Summary

Recent studies reported that radiotherapy could activate the cGAS-STING pathway, which plays a fundamental role in the immune response to cytoplasmic DNA, by activation of the transcriptional factor IRF3, leading to expression of interferon-beta. Moreover, cGAS-STING activation appears to be an important component for tumor resident Antigen-Presenting Cells activation, a crucial step for induction of CD8+ T cell response against tumor derived antigens.

In this study, it was observed the ability of radiotherapy-activated NBTXR3 to increase cGAS-STING pathway response, compared to radiotherapy alone.

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.

Summary

Background: Radiation therapy (RT) has demonstrated ability to augment antitumor immunity, promoting immunogenic cell death (ICD) and stimulating immune adjuvant effects. On the other hand, RT has also been reported to induce immunosuppressive responses. A new class of material with high electron density, hafnium oxide, was designed at the nanoscale (HfO2-NP) to efficiently absorb ionizing radiation and augment the radiation dose
deposited from within the tumor cells. […]

Methods: The potential ability of HfO2-NP exposed to RT to transform tumors into immunologically active lesions was tested in vitro and in vivo. In vitro, the level of ICD markers was evaluated in a panel of human cancer cell lines, following cells treated or not with HfO2-NP and irradiated. In vivo, a vaccination assay was performed to evaluate the host immune responses in immunocompetent mice inoculated with murine CT26 cancer cells treated or not with HfO2-NP and irradiated with 6 Gy. […]

Results: Higher DAMPs levels (cell surface expression of calreticulin, extracellular adenosine triphosphate level and extracellular high-mobility group box 1 level) were observed in the tested cancer cells treated with HfO2-NP + RT when compared to cancer cells exposed to RT. […]

Conclusions: These results suggest an efficient cell killing (ability to generate ICD) with superior potential of HfO2-NP + RT to transform the tumor into an effective in situ vaccine when compared to RT. Moreover, HfO2-NP treatment generates a marked increase of immune cells infiltration in the tumors suggesting that it may convert immunologically “cold” tumor into “hot” tumor and could be combined with immunotherapeutic agents across oncology.

Summary

Combination of NBTXR3 and cisplatin has been evaluated in vitro and in vivo. No specific toxicity was observed for the cells exposed only to NBTXR3. For the combined treatment, a marked and enhanced cell destruction when compared to the single agent. In vivo, NBTXR3 combined with low dose of cisplatin delayed tumor growth when compared to single agent cisplatin in combination with radiotherapy.

Summary

Results & Conclusion: We created and developed NBTXR3 nanoparticles with a crystalline hafnium oxide core which provide high electron density structure and inert behavior in biological media. NBTXR3 nanoparticles’ characteristics, size, charge and shape, allow for efficient interaction with biological entities, cell membrane binding and cellular uptake. The nanoparticles were shown to form clusters at the subcellular level in tumor models. Of most importance, we show NBTXR3 intratumor bioavailability with dispersion of nanoparticles in the three dimensions and persistence within the tumor structure, supporting the use of NBTXR3 as effective antitumor therapeutic agent. Antitumor activity of NBTXR3 showed marked advantage in terms of survival, tumor specific growth delay and local control in A673 and HT1080 human tumor models. Changing radiotherapy benefit-risk ratio is challenging. These data are supportive for the first clinical development of hafnium oxide nanoparticles, with an on/off mode of action through successive fractions of radiation therapy using current equipment available in hospitals.

Summary

Full Title: NBTXR3 hafnium oxide nanoparticle activated by ionizing radiation demonstrates marked radioenhancement and antitumor effect via high energy deposit in human soft tissue sarcoma

Content: Local and systemic control of Soft Tissue Sarcoma (STS) remains a clinical challenge. Radiation therapy is part of the standard of care of STS. The narrowness of its therapeutic window represents the main concern for different clinical settings. Thus, local delivery of radiation doses is critical to ensure optimal benefit-risk ratio. NBTXR3, biocompatible hafnium oxide nanoparticles were designed as therapeutics to be activated by ionizing radiation to achieve tumor control by enhancement of local energy deposition.

Summary

Nanotechnology is the engineering of objects at the nanometer scale with novel properties. Nanotechnology is being applied to medicine leading to novel diagnostic or treatment applications. Nanoscale objects are about one hundred to ten thousand times smaller than human cells. They are similar in size to large biological molecules (“biomolecules”) such as enzymes and receptors. As an example, hemoglobin, the molecule that carries oxygen in red blood cells, is approximately 5 nanometers in diameter. Nanoscale objects smaller than 100 nanometers can move out of blood vessels as they circulate through the body due to morphological features of the endothelium (fenestrae size). Those smaller than 7 nanometers can be cleared from the body by the kidney, as they circulate.

Nanotechnology devices are being developed for several cancer applications. EPR effect (Enhanced Permeability and Retention effect), originated from vascular permeability and lack of tumor lymphatic drainage allows accumulation of nanoparticles in the tumor. Therefore, nanoparticles could become important tools for tumor imaging and for tumor selective drug delivery. Furthermore, nanoparticles smaller than 50 nanometers can easily enter most cells.