Article Text

Download PDFPDF

396 Overcoming resistance to anti-PD-1 with tumor agnostic NBTXR3: from bench to bed side
  1. James Welsh1,
  2. Colette Shen2,
  3. Jessica Frakes3,
  4. Jiaxin Niu4,
  5. Jared Weiss2,
  6. Jimmy Caudell3,
  7. Hu Yun5,
  8. Hampartsoum Barsoumian5,
  9. Juliette Thariat6,
  10. Sylvie Bonvalot7,
  11. Zsusanna Papaï8,
  12. Maria Angelica Cortez5,
  13. Ping Zhang9,
  14. Katherine Jameson10,
  15. Patricia Said9,
  16. Sébastien Paris9 and
  17. Tanguy Seiwert11
  1. 1University of Texas MD Anderson Cancer, Houston, TX, USA
  2. 2University of North Carolina, Chapel Hill, NC, USA
  3. 3Moffitt Cancer Center, Tampa, USA
  4. 4Banner MD Anderson Cancer Center, Gilbert, AZ, USA
  5. 5MD Anderson Cancer Center, Houston, TX, USA
  6. 6Centre Baclesse, Caen, Cedex 2, France
  7. 7Institut Curie, Paris, Cedex 05, France
  8. 8MH Egeszsegugyi Kozpont, Hungarian Defe, Budapest, Hungary
  9. 9Nanobiotix, SA, Paris, France
  10. 10Nanobiotix, corp, Cambridge, MA, USA
  11. 11John Hopkins Medecine, Baltimore, Maryland, USA


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 [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.

Ethics Approval This study was approved by local institution’s review board

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.