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2020 – SITC – NBTXR3 with Anti-PD-1 Therapy

nano-pub — Sun, 20 Dec 2020 09:53:50 +0000

Authors

Colette Shen1, Jessica Frakes2, Jiaxin Niu3, Jared Weiss1, Jimmy Caudell2, Katherine Jameson4, Patricia Said4, Tanguy Seiwert5

1 – University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
2 – Moffitt Cancer Center, Tampa, Florida, USA
3 – Banner MD Anderson Cancer Center, Gilbert Arizona, USA
4 – Nanobiotix, Paris, France
5 – Johns Hopkins Medicine, Baltimore, Maryland, USA

Summary

Background: Cancer immunotherapies have shown promising clinical outcomes; however, the majority of patients are non-responders or will develop resistance during the course of treatment. One of the current challenges is to increase the response rate to immune checkpoint inhibitors (ICIs). Combining immunotherapy with radiation therapy (RT) is emerging as a valuable strategy to prime the immune response. However, RT dose and ultimate efficacy are limited by toxicity related to exposure of healthy tissues. First-in-class radioenhancer NBTXR3 , administered by one-time direct intratumoral injection, is designed at the nanoscale to increase RT dose deposit with subsequent increase in tumor cell killing, without increasing toxicity to normal tissue. Preclinical and early clinical data suggest NBTXR3/RT can prime the immune system and act as an in situ vaccine leading to an anti-tumor immune response, producing both local and systemic (abscopal) effects. We hypothesize NBTXR3/RT in combination with anti-PD-1 (NBTXR3/RT/PD-1), will act synergistically to increase the proportion of ICI responders or convert ICI non-responders to responders.

Methods: A multicenter, open-label, phase I trial [NCT03589339] evaluating safety and tolerability of NBTXR3/RT/PD-1 in three cohorts: (1; H&N) Locoregional recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to re-irradiation of the HN field, (2; lung) lung or (3; liver) liver metastases from any primary cancer eligible for approved anti-PD-1 treatment. NBTXR3 injected volume is based on a percentage of baseline tumor volume. Stereotactic body RT (SBRT) is delivered as per standard practice. The primary objective is to determine NBTXR3/RT/PD-1 recommended phase II dose in each cohort. Secondary objectives are to evaluate anti-tumor response (objective response rate), safety and feasibility of NBTXR3 injection, and NBTXR3 body kinetic profile.

Results: To date 6 patients have been treated: 3 in H&N (2 anti-PD-1 naïve) and 3 in lung (all anti-PD-1 non-responders. No DLT or SAE has been observed. Grade 2 nausea related to NBTXR3 or injection procedure was observed in H&N. 2 H&N patients and 3 lung patients have completed RT and initiated anti-PD-1 treatment. RT-related safety profile was as expected. Tumor shrinkage was observed in 1 anti-PD-1 naive and 2 anti-PD-1 non-responders and additional preliminary efficacy and updated safety results will be presented.

Conclusions: To date, NBTXR3 administration activated by SBRT in combination with anti-PD-1 treatment has been safe and well tolerated in patients with advanced cancers. Promising early signs of efficacy in anti-PD-1 naïve, as well as in patients having progressed on previous anti-PD-1 therapy will be presented.

The post 2020 – SITC – NBTXR3 with Anti-PD-1 Therapy first appeared on Nano Publications.

2020 – SITC – NBTXR3 From Bench to Bedside

nano-pub — Sun, 20 Dec 2020 09:53:45 +0000

Authors

J. W. Welsh1, C. Shen2, J. M. Frakes3, J. Niu4, J. Weiss2, J. Caudell3, Y. Hu1, H. Barsoumian1, J. Thariat5, S. Bonvalot6, Z. Papai7, M. A. Cortez1, P. Zhang8, K. Jameson9, P. Said8, S. Paris8 and T. Seiwert10

1 – University of Texas MD Anderson Cancer Center, Houston, TX
2 – University of North Carolina Hospitals, Chapel Hill, NC
3 – H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
4 – Banner MD Anderson Cancer Center, Gilbert, AZ
5 – Centre Baclesse, Caen, France
6 – Department of surgery, Institut Curie, Paris
7 – MH Egeszsegugyi Kozpont, Hungarian Defence Forces Medical Centre, Budapest, Hungary
8 – Nanobiotix, Paris, France
9 – Nanobiotix Corp, Cambridge, MA, United States
10 – Johns Hopkins Medicine, Baltimore, Maryland, USA

Summary

Background: Despite recent advances, resistance to immune checkpoint inhibitors (ICI), observed in over 80% of treated patients, is currently the main challenge immuno-oncology is facing. Intense efforts are being made to identify combination therapies that could improve ICI response rates. Administered intratumorally, NBTXR3 enhances the energy dose deposited by ionizing radiation within tumor cells, increasing the anti-tumor efficacy of radiation therapy (XRT) without adding toxicity to surrounding tissues. Here we present evidence that NBTXR3 activated by XRT primes the immune system, producing an anti-tumor response, including activation of the cGAS-STING pathway, that overcomes anti-PD-1 resistance both in mice models and patients.

Methods: Abscopal assays were conducted in immunocompetent mice. Tumor cell lines, sensitive or resistant to anti-PD-1, were injected in both flanks of mice. Intratumoral injection of NBTXR3 (or vehicle) followed by XRT was performed in right flank (primary) tumors only. Some mice also received anti-PD-1 injections. Tumor growth was monitored, and tumor immune cell infiltrates were analyzed by immunohistochemistry (IHC).
Separately, in the phase II/III randomized trial Act.in.Sarc [NCT02379845] patients with locally advanced soft tissue sarcoma (STS) received either NBTXR3+XRT or XRT alone followed by wide tumor resection. Pre- and post-treatment tumor samples from patients in both groups were analyzed by IHC and Digital Pathology for immune biomarkers.
The safety and efficacy (RECIST 1.1/iRECIST) of NBTXR3 plus stereotactic ablative radiotherapy (SABR) in combination with anti-PD-1 is being evaluated in three cohorts of patients with advanced cancers [NCT03589339].

Results: Pre-clinical studies demonstrated that NBTXR3+XRT induces an immune response a not observed with XRT alone and enhances systemic control. IHC showed significant increase of CD8+ T-cell infiltrates in both NBTXR3+XRT treated and untreated tumors compared to XRT alone. Similarly, increased CD8+ T-cell density (pre- vs post-treatment) was observed in tumor tissues from STS patients treated with NBTXR3+XRT. Tumor samples from the NBTXR3+XRT group also displayed increased PD-1+ cell density. Furthermore, in combination with anti-PD-1, NBTXR3+XRT improved local and systemic control in mice bearing anti-PD-1 resistant lung tumors, as well as resulted in reduced number of spontaneous lung metastases. Preliminary efficacy data from the first in human trial of NBTXR3+XRT in combination with anti-PD-1 showed tumor response in patients who progressed on prior anti-PD-1.

Conclusions: The clinical efficacy of NBTXR3+XRT has been demonstrated as a single agent. We now demonstrate that it potentiates anti-PD-1 treatment to overcome resistance mechanisms. These results highlight the potential of NBTXR3+XRT to positively impact the immuno-oncology field.

The post 2020 – SITC – NBTXR3 From Bench to Bedside first appeared on Nano Publications.

2020 – ASTRO – NBTXR3 in Combination with Anti-PD-1

nano-pub — Thu, 17 Dec 2020 17:37:36 +0000

Authors

Colette Shen1, Jessica Frakes2 Jared Weiss1, Jimmy Caudell2, Trevor Hackman1, Jason A. Akulian1, Ghassan El-Haddad2, Robert Dixon1, Yun Hu3, Alexander Pearson4, Hampartsoum B. Barsoumian3, Maria Angelica Cortez3, Katherine Jameson5, Patricia Said5, James Welsh3 and Tanguy Seiwert6

1 – University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
2 – Moffitt Cancer Center, Tampa, Florida, USA
3 – Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
4 – University of Chicago Medicine, Chicago, Illinois, USA
5 – Nanobiotix, SA, France; 6Johns Hopkins Medicine, Baltimore, Maryland, USA

Summary

Purpose/Objectives: Immune checkpoint inhibitors (ICIs) are being increasingly used to improve patient outcomes across different cancer types. However, the response rate to ICIs remains low (~15%), indicating the need for novel strategies to improve treatment outcome. Emerging evidence suggests that radiation therapy (RT) could potentially enhance the antitumor response and provide synergy with ICIs. RT dose and ultimate efficacy are however limited by toxicity related to exposure of healthy tissues. The first-in-class radioenhancer NBTXR3, administered by direct intratumoral injection, is designed at the nanoscale to increase RT dose deposition within tumor cells and RT-dependent tumor cell killing, without increasing toxicity to surrounding normal tissue. Preclinical and early clinical data suggest NBTXR3 activated by RT can trigger an anti-tumor immune response, producing both local and systemic (abscopal) effects. We hypothesize that NBTXR3 activated by RT, in combination with anti-PD-1 therapy (R3/RT/PD-1), will act synergistically to maximize the local RT effect and produce a systemic response sufficient to increase the proportion of ICI responders or convert ICI non-responders to responders.

Materials/Methods: This multicenter, open-label, phase I trial [NCT03589339] will evaluate safety and tolerability of R3/RT/PD-1 in three cohorts: (1) Locoregional recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to re-irradiation of the HN field, (2) Lung metastases, or (3) Liver metastases, both from any primary cancer eligible for anti-PD-1 treatment. Approximately two-thirds of patients in each cohort will be anti-PD-1 non-responders. NBTXR3 injected volume is based on a percentage of baseline gross tumor volume (GTV).

Results: The primary objective is to determine the R3/RT/PD-1 recommended phase 2 dose in each cohort. Secondary objectives are to evaluate anti-tumor response (objective response rate; ORR), safety and feasibility of NBTXR3 injection, and NBTXR3 body kinetic profile. Exploratory objectives will assess biomarkers of R3/RT/PD-1 response, including PD-L1 status by IHC, as well as mRNA and cytokine immune marker profiling. Recruitment is ongoing. To date, three patients have been treated, one in cohort 1 and two in cohort 2.

Conclusions: NBTXR3 activated by RT induces an anti-tumor immune response which may convert immunologically “cold” tumors into “hot” tumors. In combination R3/RT/PD-1 holds the potential to increase the proportion of ICI responders or convert ICI non-responders to responders.

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