TY - JOUR
T1 - NBTXR3 improves the efficacy of immunoradiotherapy combining nonfucosylated anti-CTLA4 in an anti-PD1 resistant lung cancer model
AU - Hu, Yun
AU - Paris, Sébastien
AU - Bertolet, Genevieve
AU - Barsoumian, Hampartsoum B.
AU - Wang, Qi
AU - Da Silva, Jordan
AU - Patel, Nalini B.
AU - Nguyen, Nguyen
AU - Doss, Denaha J.
AU - Huang, Ailing
AU - Hsu, Ethan
AU - Leyton, Claudia S.Kettlun
AU - Voss, Tiffany A.
AU - Masrorpour, Fatemeh
AU - Leuschner, Carola
AU - Pietz, Jordan T.
AU - Puebla-Osorio, Nahum
AU - Gandhi, Saumil
AU - Nguyen, Quynh Nhu
AU - Wang, Jing
AU - Cortez, Maria Angelica
AU - Welsh, James W.
N1 - Publisher Copyright:
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.
PY - 2022/11/3
Y1 - 2022/11/3
N2 - 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.
AB - 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.
KW - abscopal effect
KW - immume checkpoint blockade
KW - immunoradiotherapy
KW - lung cancer
KW - NBTXR3 nanoparticle
UR - http://www.scopus.com/inward/record.url?scp=85142197840&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85142197840&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2022.1022011
DO - 10.3389/fimmu.2022.1022011
M3 - Article
C2 - 36405757
AN - SCOPUS:85142197840
SN - 1664-3224
VL - 13
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 1022011
ER -