Radiotherapy-activated NBTXR3 nanoparticles modulate cancer cell immunogenicity and TCR repertoire.

BACKGROUND: Radiotherapy is a powerful and widely used technique for the treatment of solid tumors. Beyond its ability to destroy tumor cells, it has been demonstrated that radiotherapy can stimulate the anti-tumor immune response. Unfortunately, this effect is mainly restricted to the irradiated lesion, as tumor control outside the treated field (called the 'abscopal effect') is rarely obtained. In addition, many pro-tumoral factors prevent this anti-tumor immune response from being sustained and efficient. We previously reported that radiotherapy-activated NBTXR3 produced a significant CD8-dependent abscopal effect in immunocompetent mice bearing CT26.WT tumors, while radiotherapy failed to generate such a response. METHODS: To identify the mechanisms that may explain this response, we evaluated the capacity of radiotherapy-activated NBTXR3 to modulate the immunogenicity of tumor cells by analysis of immunogenic cell death biomarkers and immunopeptidome sequencing. In vivo, we analyzed treated tumors for CD4+, CD8 + and CD68 + cell infiltrates by immunohistochemistry and digital pathology and sequenced the T cell receptor (TCR) repertoire in both treated and untreated distant tumors. RESULTS: We showed that NBTXR3 activated by radiotherapy both increased immunogenic cell death biomarkers and modulated the immunopeptidome profile of CT26.WT cells. Immunohistochemistry analysis of treated tumors revealed a significant increase in CD4+, CD8 + and CD68 + cell infiltrates for NBTXR3 activated by radiotherapy group, compared to radiotherapy. We also measured significant modifications in TCR repertoire diversity in the radiotherapy-activated NBTXR3 group, both in treated and distant untreated tumors, compared to radiotherapy alone. CONCLUSIONS: These results indicate that radiotherapy-activated NBTXR3 can act as an effective immunomodulator, modifying tumor cell immunogenicity and impacting the lymphocyte population.

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

PURPOSE: The side effects of radiotherapy induced on healthy tissue limit its use. To overcome this issue and fully exploit the potential of radiotherapy to treat cancers, the first-in-class radioenhancer NBTXR3 (functionalized hafnium oxide nanoparticles) has been designed to amplify the effects of radiotherapy. PATIENTS AND METHODS: Thanks to its physical mode of action, NBTXR3 has the potential to be used to treat any type of solid tumor. Here we demonstrate that NBTXR3 can be used to treat a wide variety of solid cancers. For this, we evaluated different parameters on a large panel of human cancer models, such as nanoparticle endocytosis, in vitro cell death induction, dispersion, and retention of NBTXR3 in the tumor tissue and tumor growth control. RESULTS: Whatever the model considered, we show that NBTXR3 was internalized by cancer cells and persisted within the tumors throughout radiotherapy treatment. NBTXR3 activated by radiotherapy was also more effective in destroying cancer cells and in controlling tumor growth than radiotherapy alone. Beyond the effects of NBTXR3 as single agent, we show that the antitumor efficacy of cisplatin-based chemoradiotherapy treatment was improved when combined with NBTXR3. CONCLUSION: These data support that NBTXR3 could be universally used to treat solid cancers when radiotherapy is indicated, opening promising new therapeutic perspectives of treatment for the benefit of many patients.

Radiotherapy-Activated Hafnium Oxide Nanoparticles Produce Abscopal Effect in a Mouse Colorectal Cancer Model.

PURPOSE: 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 antitumor-specific 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.

DNA damage enhancement by radiotherapy-activated hafnium oxide nanoparticles improves cGAS-STING pathway activation in human colorectal cancer cells.

The cGAS-STING pathway can be activated by radiation induced DNA damage and because of its important role in anti-cancer immunity activation, methods to increase its activation in cancer cells could provide significant therapeutic benefits for patients. We explored the impact of hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy on cell death, DNA damage, and activation of the cGAS-STING pathway. We demonstrate that NBTXR3 activated by radiotherapy enhances cell destruction, DNA double strand breaks, micronuclei formation and cGAS-STING pathway activation in a human colorectal cancer model, compared to radiotherapy alone.