Summary

Background: Between 70 to 90% of patient have « cold » tumors, i.e. devoid or poorly infiltrated by immune cells, rendering inoperative their treatment by immune checkpoint inhibitors. To allow these patients to benefit from these therapies, it is fundamental to prime an antitumor immune response. Radiotherapy (RT) has demonstrated its ability to induce the immunogenic cell death (ICD), a crucial event allowing the priming of the antitumor immune response. Meanwhile, a new class of material with high electron density, hafnium oxide, was designed at the nanoscale (HfO2-NP) to efficiently absorb ionizing radiation and increase the radiation dose deposition from within the tumor cells and increase killing of cancer cells. Here, we compared the ability of HfO2-NP and RT to RT alone to kill cancer cells and induce immunogenic cell death.

Methods: A panel of human and mouse cancer cell lines (mesenchymal and epithelial origin, radiosensitive and radioresistant) were treated or not with HfO2-NP, then irradiated by X-rays. Impact of the treatments on apoptosis and necrosis was assessed by FACS analysis (Annexin V/Propidium iodide). […]

Results: For all the tested cell lines treated with HfO2-NP and RT, a marked increase of apoptosis and necrosis was demonstrated, compared to cells treated with RT alone. In addition, higher levels of DAMPs (ecto-CRT, ecto-HSP70, ecto-HSP90, secreted ATP and extracellular HMGB1) were measured in the cancer cells treated with HfO2-NP and RT when compared to cancer cells exposed to RT.

Conclusions: HfO2-NP has demonstrated its capacity to kill cancer cells more efficiently than radiotherapy alone. HfO2-NP, administered via a single intratumor injection, is currently evaluated in clinical trials including soft tissue sarcoma (phase II/III), head and neck, prostate, liver and rectum cancers (phase I) and would permit to improve the local control of tumors, a crucial parameter for the cure and survival of patients. […]

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

Immunotherapy Workshop: Bethesda, MD, June 15-16, 2017

Radiotherapy (RT) has proven its ability to function like an in-situ vaccine, showing potential for successful combination with immunotherapeutic agents. Hafnium oxide nanoparticle (HfO2-NP), undergoing clinical trials for enhancing RT, was designed as high electron density material at the nanoscale. HfO2-NPs are taken up by cancer cells and, when exposed to RT, locally increase the radiation dose deposit, triggering more cancer cells death when compared to RT. We hypothesized that HfO2-NP+RT could trigger an enhanced immune response when compared to RT, both in preclinical and clinical settings.

Summary

Radio-enhancers, metal-based nanosized agents, could play a key role in oncology. They may unlock the potential of radiotherapy by enhancing the radiation dose deposit within tumors when the ionizing radiation source is ‘on’, while exhibiting chemically inert behavior in cellular and subcellular systems when the radiation beam is ‘off’. Important decision points support the development of these new type of therapeutic agents originated from nanotechnology. Here, we discuss from an industry perspective, the interest of developing radio-enhancer agents to improve tumor control, the relevance of nanotechnology to achieve adequate therapeutic attributes, and present some considerations for their development in oncology.