Abstract
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
Highlights
Lung cancer accounts for nearly 25% of all cancer deaths worldwide [1], and the 5-year survival rates for metastasized lung cancer is only 5% [2]
We previously found that delivering high radiation doses to primary tumors in combination with immune checkpoint blockade in a mouse model of metastatic lung cancer could induce potent systemic antitumor immune responses; we further showed that the addition of low doses of radiation to secondary tumors could modulate the immune microenvironment of those tumors [7]
Reasoning that augmenting and optimizing these local and systemic immune effects would enhance the effectiveness of this strategy, we explored the effects of adding NBTXR3, a hafnium oxide radioenhancing nanoparticle, to this dualradiation-dose plus checkpoint blockade therapy in a mouse model of anti-PD1 resistant metastatic lung cancer
Summary
Lung cancer accounts for nearly 25% of all cancer deaths worldwide [1], and the 5-year survival rates for metastasized lung cancer is only 5% [2]. We previously found that delivering high radiation doses to primary tumors in combination with immune checkpoint blockade in a mouse model of metastatic lung cancer could induce potent systemic antitumor immune responses; we further showed that the addition of low doses of radiation to secondary tumors could modulate the immune microenvironment of those tumors [7]. We report results from a triplecombination 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
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