy to Enhance Local and Distant Antitumor Effect in Murine Osteosarcoma. Cancers, 12(6), . https://doi.org/10.3390/cancers12061546
Takenaka, Wataru, et al. "Radiation Dose Escalation is Crucial in Anti-CTLA-4 Antibody Therapy to Enhance Local and Distant Antitumor Effect in Murine Osteosarcoma." Cancers vol. 12,6 (2020). doi: https://doi.org/10.3390/cancers12061546
Takenaka W, Takahashi Y, Tamari K, Minami K, Katsuki S, Seo Y, Isohashi F, Koizumi M, Ogawa K. Radiation Dose Escalation is Crucial in Anti-CTLA-4 Antibody Therapy to Enhance Local and Distant Antitumor Effect in Murine Osteosarcoma. Cancers (Basel). 2020 Jun 12;12(6). doi: 10.3390/cancers12061546. PMID: 32545427; PMCID: PMC7352693.
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Cancers (Basel). 2020 Jun 12;12(6). doi: 10.3390/cancers12061546.

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

Cancers

Wataru Takenaka, Yutaka Takahashi, Keisuke Tamari, Kazumasa Minami, Shohei Katsuki, Yuji Seo, Fumiaki Isohashi, Masahiko Koizumi, Kazuhiko Ogawa

Affiliations

  1. Department of Medical Physics and Engineering, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
  2. Department of Radiation Oncology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.

PMID: 32545427 PMCID: PMC7352693 DOI: 10.3390/cancers12061546

Abstract

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.

Keywords: abscopal effect; dose escalation; immune checkpoint blockade; osteosarcoma; radiation

Conflict of interest statement

The authors declare no conflict of interest.

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