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NBTXR3 improves the efficacy of immunoradiotherapy combining nonfucosylated anti-CTLA4 in an anti-PD1 resistant lung cancer model

The efficacy of immunoradiotherapy consisting of radiation therapy and immune checkpoint blockade relies on effectively promoting the systemic antitumor immune response’s activation while simultaneously reducing local factors favoring immune suppression. We previously demonstrated that NBTXR3, a nan...

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Autores principales: Hu, Yun, Paris, Sébastien, Bertolet, Genevieve, Barsoumian, Hampartsoum B., Wang, Qi, Da Silva, Jordan, Patel, Nalini B., Nguyen, Nguyen, Doss, Denaha J., Huang, Ailing, Hsu, Ethan, Leyton, Claudia S. Kettlun, Voss, Tiffany A., Masrorpour, Fatemeh, Leuschner, Carola, Pietz, Jordan T., Puebla-Osorio, Nahum, Gandhi, Saumil, Nguyen, Quynh-Nhu, Wang, Jing, Cortez, Maria Angelica, Welsh, James W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9669748/
https://www.ncbi.nlm.nih.gov/pubmed/36405757
http://dx.doi.org/10.3389/fimmu.2022.1022011
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author Hu, Yun
Paris, Sébastien
Bertolet, Genevieve
Barsoumian, Hampartsoum B.
Wang, Qi
Da Silva, Jordan
Patel, Nalini B.
Nguyen, Nguyen
Doss, Denaha J.
Huang, Ailing
Hsu, Ethan
Leyton, Claudia S. Kettlun
Voss, Tiffany A.
Masrorpour, Fatemeh
Leuschner, Carola
Pietz, Jordan T.
Puebla-Osorio, Nahum
Gandhi, Saumil
Nguyen, Quynh-Nhu
Wang, Jing
Cortez, Maria Angelica
Welsh, James W.
author_facet Hu, Yun
Paris, Sébastien
Bertolet, Genevieve
Barsoumian, Hampartsoum B.
Wang, Qi
Da Silva, Jordan
Patel, Nalini B.
Nguyen, Nguyen
Doss, Denaha J.
Huang, Ailing
Hsu, Ethan
Leyton, Claudia S. Kettlun
Voss, Tiffany A.
Masrorpour, Fatemeh
Leuschner, Carola
Pietz, Jordan T.
Puebla-Osorio, Nahum
Gandhi, Saumil
Nguyen, Quynh-Nhu
Wang, Jing
Cortez, Maria Angelica
Welsh, James W.
author_sort Hu, Yun
collection PubMed
description The efficacy of immunoradiotherapy consisting of radiation therapy and immune checkpoint blockade relies on effectively promoting the systemic antitumor immune response’s activation while simultaneously reducing local factors favoring immune suppression. We previously demonstrated that NBTXR3, a nanoparticle radioenhancer, significantly improved immune responses in a murine anti-PD1-resistant metastatic lung cancer model. We hypothesize that radioactivated-NBTXR3 addition to anti-PD1 and a second-generation anti-CTLA4 could improve treatment effectiveness. To test this hypothesis, we inoculated mice with 344SQR cells in the right and left legs to establish primary and secondary tumors. The primary tumors were intratumorally injected with NBTXR3 nanoparticles on day 7, followed by three fractions of 12 Gy radiation on days 8, 9, and 10. The secondary tumors received two fractions of 1Gy radiation on days 13 and 14. Multiple rounds of anti-PD1, anti-CTLA4 or nonfucosylated anti-CTLA4 were given to the mice. Immune profiling of the tumors revealed that the combination of NBTXR3 with immunoradiotherapy significantly upregulated the activities of a wide range of antitumor immune pathways and reduced the abundance of regulatory suppressor T cells. This combination effectively eradicated the primary and secondary tumors and increased animal survival to 75%. Remarkably, previously treated with NBTXR3-containing treatment, the survivor mice exhibited a long-lasting antitumor memory immune response. This data provides compelling evidence of the efficacy of NBTXR3 to synergize with the immunoradiotherapy approach when combined with an anti-PD1 and multiple checkpoints such as a second generation anti-CTLA4 and show the potential for clinical uses of antitumor immunomodulatory effects of NBTXR3.
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spelling pubmed-96697482022-11-18 NBTXR3 improves the efficacy of immunoradiotherapy combining nonfucosylated anti-CTLA4 in an anti-PD1 resistant lung cancer model Hu, Yun Paris, Sébastien Bertolet, Genevieve Barsoumian, Hampartsoum B. Wang, Qi Da Silva, Jordan Patel, Nalini B. Nguyen, Nguyen Doss, Denaha J. Huang, Ailing Hsu, Ethan Leyton, Claudia S. Kettlun Voss, Tiffany A. Masrorpour, Fatemeh Leuschner, Carola Pietz, Jordan T. Puebla-Osorio, Nahum Gandhi, Saumil Nguyen, Quynh-Nhu Wang, Jing Cortez, Maria Angelica Welsh, James W. Front Immunol Immunology The efficacy of immunoradiotherapy consisting of radiation therapy and immune checkpoint blockade relies on effectively promoting the systemic antitumor immune response’s activation while simultaneously reducing local factors favoring immune suppression. We previously demonstrated that NBTXR3, a nanoparticle radioenhancer, significantly improved immune responses in a murine anti-PD1-resistant metastatic lung cancer model. We hypothesize that radioactivated-NBTXR3 addition to anti-PD1 and a second-generation anti-CTLA4 could improve treatment effectiveness. To test this hypothesis, we inoculated mice with 344SQR cells in the right and left legs to establish primary and secondary tumors. The primary tumors were intratumorally injected with NBTXR3 nanoparticles on day 7, followed by three fractions of 12 Gy radiation on days 8, 9, and 10. The secondary tumors received two fractions of 1Gy radiation on days 13 and 14. Multiple rounds of anti-PD1, anti-CTLA4 or nonfucosylated anti-CTLA4 were given to the mice. Immune profiling of the tumors revealed that the combination of NBTXR3 with immunoradiotherapy significantly upregulated the activities of a wide range of antitumor immune pathways and reduced the abundance of regulatory suppressor T cells. This combination effectively eradicated the primary and secondary tumors and increased animal survival to 75%. Remarkably, previously treated with NBTXR3-containing treatment, the survivor mice exhibited a long-lasting antitumor memory immune response. This data provides compelling evidence of the efficacy of NBTXR3 to synergize with the immunoradiotherapy approach when combined with an anti-PD1 and multiple checkpoints such as a second generation anti-CTLA4 and show the potential for clinical uses of antitumor immunomodulatory effects of NBTXR3. Frontiers Media S.A. 2022-11-03 /pmc/articles/PMC9669748/ /pubmed/36405757 http://dx.doi.org/10.3389/fimmu.2022.1022011 Text en Copyright © 2022 Hu, Paris, Bertolet, Barsoumian, Wang, Da Silva, Patel, Nguyen, Doss, Huang, Hsu, Leyton, Voss, Masrorpour, Leuschner, Pietz, Puebla-Osorio, Gandhi, Nguyen, Wang, Cortez and Welsh https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Hu, Yun
Paris, Sébastien
Bertolet, Genevieve
Barsoumian, Hampartsoum B.
Wang, Qi
Da Silva, Jordan
Patel, Nalini B.
Nguyen, Nguyen
Doss, Denaha J.
Huang, Ailing
Hsu, Ethan
Leyton, Claudia S. Kettlun
Voss, Tiffany A.
Masrorpour, Fatemeh
Leuschner, Carola
Pietz, Jordan T.
Puebla-Osorio, Nahum
Gandhi, Saumil
Nguyen, Quynh-Nhu
Wang, Jing
Cortez, Maria Angelica
Welsh, James W.
NBTXR3 improves the efficacy of immunoradiotherapy combining nonfucosylated anti-CTLA4 in an anti-PD1 resistant lung cancer model
title NBTXR3 improves the efficacy of immunoradiotherapy combining nonfucosylated anti-CTLA4 in an anti-PD1 resistant lung cancer model
title_full NBTXR3 improves the efficacy of immunoradiotherapy combining nonfucosylated anti-CTLA4 in an anti-PD1 resistant lung cancer model
title_fullStr NBTXR3 improves the efficacy of immunoradiotherapy combining nonfucosylated anti-CTLA4 in an anti-PD1 resistant lung cancer model
title_full_unstemmed NBTXR3 improves the efficacy of immunoradiotherapy combining nonfucosylated anti-CTLA4 in an anti-PD1 resistant lung cancer model
title_short NBTXR3 improves the efficacy of immunoradiotherapy combining nonfucosylated anti-CTLA4 in an anti-PD1 resistant lung cancer model
title_sort nbtxr3 improves the efficacy of immunoradiotherapy combining nonfucosylated anti-ctla4 in an anti-pd1 resistant lung cancer model
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9669748/
https://www.ncbi.nlm.nih.gov/pubmed/36405757
http://dx.doi.org/10.3389/fimmu.2022.1022011
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