Abstract 3225: Enhancement of anti-PD1 and anti-CTLA4 efficacy by NBTXR3 nanoparticles exposed to radiotherapy

Abstract

The use of checkpoints inhibitors (CPI) has radically changed the medical practices for cancer treatment. Unfortunately, the activity of CPI depends on a preexisting anti-tumor immune response, limiting their use to a small percentage of patients. It is crucial to propose solutions to prime an effective anti-tumor immune response and convert CPI non-responder patients to responders. Recent preclinical/clinical studies have reported that radiotherapy (RT) acts as an efficient modulator of tumor immunogenicity. RT can set in motion processes facilitating tumor recognition by the immune system. Unfortunately, RT rarely generates a sustained anti-tumor immunity and reduction of metastases burden outside the irradiated area - a phenomenon called ‘abscopal effect’ - is hardly obtained after RT and the toxicity to healthy tissues limits the maximum dose of irradiation delivered to patients. NBTXR3 is composed hafnium oxide nanoparticles (HfO2-NP) designed to increase energy dose deposition from inside the cancer cells. The size, shape and surface charge of HfO2-NP allow strong interactions with cancer cells and persistence within the tumor mass after a single intra-tumor administration during the whole RT treatment. The high electron density of HfO2-NP increases interaction probability with ionizing radiations (when compared to tumor tissues with low electron density), resulting in the enhancement of tumor destruction, compared to RT alone. The recent results of phase III in locally advanced Soft Tissue Sarcoma patients demonstrated the significant superiority and clinical benefits of intratumorally injected HfO2-NP activated by RT to treat cancer compared to RT alone, validating the first-in-class mode of action of NBTXR3. In addition, preclinical studies have reported that HfO2-NP activated by RT can induce an anti-tumor immune-response and an abscopal effect. Here, we explored the ability of RT-activated NBTXR3 to increase the efficacy of anti-PD1 or anti-CTLA4 using abscopal assay in immunocompetent mice. In a first assay, mice were subcutaneously injected with 344SQP (mouse lung cancer) cells on both flanks. Then, right tumors were injected with HfO2-NP (or vehicle) and irradiated (or not), while left tumors remain untreated. Some groups of mice received injections of anti-PD1. The same approach was used with CT26 (mouse colorectal cancer) cells, except that mice received anti-CTLA4. For the 344SQP model, tumor growth analysis revealed that NBTXR3+RT and anti-PD1 treatment allows a better tumor control on both sides, compared to other conditions. For CT26 model, NBTXR3+RT and anti-CTLA4 treatment led to a better tumor growth control on both sides, compared to other conditions. These results suggest that NBTXR3 activated by RT could potentiate the anti-PD1 and anti-CTLA4 efficacy, opening new opportunities for the treatment of patients by combination of NBTXR3+RT+CPI. Citation Format: Yun Hu, Ping Zhang, Audrey Darmon, Maria Angelica Cortez, Sébastien Paris, James Welsh. Enhancement of anti-PD1 and anti-CTLA4 efficacy by NBTXR3 nanoparticles exposed to radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3225.

Nanoparticles in the clinic: An update

“…The newest trials are only investigating NBTXR3/Hensify for intratumoral injections, but have expanded their indications to include treatment of prostate cancer (NCT02805894) and lung cancer with combined immunotherapy (NCT03589339). The reasoning for including immunotherapy with NBTXR3/Hensify treatment builds on preclinical data that demonstrated improved efficacy of immunotherapies following NBTXR3/Hensify treatment, stemming from an increased antitumor immune response . Since the mechanism of action of NBTXR3/Hensify is unique and unlike other approved nanoparticles or therapeutics, NBTXR3/Hensify may represent the next‐generation of nanoparticle therapeutics; specifically, nanoparticle therapeutics that can provide therapeutic benefits in a complementary and possibly synergistic way to standard therapeutic modalities.…”

“…The reasoning for including immunotherapy with NBTXR3/Hensify treatment builds on preclinical data that demonstrated improved efficacy of immunotherapies following NBTXR3/Hensify treatment, stemming from an increased antitumor immune response. 17,18 Since the mechanism of action of NBTXR3/ Hensify is unique and unlike other approved nanoparticles or therapeutics, NBTXR3/Hensify may represent the next-generation of nanoparticle therapeutics; specifically, nanoparticle therapeutics that can provide therapeutic benefits in a complementary and possibly synergistic way to standard therapeutic modalities. Table 1, which previously listed FDA/EMA approved nanomedicines as of 2016, is now updated to include these recently approved nanoparticles.…”