Summary

Soft tissue sarcoma (STS) is a rare type of cancer, which occurs in tissues connecting, supporting and/or surrounding other structures of the body, like muscle, fat, etc. More than 50 subtypes of STS exist, characterized by a strong propensity to local recurrence and metastatic spreading. Consistently, the immune microenvironment in sarcomas is highly variable. A new class of high electron density material, hafnium oxide, was designed at the nanoscale to efficiently absorb ionizing radiation from within the tumor cells and increase the dose deposition into the tumor.

These nanoparticles (HfO2-NP), delivered into the tumor by a single injection and activated by radiotherapy, have the ability to enhance immunogenic cell death and immune response in preclinical studies. Here, we explore in a phase II/III trial in patients with locally advanced STS, the effects of nanosized hafnium oxide exposed to RT in terms of tumor immune profile changes in patients, when compared to RT alone.

Regarding immune cells infiltrates (post- vs pre-treatment), promising results are reported for patients treated with HfO2-NP activated by RT, when compared to RT. So far, these results show that HfO2-NP + RT induces a specific adaptive immune pattern. As such, it may convert immunologically “cold” tumor into “hot” tumor and be effectively combined with immunotherapeutic agents across oncology. More tissue samples are under evaluation to reinforce these findings.

Summary

HfO2-NP + RT bring marked changes to the tumor immune profile both in mouse model and in patients with STS, compared to RT. So far, these results show that HfO2-NP + RT induces a specific adaptive immune pattern.

In mouse, an abscopal effect was observed with HfO2-NP but not with RT alone. IHC analyses show that a significant increase of CD8+ cells is present in treated and untreated tumors, but no effect was observed for RT alone. IHC analysis (post- vs pretreatment) show a marked increase of the biomarkers for patient treated with HfO2-NP + RT, particularly for CD8+ and PD1. No differences are seen for RT alone. The profile of gene expression HfO2-NP + RT differs from RT alone. Functional analysis of genes expression up-regulated in HfO2-NP + RT shows an increase of the cytokine and immune checkpoints expression, as T cell activation markers, compared to RT alone.

Summary

The enclosed abstract was presented at the 13th Journées cancéropole Grand Sud-Ouest at Poitiers. The abstract Hafnium oxide nanoparticles as an emergent promising treatment for solid tumors describes how hafnium oxide nanoparticles were designed at the nanoscale in the form of crystalline 50nm-particles to efficiently absorb ionizing radiation and increase the radiation dose deposited – “hot spots” of energy deposit – from within the tumor cells for efficient cell killing.

Hafnium oxide nanoparticles (NBTXR3), administered as a single intratumoral injection and activated by radiotherapy, is currently evaluated in a phase II/III clinical trial in soft tissue sarcoma (STS) [NCT02379845], and in phase I/II clinical trials for head and neck [NCT01946867], prostate [NCT02805894], liver [NCT02721056; NCT02721056] and rectum cancers [NCT02465593]. So far, patients treated with NBTXR3 received radiotherapy as planned and showed a very good local safety profile.

Summary

The enclosed abstract was presented at the 2017 Connective Tissue Oncology Society Annual Meeting (CTOS), Maui, Hawaii. The abstract NBTXR3 Treatment Induces Antitumoral Immune Response in Human Soft Tissue Sarcoma describes how NBTXR3 activated by RT triggers an enhanced adaptive immune response and contributes to transform “cold” tumor into “hot” tumor.

Summary

The enclosed abstract was presented at the 35th Annual Chemotherapy Foundation Symposium, New York. The abstract Hafnium oxide nanoparticles: an emergent promising treatment for solid tumors describes the story of hafnium oxide nanoparticles, NBTXR3, from the preclinical to the clinical development up to date.

Preclinical studies have demonstrated increase of cancer cells death in vitro and marked antitumor efficacy in vivo in presence of these nanoparticles (HfO2-NP) exposed to RT, when compared to RT alone. Hafnium oxide nanoparticles efficacy was assessed in cancer epithelial and mesenchymal tumor models and on patient-derived tumor xenografts in nude mice, showing superior anti-tumor effects, over radiation therapy alone in terms of complete response and overall survival. Additionally, in vivo cancer epithelial models in immunocompetent mouse have showed that HfO2-NP + RT triggers immunogenic conversion of the tumor microenvironment and generate an abscopal effect while this effect is not observed with RT alone.

HfO2-NP (NBTXR3), administered as a single intratumoral injection and activated by radiotherapy, is currently evaluated in clinical trials including soft tissue sarcoma (STS) [NCT02379845], head and neck [NCT01946867], prostate [NCT02805894], liver [NCT02721056; NCT02721056] and rectum cancers [NCT02465593]. Patients treated in phases I have had a good tolerance to the product and received radiotherapy as planned, confirming a very good local safety profile.

Besides, consistently with non-clinical studies, preliminary results of the phase II/III in patients with STS, beyond the expected cytotoxic effect induced by NBTXR3 + RT, suggest a release of tumor neoantigens during cancer cell death and stimulation of local immunological effects. This immunogenic cell death might convert “cold” tumor into “hot” tumor. Further analyses are ongoing to reinforce these findings.