A radioenhancing nanoparticle mediated immunoradiation improves survival and generates long-term antitumor immune memory in an anti-PD1-resistant murine lung cancer model

Journal of Nanobiotechnology

Dawei Chen¹  Hampartsoum Barsoumian²  Chike O. Abana²  James W. Welsh²  Mark Wasley²  Liangpeng Yang²  Maria Angelica Cortez²  Yun Hu²  Quynh-Nhu Nguyen²  Saumil Gandhi²  Fatemeh Masrorpour²  Joe D. Dunn²  Duygu Sezen³  Kewen He⁴  Sébastien Paris⁵ 

[1] Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China;Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Boulevard, 77030, Houston, TX, USA;Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Boulevard, 77030, Houston, TX, USA;Department of Radiation Oncology, Koc University School of Medicine, Istanbul, Turkey;Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Boulevard, 77030, Houston, TX, USA;Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China;Department of Translational Science, Nanobiotix, Paris, France;

关键词: Nanoparticle;    Metastatic lung cancer;    Radioimmunotherapy;    Checkpoint blockade;    Immune memory;    NBTXR3;    Radiation enhancer;    Radiotherapy;   

DOI  :  10.1186/s12951-021-01163-1

来源: Springer

【 摘 要 】

BackgroundCombining radiotherapy with PD1 blockade has had impressive antitumor effects in preclinical models of metastatic lung cancer, although anti-PD1 resistance remains problematic. Here, we report results from a triple-combination therapy in which NBTXR3, a clinically approved nanoparticle radioenhancer, is combined with high-dose radiation (HDXRT) to a primary tumor plus low-dose radiation (LDXRT) to a secondary tumor along with checkpoint blockade in a mouse model of anti-PD1-resistant metastatic lung cancer.MethodsMice were inoculated with 344SQR cells in the right legs on day 0 (primary tumor) and the left legs on day 3 (secondary tumor). Immune checkpoint inhibitors (ICIs), including anti-PD1 (200 μg) and anti-CTLA4 (100 μg) were given intraperitoneally. Primary tumors were injected with NBTXR3 on day 6 and irradiated with 12-Gy (HDXRT) on days 7, 8, and 9; secondary tumors were irradiated with 1-Gy (LDXRT) on days 12 and 13. The survivor mice at day 178 were rechallenged with 344SQR cells and tumor growth monitored thereafter.ResultsNBTXR3  +  HDXRT  +  LDXRT  +  ICIs had significant antitumor effects against both primary and secondary tumors, improving the survival rate from 0 to 50%. Immune profiling of the secondary tumors revealed that NBTXR3  +  HDXRT  +  LDXRT increased CD8 T-cell infiltration and decreased the number of regulatory T (Treg) cells. Finally, none of the re-challenged mice developed tumors, and they had higher percentages of CD4 memory T cells and CD4 and CD8 T cells in both blood and spleen relative to untreated mice.ConclusionsNBTXR3 nanoparticle in combination with radioimmunotherapy significantly improves anti-PD1 resistant lung tumor control via promoting antitumor immune response.Graphical Abstract

【 授权许可】

CC BY