Abstract 2973: Analysis of NBTXR3 nanoparticles recapture after release by dying cells

Abstract

Abstract In 2011, NBTXR3 emerged as the pioneering radioenhancer used in clinical practice to treat patients with locally advanced soft tissue sarcoma (LA-STS). Following the successful completion of a phase II/III clinical study for LA-STS, with a doubling of the pCR rate in the NBTXR3 arm compared with the control arm. NBTXR3 became the first radioenhancer to receive CE mark approval. NBTXR3 nanoparticles are composed of a functionalized core made of hafnium oxide, a high atomic number element. They were designed to enhance the effects of radiotherapy (RT) within cells without causing additional side effects on healthy tissues. Exploiting this physical mechanism, radiation-activated NBTXR3 (NBTXR3+RT) has exhibited superior efficacy in eradicating tumor cells and managing tumor growth in various preclinical models and in human studies. It surpasses the effects of RT alone while maintaining a favorable safety profile. Recent preclinical investigations have uncovered that the advantages of NBTXR3 go beyond mere radioenhancement and improved cancer cell destruction. Notably, NBTXR3 has been reported to possess immunomodulatory properties through several mechanisms, including 1) improved induction of DNA damage, leading to enhanced activation of the cGAS-STING pathway, 2) promotion of immunogenic cell death, 3) enhancement of immunopeptidome presentation, 4) generation of an antitumor immune response that results in the production of an abscopal effect mediated by CD8+ cytotoxic lymphocytes. Significantly, a series of recent studies using a two-tumor mouse model of anti-PD1-resistant lung cancer demonstrated that the addition of NBTXR3 significantly improved the efficacy of various treatment regimens (combinations of RT plus anti-PD1 and other checkpoint inhibitors) in terms of tumor growth, abscopal effect, and overall survival. Furthermore, similar benefits can be achieved when NBTXR3 is combined with proton therapy (PBT). Moreover, all these studies (both X-ray and PBT) reported a robust activation of the antitumor immune response, the restoration of the effectiveness of anti-PD1 therapy, and the induction of a memory response in cured mice. But our knowledge of the underlying biological processes that lead to these effects remains rather limited. For example, no information is available about the fate of these nanoparticles once they are injected into a tumor or when they are released by dying cancer cells. To gain a better understanding of these issues, we conducted a series of in vitro and in vivo experiments. We demonstrate that the endocytosis occurs similarly both in vivo and in vitro, at the level of tumor cells. Furthermore, we demonstrate in vitro that nanoparticles taken up by these tumor cells and subsequently released upon their death can be reinternalized by other tumor cells, thus facilitating their destruction by RT. These initial findings provide a deeper insight into the behavior of NBTXR3. Citation Format: Jordan Da silva, Célia Bienassis, Sebastien Paris. Analysis of NBTXR3 nanoparticles recapture after release by dying cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2973.