A curative treatment strategy using tumor debulking surgery combined with immune checkpoint inhibitors for advanced pediatric solid tumors

An in vivo study using a murine model of osteosarcoma

Takahiro Shimizu, Yasushi Fuchimoto, Hajime Okita, Kazumasa Fukuda, Yuukou Kitagawa, Shigeru Ueno, Tatsuo Kuroda

Research output: Contribution to journalArticle

Abstract

Background/purpose: This study aimed to assess the significance of tumor debulking surgery by using immune checkpoint inhibitors for advanced pediatric solid tumors in a murine model of advanced osteosarcoma. Methods: In C3H mice, 5 × 106 LM8 (osteosarcoma cell line with a high metastatic potential in the lungs originating from the C3H mouse) cells were transplanted subcutaneously. Thereafter, the mice were divided into 4 groups as follows: the control group received no intervention (CG, n = 5), the surgery group underwent subcutaneous tumor resection (tumor debulking surgery) 11 days after transplantation (SG, n = 10), the immunotherapy group received a cocktail consisting of 200 μg each of three antibodies (anti-Tim-3, anti-PD-L1, and anti-OX-86) intraperitoneally on posttransplantation days 11, 14, 18, and 21 (IG, n = 10), and the combination therapy group, tumor debulking surgery on day 11 and the cocktail intraperitoneally on days 11, 14, 18, and 21 (COMBG, n = 10). Survival curves were plotted by using the Kaplan–Meier method and compared with those plotted using the log-rank test. Next, the lungs of mice in the 4 groups were pathologically evaluated. Results: The COMBG showed significantly longer survival than the other three groups (P ≤ 0.002), whereas the SG and IG revealed no difference in survival rate compared to CG. Pathological evaluations revealed no lung metastasis 16 weeks after tumor transplantation in the survivors of COMBG. Conclusions: The results of this study suggest that tumor debulking surgery combined with immune checkpoint inhibitors could be a curative treatment for advanced pediatric solid tumors.

Original languageEnglish
JournalJournal of Pediatric Surgery
DOIs
Publication statusAccepted/In press - 2018 Jan 1

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Osteosarcoma
Pediatrics
Neoplasms
Inbred C3H Mouse
Therapeutics
Ambulatory Surgical Procedures
Lung
Transplantation
Group Psychotherapy
Immunotherapy
Anti-Idiotypic Antibodies
Neoplasm Metastasis
Cell Line
Control Groups

Keywords

  • Advanced pediatric solid tumor
  • Immune checkpoint inhibitors
  • Osteosarcoma
  • OX40
  • PD-1/PD-L1
  • Tumor debulking surgery

ASJC Scopus subject areas

  • Surgery
  • Pediatrics, Perinatology, and Child Health

Cite this

@article{56804cbb26f349d0a95ea17969682ca1,
title = "A curative treatment strategy using tumor debulking surgery combined with immune checkpoint inhibitors for advanced pediatric solid tumors: An in vivo study using a murine model of osteosarcoma",
abstract = "Background/purpose: This study aimed to assess the significance of tumor debulking surgery by using immune checkpoint inhibitors for advanced pediatric solid tumors in a murine model of advanced osteosarcoma. Methods: In C3H mice, 5 × 106 LM8 (osteosarcoma cell line with a high metastatic potential in the lungs originating from the C3H mouse) cells were transplanted subcutaneously. Thereafter, the mice were divided into 4 groups as follows: the control group received no intervention (CG, n = 5), the surgery group underwent subcutaneous tumor resection (tumor debulking surgery) 11 days after transplantation (SG, n = 10), the immunotherapy group received a cocktail consisting of 200 μg each of three antibodies (anti-Tim-3, anti-PD-L1, and anti-OX-86) intraperitoneally on posttransplantation days 11, 14, 18, and 21 (IG, n = 10), and the combination therapy group, tumor debulking surgery on day 11 and the cocktail intraperitoneally on days 11, 14, 18, and 21 (COMBG, n = 10). Survival curves were plotted by using the Kaplan–Meier method and compared with those plotted using the log-rank test. Next, the lungs of mice in the 4 groups were pathologically evaluated. Results: The COMBG showed significantly longer survival than the other three groups (P ≤ 0.002), whereas the SG and IG revealed no difference in survival rate compared to CG. Pathological evaluations revealed no lung metastasis 16 weeks after tumor transplantation in the survivors of COMBG. Conclusions: The results of this study suggest that tumor debulking surgery combined with immune checkpoint inhibitors could be a curative treatment for advanced pediatric solid tumors.",
keywords = "Advanced pediatric solid tumor, Immune checkpoint inhibitors, Osteosarcoma, OX40, PD-1/PD-L1, Tumor debulking surgery",
author = "Takahiro Shimizu and Yasushi Fuchimoto and Hajime Okita and Kazumasa Fukuda and Yuukou Kitagawa and Shigeru Ueno and Tatsuo Kuroda",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.jpedsurg.2018.08.023",
language = "English",
journal = "Journal of Pediatric Surgery",
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TY - JOUR

T1 - A curative treatment strategy using tumor debulking surgery combined with immune checkpoint inhibitors for advanced pediatric solid tumors

T2 - An in vivo study using a murine model of osteosarcoma

AU - Shimizu, Takahiro

AU - Fuchimoto, Yasushi

AU - Okita, Hajime

AU - Fukuda, Kazumasa

AU - Kitagawa, Yuukou

AU - Ueno, Shigeru

AU - Kuroda, Tatsuo

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background/purpose: This study aimed to assess the significance of tumor debulking surgery by using immune checkpoint inhibitors for advanced pediatric solid tumors in a murine model of advanced osteosarcoma. Methods: In C3H mice, 5 × 106 LM8 (osteosarcoma cell line with a high metastatic potential in the lungs originating from the C3H mouse) cells were transplanted subcutaneously. Thereafter, the mice were divided into 4 groups as follows: the control group received no intervention (CG, n = 5), the surgery group underwent subcutaneous tumor resection (tumor debulking surgery) 11 days after transplantation (SG, n = 10), the immunotherapy group received a cocktail consisting of 200 μg each of three antibodies (anti-Tim-3, anti-PD-L1, and anti-OX-86) intraperitoneally on posttransplantation days 11, 14, 18, and 21 (IG, n = 10), and the combination therapy group, tumor debulking surgery on day 11 and the cocktail intraperitoneally on days 11, 14, 18, and 21 (COMBG, n = 10). Survival curves were plotted by using the Kaplan–Meier method and compared with those plotted using the log-rank test. Next, the lungs of mice in the 4 groups were pathologically evaluated. Results: The COMBG showed significantly longer survival than the other three groups (P ≤ 0.002), whereas the SG and IG revealed no difference in survival rate compared to CG. Pathological evaluations revealed no lung metastasis 16 weeks after tumor transplantation in the survivors of COMBG. Conclusions: The results of this study suggest that tumor debulking surgery combined with immune checkpoint inhibitors could be a curative treatment for advanced pediatric solid tumors.

AB - Background/purpose: This study aimed to assess the significance of tumor debulking surgery by using immune checkpoint inhibitors for advanced pediatric solid tumors in a murine model of advanced osteosarcoma. Methods: In C3H mice, 5 × 106 LM8 (osteosarcoma cell line with a high metastatic potential in the lungs originating from the C3H mouse) cells were transplanted subcutaneously. Thereafter, the mice were divided into 4 groups as follows: the control group received no intervention (CG, n = 5), the surgery group underwent subcutaneous tumor resection (tumor debulking surgery) 11 days after transplantation (SG, n = 10), the immunotherapy group received a cocktail consisting of 200 μg each of three antibodies (anti-Tim-3, anti-PD-L1, and anti-OX-86) intraperitoneally on posttransplantation days 11, 14, 18, and 21 (IG, n = 10), and the combination therapy group, tumor debulking surgery on day 11 and the cocktail intraperitoneally on days 11, 14, 18, and 21 (COMBG, n = 10). Survival curves were plotted by using the Kaplan–Meier method and compared with those plotted using the log-rank test. Next, the lungs of mice in the 4 groups were pathologically evaluated. Results: The COMBG showed significantly longer survival than the other three groups (P ≤ 0.002), whereas the SG and IG revealed no difference in survival rate compared to CG. Pathological evaluations revealed no lung metastasis 16 weeks after tumor transplantation in the survivors of COMBG. Conclusions: The results of this study suggest that tumor debulking surgery combined with immune checkpoint inhibitors could be a curative treatment for advanced pediatric solid tumors.

KW - Advanced pediatric solid tumor

KW - Immune checkpoint inhibitors

KW - Osteosarcoma

KW - OX40

KW - PD-1/PD-L1

KW - Tumor debulking surgery

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