Summary

The physical mode of action of NBTXR3 may represent a breakthrough approach for the local treatment of liver cancers, as it does not engage liver and renal functions, i.e. nanoparticles are not metabolized and not excreted by kidney. A phase I/II trial has been implemented for the treatment of hepatocellular carcinoma and liver metastasis [NCT02721056].

At the 2018 Gastrointestinal Cancers Symposium (also known as ASCO-GI) at San Francisco (CA, USA), Dr. Chajon presented preliminary results on this study.

Overall, the injection of NBTXR3 was safe and well tolerated at these levels. Patients received the planned RT. No DLT occurred. Enrollment is now opened at the 22% level. NBTXR3 shows promising results in terms of safety and antitumor activity and is also currently evaluated in other six clinical studies.

Summary

Recent results of a phase II/III in locally advanced Soft Tissue Sarcoma patients demonstrated clinical benefits of intratumorally injected HfO2-NP activated by radiotherapy compared to radiotherapy alone, validating their first-in-class mode of action. In addition, animal studies have reported that HfO2-NP+RT can induce an abscopal effect, where RT alone cannot. Here, using a mouse abscopal assay, we measured T cells infiltrates in treated and untreated tumors after HfO2-NP intratumor injection and activation with RT, and their role in the abscopal effect.

These data indicate that the immunogenic conversion of the tumor microenvironment triggered by HfO2-NP+RT generates the abscopal effect by activation of CD8+ T cells. HfO2-NP+RT may potentiate a pro-inflammatory microenvironment appropriate for enabling an anti-tumor immune response. It may act as effective in-situ cancer vaccine and be combined with immunotherapeutic agents across oncology.

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

Loco-regional control in head and neck cancer has been improved by combining radiotherapy (RT) with chemical agents, radiosensitizers and monoclonal antibodies. However, these associations come with challenging limitations in terms of pharmacology, local control, clinical outcome benefits or patient quality of life. In addition, high doses of radiation may result in several undesired reactions which underline the need for new therapeutic approaches.

Functionalized hafnium oxide nanoparticles (NBTXR3) is a new class of material with high electron density, designed in the form of crystalline 50nm-particles (HfO2-NP) to efficiently absorb ionizing radiation and allow the absorption/deposition of a high radiation dose within the cancer cells, to physically kill the cells and modify the tumor immune profile.

HfO2-NP (NBTXR3), administered as a single intratumoral injection and activated by radiotherapy, is currently evaluated in a phase I clinical trial for head and neck cancer [NCT01946867] in elderly and frail patients that cannot receive the standard of care.

At the 2017 THNO in Nice, France, prof. C. Le Tourneau presented preliminary results of NBTXR3 in patients suffering from HNSCC. The treatment was associated with a positive safety profile, and preliminary effiacy evaluation, the local Complete Response rate is 83% (dose level 15% and 22%), with a duration of response of 22 months.

Summary

Background: Soft tissue sarcoma (STS) is a large and heterogeneous group of malignant mesenchymal neoplasms characterized by a strong tendency toward local recurrence and metastatic spreading. Consistently, the immune microenvironment in sarcomas is highly variable. A new class of material with high electron density, hafnium oxide, was designed at the nanoscale to efficiently absorb ionizing radiation from within the tumor cells and augment the dose deposited to a tumor. […]

Material and Methods: Tumor tissues pre- (biopsy) and post-treatment (resection) are collected from patients with locally advanced STS (NCT02379845), who received either HfO2-NP activated by RT or RT alone. Immunohistochemistry and Digital Pathology for immune biomarkers and Pan-Immune gene expression profiling are analyzed.

Results: A significant increase of CD8+ T cells and a marked increase of CD3+ and PD-1 T cells and CD103+ immune cell infiltration post- vs pre-treatment are observed for HfO2-NP + RT while not differences are seen for RT alone (more than 10 patients analyzed in each arm). Functional analysis of genes expression up-regulated in HfO2-NP + RT post- vs pre-treatment shows an enrichment of cytokine activity (IL7, IFNA, IL11, IFNG), adaptive immunity (RAG1, TAP1, TAP2, TBX21, IFNG, LTK, CD37, CD22) and T cell receptor signaling pathway (CD28, CTLA4, CD274, BTLA, TIGIT, CD5, ZAP70) when compared to RT.

Conclusions: Promising results are observed in patients who received HfO2-NP + RT in terms of immune cells infiltration post- vs pre-treatment when compared to RT. […]

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

Background: Hafnium oxide, an electron-dense material, was designed at the nanoscale to increase the radiation dose deposited from within the cancer cells: “Hot spot” of energy deposit where the nanoparticles are when exposed to radiation therapy (RT). Preclinical studies have demonstrated increase of cancer cells killing in vitro and marked antitumor efficacy in vivo with presence of these nanoparticles (HfO2-NP) exposed to RT, when compared to RT alone. […]

Material and Methods: CT26 (murine colorectal cancer cells) were subcutaneously injected in the flank of BALB/c mice. Once the mean tumors volume reached 115±30 mm3, tumors were intratumor injected with HfO2-NP and irradiated with 2Gyx3 or 4Gyx3, or irradiated only. Tumors were collected 5 days after the last RT fraction and analyzed for immune cell infiltrates by immunohistochemistry (2Gyx3 and 4Gyx3) and cytokines content by flow cytometry (2Gyx3). […]

Results: In mice bearing CT26 tumors, a marked increase of cytokines content and immune cell infiltrates was observed with HfO2-NP + 2Gyx3 when compared to RT alone. The tumor immune cell infiltrates were
further enhanced with HfO2-NP + 4Gyx3. In mice inoculated with 4T1 cells treated with HfO2-NP + 40Gy, a marked increase of immune cell infiltrate (CD8+) was observed in tumors when compared to tumors in mice inoculated with 4T1 cells treated with 40Gy and control.

Conclusions: These in vivo data generated from CT26 and 4T1 tumor models suggest that HfO2-NP + RT triggers immunogenic conversion of the tumor microenvironement when compared to RT alone. HfO2-NP treatment may represent a therapeutical approach for broad applications since it does not rely on any molecular characteristics of the tumor.

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

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

Background: Functionalized hafnium oxide nanoparticles (NBTXR3) have been developed as selective radioenhancers, which may represent a breakthrough approach for the local treatment of solid tumors. The high electron density of the nanoparticles, when exposed to radiotherapy (RT), allow the absorption/deposition of a high radiation dose within the tumor cells, to physically kill the cells and possibly improve outcome. A phase I trial was implemented for the treatment of locally advanced HNSCC in patients (pts) older than 65 years who cannot receive cisplatin.

Methods: Pts received a single intratumor (IT) injection of NBTXR3, volume dose levels escalated at 5%, 10%, 15% and 22% of baseline tumor volume, followed by RT (IMRT, 70Gy/ 35 fractions / 7 weeks). Primary endpoints included feasibility of the IT implantation and safety. Secondary endpoints included IT residency of NBTXR3 using CT scan and RECIST 1.1 response.

Results: Enrollment was completed for volume 5%, 10%, and 15% (11 pts) and 1 patient at volume dose level 22%. Feasibility of the IT injection was confirmed. The treatment was easily administered, was safe with no SAE, or early DLT, which allowed the pts for completion of the planned RT schedule. Adverse events related to the injection procedure included grade 1-2 injection pain (1 pt), and tumor hemorrhage (1 pt). Results demonstrated that a single injection of NBTXR3 provides adequate bioavailability of NBTXR3 IT over seven weeks of RT. No leakage of NBTXR3 to the adjoining healthy tissues was observed. Preliminary results of antitumor activity according to RECIST 1.1 are presented below: 11 evaluable pts, 10 showed complete or partial response (RECIST 1.1) including, 1/5 complete response at dose levels ≤ 10% and 3/6 complete responses at dose levels > 10% Follow up results with duration of response and tolerance will be disclosed.

Conclusions: Injection of NBTXR3 was safe and well tolerated. All pts received the planned RT.