Injectable nanos vs. tumors

PARIS & CAMBRIDGE, Mass.—Nanobiotix, a late clinical-stage nanomedicine company, announced in early May that it was launching a research collaboration with Weill Cornell Medicine to begin nonclinical studies of NBTXR3’s mechanism of action. NBTXR3 is a first-in-class product that, when activated by radiotherapy, is designed to destroy tumors and metastasis through physical cell death, and to induce immunogenic cell death leading to specific activation of the immune system. The research collaboration between Weill Cornell Medicine and Nanobiotix will be conducted over the course of one year, with the goal of continuing the exploration of the role of NBTXR3 in immuno-oncology.

NBTXR3 is an injectable liquid solution incorporating nanoparticles, which are designed to penetrate cancer cells. The solution is injected directly into tumors before radiation treatments begin, and is reportedly designed so that the nanoparticles will only reside within cancerous cells. Once injected, the particles purportedly increase the ability of the tumor to absorb the radiation treatment, which ultimately reduces the amount needed to destroy cancerous cells. Because the particles reside only within cancer tumors, the impact on healthy tissue is presumably limited. NBTXR3 has a high degree of biocompatibility, requires a single administration before the whole radiotherapy treatment and has the ability to fit into current worldwide standards of radiation care.

The main objective of the collaboration is to study the impact of NBTXR3 activated by radiotherapy on the cGAS-STING pathway, using different in-vitro and in-vivo murine models (mammary). Along with immunogenic cell death, the cGAS-STING pathway has emerged as the key component of the antitumor immune response. Data generated from this collaboration could support current evidence indicating that NBTXR3 activated by radiotherapy can increase the antitumor immune response, compared to radiotherapy alone, and transform an irradiated tumor into an efficient in-situ vaccine.

Dr. Sandra Demaria, professor of radiation oncology and chief of the Division of Experimental Radiotherapy in the Department of Radiation Oncology at Weill Cornell Medicine and principal investigator for the study, said, “We have learned that radiotherapy has the potential to convert a tumor into an in-situ vaccine and enhance systemic tumor responses to immunotherapy. But there is room for improvement—NBTXR3 nanoparticles enhance the pro-immunogenic effects of radiotherapy, and we want to understand how they work. This knowledge will further the development of this innovative approach for the treatment of cancer patients who are resistant to immune checkpoint inhibitors.”

Nanobiotix received the FDA’s approval to launch a clinical study of NBTXR3 activated by radiotherapy in combination with anti-PD1 antibody in lung and head and neck cancer patients (non-small cell lung cancer and head and neck squamous cell carcinoma). This trial, which was scheduled to start in the second quarter of 2018, aims to expand the potential of NBTXR3, including using it to treat recurrent or metastatic disease.

NBTXR3 is being evaluated in head and neck cancer (locally advanced squamous cell carcinoma of the oral cavity or oropharynx), and the trial targets frail and elderly patients who have advanced cancer with very limited therapeutic options. The Phase 1/2 trial has already delivered very promising results regarding the local control of the tumors and a potential metastatic control through in-situ vaccination. The first market authorization process (CE marking) is ongoing in Europe in the soft tissue sarcoma indication.

The other ongoing studies are treating patients with liver cancers (hepatocellular carcinoma and liver metastasis), locally advanced or unresectable rectal cancer in combination with chemotherapy, head and neck cancer in combination with concurrent chemotherapy and prostate adenocarcinoma.

In April, Nanobiotix announced preclinical data evaluating the activation of the cGAS-STING pathway by NBTXR3 at the American Association for Cancer Research Annual Meeting 2018. The poster, “Activation of the cGAS-STING pathway by NBTXR3 nanoparticles exposed to radiotherapy” by J. Marill, N. Mohamed Anesary, A. Darmon, P. Zhang and S. Paris, presented data showing a dose-dependent increase in cGAS-STING pathway activation with NBTXR3, activated by radiotherapy through both in-vitro and in-vivo analyses. In-vitro analyses show a significant increase in luciferase activity was observed in HCT116-DUAL cells treated with NBTXR3 plus radiotherapy, compared to radiotherapy alone.

Dr. Elsa Borghi, chief medical officer of Nanobiotix, commented, “cGAS-STING activation is of fundamental importance in establishing an adaptive antitumor immune response. These encouraging preliminary results suggest that NBTXR3 activated by radiotherapy could increase the activation of this pathway, compared to radiotherapy alone.”

Nanobiotix also announced in April an agreement with The University of Texas MD Anderson Cancer Center to work on NBTXR3. This project will provide the ability to develop preclinical data using NBTXR3 activated by radiotherapy plus anti-PD1 Nivolumab (murine version of Opdivo). Dr. James Welsh, associate professor in the Department of Radiation Oncology, will be the principal investigator and lead the research program.

The project between MD Anderson and Nanobiotix will take place over the course of two years and will focus on three aims, leading to the maximization of NBTXR3 potential benefits in triggering an immune response: evaluating the abscopal response through the combination of NBTXR3 plus an anti-PD1 antibody and radiation therapy in specific and resistant murine lung cancer models, in order to measure NBTXR3’s potential to control metastatic disease; evaluating if NBTXR3 can further improve T cell activation for standard radiotherapy fractions compared to SBRT, notably by determining the STING activation in vitro in cancer cells with and without NBTXR3; and continuing the characterization of the different mechanisms and types of cell death induced by NBTXR3 activated by radiation.