<p>Radiotherapy-Activated Hafnium Oxide Nanoparticles Produce Abscopal Effect in a Mouse Colorectal Cancer Model</p>

Abstract

Despite tremendous results achieved by immune checkpoint inhibitors, most patients are not responders, mainly because of the lack of a pre-existing anti-tumor immune response. Thus, solutions to efficiently prime this immune response are currently under intensive investigations. Radiotherapy elicits cancer cell death, generating an antitumorspecific T cell response, turning tumors in personalized in situ vaccines, with potentially systemic effects (abscopal effect). Nonetheless, clinical evidence of sustained anti-tumor immunity as abscopal effect are rare. Methods: Hafnium oxide nanoparticles (NBTXR3) have been designed to increase energy dose deposit within cancer cells. We examined the effect of radiotherapy-activated NBTXR3 on anti-tumor immune response activation and abscopal effect production using a mouse colorectal cancer model. Results: We demonstrate that radiotherapy-activated NBTXR3 kill more cancer cells than radiotherapy alone, significantly increase immune cell infiltrates both in treated and in untreated distant tumors, generating an abscopal effect dependent on CD8+ lymphocyte T cells. Conclusion: These data show that radiotherapy-activated NBTXR3 could increase local and distant tumor control through immune system priming. Our results may have important implications for immunotherapeutic agent combination with radiotherapy.

NBTXR3 Radiotherapy-Activated Functionalized Hafnium Oxide Nanoparticles Show Efficient Antitumor Effects Across a Large Panel of Human Cancer Models

“…All the clonogenic assays presented in this article show that NBTXR3+RT increased cancer cell death, in a dose-dependent manner, compared to the same dose of RT alone. Considering previous studies, 2 , 4 , 19 , 20 the enhancement of cell death following NBTXR3+RT treatment compared to RT alone has now been demonstrated in fifteen different cancer cell lines originating from nine different organs/tissues ( Figure 6 , Table 1 ). This also clearly demonstrates that, thanks to its radioenhancing capacity, NBTXR3 can kill any type of cancer cell.…”

“…Indeed, the heightened release of tumor-associated antigens triggered by NBTXR3+RT treatment could play a critical role in the priming or amplification of the adaptive antitumor immune response, as recently reported in the CT26 mouse colorectal model. 20

Figure 6 Review of studies with NBTXR3. The various experiments carried out in vitro and in vivo on the various human models demonstrated the effectiveness of NBTXR3 and its capacity to treat any kind of solid tumor.

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“…Preclinical and clinical studies have not revealed any leakage of NBTXR3 into surrounding tissues and showed that NBTXR3 remains within the tumor throughout RT treatment. 2 , 10 , 20 To expand these results, we examined the retention of NBTXR3 in seven different tumor models by µCT. We demonstrate that NBTXR3 was detectable within the tumor from few days to several weeks after intratumoral injection.…”

Therapy-Induced Modulation of the Tumor Microenvironment: New Opportunities for Cancer Therapies

“…The combination of hafnium oxide NP (NBTXR3, a high-Z nanomaterial with high-level electron density that increases energy dose deposit within cells) plus radiation vs. radiation alone has recently demonstrated meaningful clinical benefit in locally advanced soft tissue sarcoma by doubling pathologic response rates (16 vs. 8%) (138). Significantly, recent research has reported that radiationactivated hafnium oxide NP can augment tumor infiltrates of CD8 + T cells and generate an antitumor immune response, with systemic effect on untreated tumors on the same animals in a murine model of colon cancer (139).…”

Immunogenicity of Externally Activated Nanoparticles for Cancer Therapy

“…Due to the high atomic number of hafnium, which results in greater interaction cross-sections with ionizing radiation, resulting in more energy deposition, hafnium oxide nanoparticles have been explored for immunogenic radiosensitization. Zhang et al [44] noted that these nanoparticles, when deposited intratumorally in murine colorectal cancers, can sensitize these tumors to radiotherapy. Furthermore, these resulted in greater immune cell infiltration in the irradiated tumor as well as in distant (unirradiated) tumors.…”