2021 – Dual blockade of LAG3 and TIGIT improves the treatment efficacy of a nanoparticle-mediated immunoradiation in anti-PD1 resistant lung cancer in mice

nano-pub — Mon, 06 Jun 2022 07:30:51 +0000

Authors

Yun Hu1, James Welsh1, Sebastien Paris2, Genevieve Bertolet1, Hampartsoum Barsoumian1, Lily Schuda1, Kewen He1, Duygu Sezen1, Mark Wasley1, Joylise Mitchell1, Tiffany Voss1, Fatemeh Masrorpour1, SILVA Jordan2, Claudia Kettlun Leyton1, Liangpeng Yang1, Nahum Puebla-Osorio1, Saumil Gandhi1, QuynhNhu Nguyen1, Angelica Cortez1

1 – MD Anderson Cancer Center, Houston, TX, USA
2 – Nanobiotix, Paris, France

Summary

Background: TIGIT and LAG3 are inhibitory receptors expressed on cytotoxic CD8+ T cells and NK cells and directly inhibit the activation and proliferation of these cells. We proposed that blockade of TIGIT and LAG3 could improve antitumor immune response in a mouse model of anti-PD1 (aPD1)-resistant mice.

Methods: 129Sv/Ev mice were inoculated with 50,000 aPD1-resistant 344SQR cells in the right leg on day 0 (primary tumor) and with 50,000 cells in the left leg on day 4 (secondary tumor). Primary tumors were injected with NBTXR3 radioenhancer nanoparticles on day 7 and irradiated with 12 Gy on days 8, 9, and 10. Anti-PD1, aLAG3, and aTIGIT were given to mice by intraperitoneal injections on days 5, 8, 11, 14, 21, 28, 35, and 42. On day 21, primary tumors, secondary tumors, and blood samples were harvested and analyzed with flow cytometry to evaluate changes in immune cell populations. The RNA extracted from the tumors were also analyzed by Nanostring. Mice in which tumors were completely eradicated were re-challenged with another 50,000 344SQR cells in the right flank at least two months post radiation; no further treatment was given to these mice, and tumor growth was monitored.

Results: The addition of aTIGIT, aLAG3, or aTIGIT+aLAG3 to NBTXR3+XRT+aPD1 therapy significantly improved control of tumors, and the addition of aTIGIT+aLAG3 also led to fewer spontaneous lung metastases. The addition of either aTIGIT or aLAG3 to NBTXR3+XRT+aPD1 extended mouse survival time relative to NBTXR3+XRT+aPD1. None of the 8 mice in either the NBTXR3+XRT+aPD1+aTIGIT group or the NBTXR3+XRT+aPD1+aLAG3 group survived more than 32 days; in contrast, 3 of the 8 mice that received NBTXR3+XRT+aPD1+aTIGIT+aLAG3 survived until the end of the experiment. These surviving mice were found to have developed memory against 344SQR cells, and no further tumor growth was observed after re-challenge. Flow cytometry analysis showed that adding aTIGIT+aLAG3 to NBTXR3+XRT+aPD1 increased the percentages of proliferating CD8+ T cells in primary tumors, secondary tumors, and blood. Furthermore, Nanostring transcriptomic analysis of cells isolated from the tumors of mice thus treated showed evidence of classical two-step immunological priming, with an elevation of innate immune genes at the primary tumor and full-blown activation of the immune system within the secondary tumor.

Conclusions: Blockade of TIGIT and LAG3 with NBTXR3+XRT+aPD1 improved CD8+ T-cell proliferation, augmented the antitumor response at both irradiated and unirradiated (abscopal) tumors, and induced potent long-term antitumor memory in mice.

The post 2021 – Dual blockade of LAG3 and TIGIT improves the treatment efficacy of a nanoparticle-mediated immunoradiation in anti-PD1 resistant lung cancer in mice first appeared on Nano Publications.

2021 – NBTXR3 activated by SBRT combined with nivolumab or pembrolizumab in patients with advanced cancers: phase I trial

nano-pub — Mon, 06 Jun 2022 07:47:18 +0000

Authors

C. Shen1, J.M. Frakes2, J. Niu3, A.J. Rosenberg4, J. Weiss5, J.J. Caudell6, K. Jameson7, P. Said8, and T.Y. Seiwert9

1 – Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC,
2 – H. Lee Moffitt Cancer Center and Research Institute, Department of Radiation Oncology, Tampa, FL,
3 – Banner MD Anderson Cancer Center, Gilbert, AZ,
4 – Department of Medicine, Section of Hematology/Oncology, University of Chicago Medical Center, Chicago, IL,
5 – University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC,
6 – Moffitt Cancer Center, Tampa, FL,
7 – Nanobiotix Corp, Cambridge, MA,
8 – Nanobiotix, Paris, France,
9 – Department of Medicine, Section of Hematology/Oncology, The University of Chicago Medicine, Chicago, IL

Summary

Introduction: Immune checkpoint inhibitors (ICIs) have improved treatment outcomes in a variety of cancers; however the majority of patients (pts) exhibit resistance. Emerging evidence suggests radiation therapy (RT) can enhance response to ICIs by producing an immunomodulatory effect. NBTXR3, composed of functionalized hafnium oxide nanoparticles, is injected intratumorally and activated by RT. NBTXR3 increases RT energy deposition inside tumor cells and subsequent tumor cell death, without adding toxicity to healthy tissues. Preclinical data demonstrate NBTXR3/RT can trigger a local and systemic anti-tumor immune response and overcome anti-PD-1 resistance. NBTXR3/RT combined with anti-PD-1 may prime the immune system to increase the proportion of ICI responders or convert ICI non-responders to responders.

Materials and Methods: A multicenter, open-label, phase I trial [NCT03589339] evaluating NBTXR3/SBRT/anti-PD-1 (nivolumab or pembrolizumab) in 3 cohorts (1) Locoregional recurrent or recurrent and metastatic HNSCC amenable to HN re-irradiation, (2) lung or (3) liver metastases from any primary cancer eligible for anti-PD-1. Stereotactic body RT (SBRT) is delivered at tumor-site specific doses per standard practice. Primary objective is to determine the NBTXR3/SBRT/anti-PD-1 recommended phase 2 dose in each cohort. Secondary objectives are anti-tumor response (objective response rate), safety, and feasibility of NBTXR3 injection.

Results: Nine pts have been treated, 3 HNSCC, 4 lung and 2 liver. HNSCC was the primary cancer in 2 pts in the lung and 1 pt in the liver cohort. 7/9 pts were anti-PD-1 non-responders. Overall tumor regression was observed in 8/9 pts. NBTXR3/SBRT/anti-PD-1 resulted in tumor regression in 6/7 pts who had progressed on prior anti-PD-1. One anti-PD-1 naïve HNSCC pt achieved a complete response lasting over a year in the injected lymph node. 2 SAEs related to anti-PD-1 and possibly related to NBTXR3 (G5 pneumonitis, G4 hyperglycemia) were observed in 1 anti-PD-1 naïve HNSCC pt and considered DLTs. This pt also experienced 2 other SAEs (G4 diabetic ketoacidosis, G4 acute kidney injury) related to anti-PD-1. SBRT-related safety profile was as expected.

Conclusions: Safety data from this first-in-human phase I trial evaluating NBTXR3/SBRT/anti-PD-1 in pts with advanced cancers show NBTXR3 intratumoral injection is feasible and well-tolerated in HNSCC, lung, and liver metastases. NBTXR3/SBRT/anti-PD-1 demonstrated promising signs of efficacy and led to tumor regression in pts having progressed on prior anti-PD-1. These data support further development of NBTXR3/SBRT in combination with anti-PD-1 as well as other ICIs.

The post 2021 – NBTXR3 activated by SBRT combined with nivolumab or pembrolizumab in patients with advanced cancers: phase I trial first appeared on Nano Publications.

Non classifié(e) | Nano Publications

2021 – Dual blockade of LAG3 and TIGIT improves the treatment efficacy of a nanoparticle-mediated immunoradiation in anti-PD1 resistant lung cancer in mice

Authors

Summary

2021 – NBTXR3 activated by SBRT combined with nivolumab or pembrolizumab in patients with advanced cancers: phase I trial

Authors

Summary