Summary

Background: PEP503 (as known as NBTXR3) is a novel radio-enhancer composed of functionalized hafnium oxide nanoparticles for a higher energy deposit by radiotherapy comparing to radiotherapy alone without it. A prior phase 3 study for soft tissue sarcoma has demonstrated the clinical benefit. The phase 1b part of the study aimed to test the feasibility of PEP503 intra-tumor injection and examine the safety profile of various dose levels of PEP503 in combination with concurrent chemo-radiation (CCRT) for locally advanced rectal cancers.

Methods: Patients who had rectal adenocarcinoma of T3-4 or locally unresectable disease suitable for neoadjuvant CCRT were eligible. A single administration of PEP503 intra-tumor injection with multiple needle punctures was applied 24 to 72 hours before the start of IMRT or IMAT at 50 Gy in 25 fractions in combination with capecitabine or infusion 5-FU over 5~6 weeks. Dose escalation of 4 levels of PEP503 injected volume was based on 5%, 10%, 15%, and 22% of the baseline tumor volume by MRI. Intra-tumor dispersion of nanoparticles was inspected by CT-scan and the body kinetics evaluation was performed. The total mesorectal excision was planned around 8~12 weeks later after the completion of CCRT. Preliminary efficacy including tumor response after CCRT and the pathological response with tumor regression grade (TRG) after surgery was collected.

Results: Twenty patients were enrolled, with 7, 4, 3, and 6 patients at 5%, 10%, 15%, and 22% dose levels, respectively. An injection procedure-related dose-limiting toxicity of urinary tract infection with sepsis was reported in the first treated patient at 5%. There was no adverse event (AE) or serious AE directly caused by PEP503. The most frequently reported AEs related to CCRT across all dose levels were diarrhea (~45%), WBC decreased (~40%), and dermatitis (~25%), but all were grade 1 or 2. The safety profile of CCRT with PEP503 was similar to it of CCRT without PEP503 for rectal cancer patients. The CT scans, before and after CCRT, displayed the dispersion of PEP503 among different tumor shapes and contours without leakage to the surrounding healthy tissues. In most patients, hafnium was not detected in the circulation in 60 minutes after PEP503 injection and not found in urine. Around 70% of patients showed tumor response after the CCRT and half of the patients receiving surgery achieved good tumor regression (AJCC TRG 0 or TRG 1). In the small phase 1b dose-escalation part of the trial, the dose-dependency of the efficacy endpoints could not be assessed.

Conclusions: Intra-tumor injection of PEP503/NBTXR3 with CCRT is feasible without additional toxicities for rectal cancer patients. The extension phase 2 of the trial to investigate the clinical benefits of PEP503 at 22% of tumor volume is ongoing in Taiwan.

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

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: 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.