NBTXR3 Nanoparticles can activate the cGAS-STING pathway
NANOBIOTIX, a late clinical-stage nanomedicine company pioneering new approaches to the local treatment of cancer, today announced that preclinical data evaluating the activation of the cGAS-STING pathway by NBTXR3 has been presented at the American Association for Cancer Research (AACR) Annual Meeting 2018 in Chicago, Illinois (April 14-18, 2018).
NBTXR3 is a first-in-class product designed to destroy, when activated by radiotherapy, tumors and metastasis through physical cell death and to induce immunogenic cell death leading to specific activation of the immune system.
Establishing how NBTXR3, activated by radiotherapy, impacts and primes the immune response against tumor cells is central to Nanobiotix's immuno-oncology program. Recently, the cGAS-STING pathway has emerged as the key component of the anti-tumor immune response, along with immunogenic cell death. Therefore, evaluation of the impact of NBTXR3 on this conserved signaling cascade is essential.
Dr Elsa Borghi, CMO, commented, "cGAS-STING activation is of fundamental importance in establishing an adaptive anti-tumor immune response. These encouraging preliminary results suggest that NBTXR3 activated by radiotherapy could increase the activation of this pathway, compared to radiotherapy alone."
"Activation of the cGAS-STING pathway by NBTXR3 nanoparticles exposed to radiotherapy"
J. Marill, N. Mohamed Anesary, A. Darmon, P. Zhang and S. Paris.
Poster number #4571
In this poster, Nanobiotix presents 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 (reflecting the transcriptional activity of IRF) was observed in HCT116-DUAL(TM) cells treated with NBTXR3 plus RT, compared to radiotherapy alone. Further, NBTXR3 activated by radiotherapy triggers an increased generation of micronuclei (involved cGAS-STING response) compared to radiotherapy alone.
In vivo, NBTXR3 activated by radiotherapy leads to a greater production of IFN-b and overexpression of its gene, compared to radiotherapy alone.
Previous work has demonstrated that NBTXR3 activated by radiotherapy increased cancer cell killing efficiency along with Immunogenic Cell Death (ICD), compared to radiotherapy alone. Here, in vitro data generated from HCT116-DUAL(TM) and in vivo data from CT26 tumors further demonstrate that NBTXR3 activated by radiotherapy is able to trigger a stronger activation of the cGAS-STING pathway, compared to radiotherapy alone, even in combination with the STING agonist 2',3'-cGAMP. Moreover, NBTXR3 can maximize the effect of 2',3'-cGAMP, the natural agonist of STING, when activated by the radiotherapy.
These observations support the rationale for using NBTXR3 with radiation therapy in combination with immunotherapeutic agents and/or STING agonist to transform tumors into an in-situ cancer vaccine.
These results, obtained in human and mouse colorectal cancer cells models, could have a very positive impact on the anti-tumoral immune response, potentially transforming non-responding tumors into responding, i.e. turning them from "cold" to "hot".
NBTXR3 positioning in IO
Many IO combination strategies focus on 'priming' the tumor, which is now becoming a prerequisite of turning a "cold" tumor into a "hot" tumor.
Compared to other modalities that could be used for priming the tumor, NBTXR3 could have a number of advantages: the physical and universal mode of action that could be used widely across oncology, a one-time local injection and good fit within existing medical practice already used as a basis for cancer treatment, as well as a very good chronic safety profile and well-established manufacturing process.
Published preclinical and clinical data indicate that NBTXR3 could play a key role in oncology and could become a backbone in immuno-oncology.
Nanobiotix's immuno-oncology combination program opens the door to new developments, potential new indications, and important value creation opportunities.