Summary

Purpose: First in class hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy (RT) increase radiation dose deposit within cancer cells compared to RT alone. Given that RT can prime an anti-tumor immune response we hypothesized that this response could be enhanced by NBTXR3+RT in both animals and humans.

Method & Materials: Different abscopal assays in mice were conducted. Immunocompetent mice were injected in both flanks with murine tumor cells. Intratumoral injection of NBTXR3 (or vehicle) was performed in right flank tumors, followed by RT of right flank tumors only. Tumor growth was followed and immune cell infiltrates were analyzed by immunohistochemistry (IHC). Some mice received anti-PD-1 injections and tumor growth was monitored. Pts with locally advanced soft tissue sarcoma (STS) [NCT02379845] received either NBTXR3+RT or RT alone. Pts pre- and post-treatment tumor tissues were analyzed by IHC and Digital Pathology for immune biomarkers.

Results: Animal studies demonstrated that NBTXR3+RT induces an immune response which was not observed with RT alone. IHC showed significantly more CD8+ cells present in NBTXR3+RT treated and untreated tumors. Furthermore, NBTXR3+RT improved the effect of anti-PD-1. Similarly, increased CD8+ T cell infiltration pre- vs post-treatment was observed in tumor tissues from STS pts treated with NBTXR3+RT. An increase in biomarkers, including CD8, following NBTXR3+RT was also observed by IHC in tumor samples from STS pts compared to RT alone.

Conclusion: These results demonstrate that NBTXR3+RT induces a specific adaptive immune profile in both mice and STS pts. NBTXR3+RT also improved response to anti-PD-1 in mice, opening the potential for combination with immunotherapeutic agents in humans. We have therefore sought to investigate the safety and systemic effect of NBTXR3 activated by stereotactic ablative radiotherapy (SABR) in combination with anti-PD-1 in pts with locoregionally recurrent or metastatic (lung or liver) head and neck squamous cell carcinoma, as well as in metastatic non-small cell lung cancer and liver metastasis pts [NCT03589339].

Clinical Relevance & Application: The results of this study highlight the potential of NBTXR3 to be used in combination with immune checkpoint inhibitors in order to improve patient outcomes.

Summary

Background: Radiotherapy (RT) can prime an anti-tumor immune response. Unfortunately, this response rarely generates total tumor destruction and abscopal effect. When activated by RT, intratumorally (IT) administered hafnium oxide nanoparticles (NBTXR3) locally increase radiation dose deposit and tumor cell death compared to RT alone. We hypothesized that NBTXR3 + RT could enhance the anti-tumor immune response, both in mice and humans.

Methods: Murine CT26 cells were injected in both flanks of immunocompetent mice. When tumor volume reached 50-120mm3, NBTXR3 (or vehicle) was injected IT in right flank tumors only, then irradiated (3x4Gy). Mice were sacrificed when tumors reached 800mm3. Alternatively, tumors were collected 3 days after last RT fraction and immune cell infiltrates analyzed by immunohistochemistry (IHC). Patients (pts) with locally advanced Soft Tissue Sarcoma (STS) (NCT02379845) received NBTXR3 + RT or RT alone. Pre- and post-treatment (biopsy and resection, respectively) tumor tissues from pts were analyzed by IHC and Digital Pathology for immune biomarkers ( > 16 pts per arm).

Results: In mice, IHC analyses showed an increase of CD8+ T cells infiltrates in both flanks of mice treated with NBTXR3+RT, while this was not observed in animals treated with RT alone. Furthermore, ICH analysis of post- vs pre-treatment samples from STS pts showed a marked increase of CD8+ and PD1 biomarkers for pts treated with NBTXR3 + RT, while no differences were seen for pts treated with RT alone.

Conclusions: NBTXR3 + RT markedly changes the tumor immune profile in a similar manner in mice and pts with STS. We hypothesize that this adaptive immune response could help convert a local tumor microenvironment to a “hot” phenotype and thus improve the efficacy of immune checkpoint inhibitors. These results led us to investigate the safety and systemic effect of NBTXR3 activated by stereotactic ablative RT (SABR) in combination with anti-PD-1 antibody in pts with locoregionally recurrent or metastatic (to lung or liver) Head and Neck squamous cell carcinoma HNSCC, as well as in metastatic non-small cell lung cancer (NSCLC) and liver metastasis patients [NCT03589339].

Summary

Background: Despite proven efficacy, a limited number of patients (pts) with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) or metastatic non-small cell lung cancer (NSCLC) benefit from anti-PD-1 treatment. Indeed, most pts do not respond to initial therapy due to intrinsic re-sistance to checkpoint inhibition. There is thus an important unmet medical need for a curative treatment in these pts and converting the local immune microenvironment to a “hot” phenotype may help to overcome therapeutic resistance.

Hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy (RT) increase radiation dose de-posit within cancer cells compared to RT alone. Recently, a phase II/III randomized trial of NBTXR3 in locally advanced soft tissue sarcoma (STS) met primary and main secondary endpoints with sig-nificant superiority compared to RT alone [NCT02379845]. Furthermore NBTXR3+RT demonstrated an immunogenic cell death-mediated abscopal effect in a pre-clinical setting, and immune cell infil-tration was observed in some tumors from STS pts treated with NBTXR3+RT but not in tumors from pts treated with RT alone. NBTXR3 is currently being evaluated in 7 clinical trials, including a phase I/II study in elderly frail patients with locally advanced HNSCC [NCT01946867]. To date, no early dose limiting toxicities (DLTs) have been observed.

Methods: Overall, these results have led us to evaluate NBTXR3 activated by stereotactic ablative radiothera-py (SABR) in combination with an approved anti-PD-1 antibody in an open label phase I/II, non-randomized clinical trial in pts with more advanced diseases: locoregionally recurrent or metastatic HNSCC, metastatic NSCLC, and liver metastasis pts [NCT03589339].

The phase I primary objectives are to determine NBTXR3 maximum tolerated dose(s), incidence of early DLTs and recommended dose(s). The phase II primary objectives are Complete Response Rate of target lesions and Objective Response Rate for the locoregional recurrent and the metastatic group respectively by RECIST 1.1, and safety/tolerability of treatment at the recommended dose(s).

Summary

Recent clinical studies have demonstrated the efficacy of anti-PD-1 in recurrent/metastatic HNSCC and upfront metastatic NSCLC patients. However, most patients with recurrent/metastatic HNSCC demonstrate innate (primary) resistance to checkpoint inhibition and do not respond to initial therapy and only a subset of metastatic HNSCC/NSCLC patients benefits from this treatment. There is thus an important unmet medical need for a curative treatment of this population. We hypothesized that intra-tumoral/intralesional injection of NBXTR3 in the tumor or in one metastasis in lung or liver, followed by SABR may be a powerful mechanism to convert the local immune microenvironment to a “hot” phenotype and thus help to reverse resistance to immune checkpoint inhibition.

We thus designed an open label Phase I/II, non-randomized clinical study of NBTXR3 activated by SABR in combination with approved anti-PD1 in patients with advanced HNSCC or NSCLC. The primary objective of the phase I is to determine the maximum tolerated dose/s, the early DLTs and the recom-mended dose/s of NBTXR3. The primary objectives of the phase II part are complete response of target lesion/s by RECIST v1.1 for the locoregional recurrent group, objective Response Rate by RECIST v 1.1 for the metastatic group and incidence of adverse events in both groups with a complete safety as-sessment.