Congress Abstracts | Nano Publications

2021 – Radiotherapy-activated NBTXR3 nanoparticles Increase CD8+ T cell infiltration and diversity in tumors, and modulate the immunopeptidome of cancer cells

nano-pub — Fri, 27 May 2022 11:29:22 +0000

Authors

Audrey Darmon, Ping Zhang, Jordan Da silva*, Sebastien Paris

* Nanobiotix, Paris, France

Summary

Background: When exposed to radiotherapy (RT), NBTXR3 nanoparticles increase radiation dose deposition from within the cancer cells. NBTXR3 is intended for a single intratumor injection. Results from a phase II/III clinical trial in patients with locally advanced Soft Tissue Sarcoma demonstrated significant superiority and clinical benefits of NBTXR3 activated by RT compared to RT alone, and was well tolerated. NBTXR3 is currently being evaluated in several other tumors including head and neck, liver, and pancreatic cancer as a single agent or in combination with anti-PD1. Moreover, preclinical studies have demonstrated that NBTXR3 can produce a significant abscopal effect, whereas RT alone cannot. Here, we explored the impact of NBTXR3 activated by RT on CD8+ infiltrates and TcR repertoire diversity change, and the effect on the immunopeptidome of cancer cells.

Methods: CT26 (murine colorectal cancer cells) were subcutaneously injected in BALB/c mice in one flank. Then, tumors were intratumorally injected with NBTXR3 (or vehicle) and irradiated 24 hours later with 4Gy per fraction for 3 consecutive days. Tumors were collected 3 days after the last RT fraction and immune cell infiltrates were measured using immunohistochemistry (IHC) and digital pathology. For TcR repertoire sequencing, the same workflow was followed, except cells were injected in both flanks. Only right tumors received treatment, while left tumors remained untreated. For immunopeptidome analysis, in vitro cells were irradiated by 4Gy. After one day, cells were collected for isolation and sequencing of MHC I-loaded peptides.

Results: IHC analyses showed a significant increase of CD8+ T cell infiltrates in tumors of mice treated with NBTXR3+RT, while RT alone had no significant effect. In addition, NBTXR3+RT treatment was able to increase TcR repertoire diversity, both in treated and untreated tumors, compared to RT alone. Finally, analysis of immunopeptidome showed that NBTXR3+RT changed the profile of MHC-I-loaded peptides.

Conclusions: Our in vivo data indicate that NBTXR3+RT can modulate the microenvironment of treated tumors, leading to enhanced CD8+ T cell infiltration as well as modification of the TcR repertoire, both in treated and distant untreated tumors. These NBTXR3+RT-induced responses may be related to changes in the immunopeptidome of cancer cells triggered by this treatment.

The post 2021 – Radiotherapy-activated NBTXR3 nanoparticles Increase CD8+ T cell infiltration and diversity in tumors, and modulate the immunopeptidome of cancer cells first appeared on 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

nano-pub — Fri, 27 May 2022 11:16:31 +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 – A phase I dose expansion study of NBTXR3, radiation enhancing hafnium oxide nanoparticles, for the treatment of cisplatin-ineligible locally advanced HNSCC patients

nano-pub — Fri, 27 May 2022 11:12:04 +0000

Authors

C. Le Tourneau, V. Calugaru, V. Moreno, E. Calvo, X. Liem, S. Salas, B. Doger, T. Jouffroy, X. Mirabel, J. Rodriguez, A. Chilles, K. Bernois, N. Fakhry, S. Wong Hee Kam, C. Hoffmann

Summary

Introduction: Non-surgical standard of care (SOC) for locally advanced head and neck squamous cell carcinoma (LA HNSCC) patients is chemoradiation with cisplatin/cetuximab. Elderly patients, and those with poor performance status, comorbidities, and/or intolerance, may not benefit from current SOC, representing a high unmet need. NBTXR3, a novel radioenhancer composed of functionalized hafnium oxide nanoparticles, is activated by radiotherapy (RT). NBTXR3 increases RT energy deposit in tumor cells and subsequent tumor cell death, while sparing healthy tissues compared to RT alone. NBTXR3 subsequently primes an adaptive immune response.

Objectives: The phase I dose expansion study aims to evaluate safety and efficacy of NBTXR3 + RT in patients with stage III–IVA or T3/T4 (TNM-8) HNSCC of the oropharynx or oral cavity, ineligible to cisplatin or cetuximab and amenable for RT.

Methods: Patients received a single intratumoral injection of NBTXR3 + RT (70 Gy, 35 fractions/7 weeks). A 3 + 3 dose escalation design tested four NBTXR3 doses: 5, 10, 15, and 22% of baseline theoretical tumor volume; and established RP2D as 22%. Primary endpoints of the dose expansion part are objective response rate (ORR) and complete response rate (CRR) of the primary tumor (RECIST 1.1).

Results and Conclusion: As of March 26, 2021, 52 patients were treated in the dose expansion part. Median age and tumor volume were 71.6 years and 60.6 mL respectively. ORR of the primary lesion was 82.5% and CRR was 62.5% (N = 40) at a median of 8.1 months after NBTXR3 injection. RT-related toxicity was as expected. Six patients experienced at least one G3–4 serious adverse event (AE) related to injection procedure and/or NBTXR3 (< 1% of all AEs). Four deaths related to RT were observed, also one death from sepsis possibly related to NBTXR3, RT, and cancer disease was reported. NBTXR3 + RT showed promising efficacy, supporting further evaluation in a phase III randomized trial.

The post 2021 – A phase I dose expansion study of NBTXR3, radiation enhancing hafnium oxide nanoparticles, for the treatment of cisplatin-ineligible locally advanced HNSCC patients first appeared on Nano Publications.

2021 – Study of Novel Radioenhancer NBTXR3 Plus Radiotherapy in Patients With Locally Advanced Soft Tissue Sarcoma: Results of the Long-Term Evaluation in the Phase II/III Act.In.Sarc Trial

nano-pub — Fri, 27 May 2022 10:06:03 +0000

Authors

S.Bonvalot1, P.Rutkowski2, J.O.Thariat3, S.Carrere4, A.Ducassou5, M.P.Sunyach6, P.Ágoston7, A.Hong8, A.Mervoyer9, M.Rastrelli10, C.LePechoux11, V.Moreno12, R.Li13, B.Tiangco14, Z.Papai15

1 – Curie Institute, Paris, France
2 – Centrum Onkologii-Instytut im. Sklodowskiej-Curie w Warszawie, Warszawa, Poland
3 – Centre François Baclesse, Caen, France
4 – Montpellier Cancer Institute, Montpellier, France
5 – Institut Claudius Regaud – IUCT Oncopôle, Toulouse, France
6 – Centre Leon Berard, Lyon, France
7 – National Institute of Oncology, Budapest, Hungary
8 – Melanoma Institute Australia, Sydney, NSW, Australia
9 – Institut de Cancerologie de l’Ouest-Rene Gauducheau, Saint-Herblain, France
10 – Istituto Oncologico Veneto IRCCS, Padova, Italy
11 – Institut Gustave Roussy, Villejuif, France
12 – Hospital Fundación Jimenez Diaz, Madrid, Spain
13 – St. Luke’s Medical Center, Quezon City, Philippines
14 – The Medical City Cancer Center, Pasay City, Philippines
15 – Magyar Honvedseg Egeszsegugyi Kozpont, Budapest, Hungary

Summary

Purpose/Objective(s): NBTXR3, a novel radioenhancer activated by radiotherapy (RT) demonstrated superior efficacy, as preoperative treatment in patients with locally advanced soft tissue sarcoma (LA STS) compared to RT alone. Primary endpoint of pCR rate (16% vs 8%; P = 0.044) and main secondary endpoint of R0 margin rate (16% vs 8%; P = 0.042) were met while no modification of the early RT-associated safety profile was observed, leading to market authorization. Here we report on the long-term safety, limb function and quality of life.

Materials/Methods: This phase II/III randomized (1:1), international trial included adult patients with LA STS of the extremity or trunk wall, requiring preoperative RT. Patients received either a single intratumoral injection of NBTXR3 (equivalent to 10% of tumor volume, at 53.3g/L), plus EBRT (arm A) or EBRT alone (arm B) (50 Gy in 25 fractions), followed by surgery. Here we report on safety of NBTXR3+RT which was evaluated as secondary endpoint. Data were recorded on the “all treated population” during at least a two-year follow-up. Important parameters related to HR-QoL including functional outcome were studied using the EQ-5D, RNLI, TESS and MSTS questionnaires.

Results: Patients had at least two-year follow-up and the lost to follow-up rate was very low (1.9%). RT-related SAEs were observed in 11.2% (10/89) vs 13.3% (12/90) in A vs B. Post-treatment AEs, any grade, were observed in 51.7% (46/89) vs 57.8% (52/90) and serious post-treatment AEs in 13.5% (12/89) vs 24.4% (22/90) of patients in A vs B. Long-term safety continues to demonstrate that NBTXR3 plus RT has no impact on post-surgical wound complications (24.7% vs 36.7%, A vs B). Furthermore, the evaluation of radiation late toxicities in limbs such as fibrosis, arthrosis and edema that may alter limb function showed no difference between arms (4.5% vs 7.7%, 2.2% vs 0.0% and 6.7% vs 2.2% respectively in A vs B). In addition, sequelae or chronic tissue disturbances at the former tumor localization were similar in both treatment arms, confirming that the increase of energy dose deposit and the physical presence of NBTXR3 did not impact post-treatment limb functions. Accordingly, HR-QoL evaluation yielded no difference in functional outcome. Finally, second primary cancer was observed in 1 patient in arm A and 6 patients in arm B and the intratumoral injection of NBTXR3 did not induce cancer cell seeding at the former tumor site.

Conclusion: These results demonstrate that the use of NBTXR3 did not change the late onset toxicity profile of EBRT, nor modified its bystander effect. Taken together, the long-term safety data presented here, and the previously published efficacy data reinforce the favorable benefit-risk ratio of the use of NBTXR3 in patients with LA STS. NCT02379845

The post 2021 – Study of Novel Radioenhancer NBTXR3 Plus Radiotherapy in Patients With Locally Advanced Soft Tissue Sarcoma: Results of the Long-Term Evaluation in the Phase II/III Act.In.Sarc Trial first appeared on Nano Publications.

2021 – Overcoming Resistance to Anti-PD-1 With Tumor Agnostic NBTXR3: From Bench to Bedside

nano-pub — Fri, 27 May 2022 09:52:18 +0000

Authors

T.Y. Seiwert1, C. Shen2, J.M. Frakes3, Y. Hu4, J. Niu5, J. Weiss6, J.J. Caudell7, H.B. Barsoumian4, J.O. Thariat8, S. Bonvalot9, Z. Papai10, M.A. Cortez4, P. Zhang11, K. Jameson12, P. Said11, S. Paris11, and J.W. Welsh4

1 – Department of Medicine, Section of Hematology/Oncology, The University of Chicago Medicine, Chicago, IL
2 – Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC
3 – H. Lee Moffitt Cancer Center and Research Institute, Department of Radiation Oncology, Tampa, FL
4 – Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
5 – Banner MD Anderson Cancer Center, Gilbert, AZ
6 – University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC
7 – Moffitt Cancer Center, Tampa, FL
8 – Centre Francois Baclesse, Caen, France
9 – Curie Institute, Paris, France
10 – Magyar Honvedseg Egeszsegugyi Kozpont, Budapest, Hungary
11 – Nanobiotix, Paris, France, 12Nanobiotix Corp, Cambridge, MA

Summary

Purpose/Objective(s): Immune checkpoint inhibitors (ICI) can improve outcomes in patients who respond to treatment, however most patients exhibit resistance. Overcoming this resistance is the main challenge in immune-oncology and recent studies suggest radiotherapy (RT) may improve ICI response rates. NBTXR3, composed of functionalized hafnium oxide nanoparticles, is injected intratumorally and activated by RT. NBTXR3 increases RT energy deposit inside tumor cells and subsequent tumor cell death, without adding toxicity to healthy tissues. Here we present evidence that NBTXR3 activated by RT primes the immune system, producing an anti-tumor immune response, including activation of the cGAS-STING pathway, that overcomes anti-PD-1 resistance both in murine models and patients.

/Methods: Abscopal assays were conducted in immunocompetent mice. Anti-PD-1 sensitive or resistant lung tumor cell lines were injected in both flanks. Intratumoral injection of NBTXR3 (or vehicle) followed by RT 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 analyzed by immunohistochemistry (IHC). Separately, in the phase II/III randomized Act.in.Sarc [NCT02379845] trial patients with locally advanced soft tissue sarcoma (STS) received either NBTXR3+RT or RT alone followed by 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 of NBTXR3 plus stereotactic body radiotherapy (SBRT) in combination with anti-PD-1 is being evaluated in three cohorts of patients with advanced cancers in the Phase I 1100 [NCT03589339] trial.

Results: Pre-clinical studies demonstrated that NBTXR3+RT induces an immune response not observed with RT alone and enhances systemic control. IHC showed significant increase of CD8+ T-cell infiltrates in both NBTXR3+RT treated and untreated tumors compared to RT alone. Increased CD8+ T-cell and decreased FOXP3+ Treg density (pre- vs post-treatment) was also observed in tumors from STS patients treated with NBTXR3+RT. Furthermore, NBTXR3+RT in combination with anti-PD-1 improved local and systemic control in mice bearing anti-PD-1 resistant lung tumors, produced long-term memory, and reduced spontaneous lung metastases. Preliminary efficacy data from the 1100 trial showed tumor regression in 8/9 patients. Of note, tumor regression was observed in 6/7 patients who had progressed on prior anti-PD-1.

Conclusion: The clinical efficacy of NBTXR3+RT has been demonstrated as a single agent in STS. Here we demonstrate that it overcomes resistance to anti-PD-1 treatment mechanisms in mice and led to tumor regression in patients having progressed on anti-PD-1 therapy. These results highlight the potential of NBTXR3+RT to positively impact the immuno-oncology field.

The post 2021 – Overcoming Resistance to Anti-PD-1 With Tumor Agnostic NBTXR3: From Bench to Bedside first appeared on Nano Publications.

2021 – NBTXR3 Activated by Radiotherapy in Combination With Nivolumab or Pembrolizumab in Patients With Advanced Cancers: A Phase I Trial

nano-pub — Fri, 27 May 2022 09:52:17 +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;
2 – Moffitt Cancer Center;
3 – Banner MD Anderson Cancer Center;
4 – Nanobiotix;
5 – Johns Hopkins Medicine

Summary

Purpose/Objective(s): Immune checkpoint inhibitors (ICIs) have led to improved treatment outcomes in a variety of cancers; however, the majority of patients exhibit resistance to ICIs. Overcoming this resistance is a major challenge in immune-oncology. Radiation therapy (RT) has emerged as a promising combination with ICIs since it may act synergistically with ICIs by producing an immunomodulatory effect. NBTXR3, composed of functionalized hafnium oxide nanoparticles, is injected intratumorally and activated by RT. NBTXR3 increases RT energy deposit 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/Methods: This multicenter, open-label, phase I trial [NCT03589339] is evaluating NBTXR3/RT/anti-PD-1 in 3 cohorts: (1) Locoregional recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to HN re-irradiation and (2) lung or (3) liver metastases from any primary cancer eligible for anti-PD-1. Stereotactic body RT (SBRT) is delivered at tumor-site selective doses per standard practice. The primary objective is to determine the NBTXR3/RT/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 patients have been treated: 3 HNSCC, 4 lung, 2 liver. Overall tumor regression was observed in 8/9 patients of which 7 were anti-PD-1 non-responders. A complete response lasting over 1 year was observed in the injected lymph node in 1 anti-PD-1 naïve patient. 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 patient and considered DLTs. This patient also experienced 2 other G4 SAEs related to anti-PD-1 (diabetic ketoacidosis, acute kidney injury). SBRT-related safety profile was as expected. Updated safety and efficacy results with additional patients and longer follow-up will be presented.

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

The post 2021 – NBTXR3 Activated by Radiotherapy in Combination With Nivolumab or Pembrolizumab in Patients With Advanced Cancers: A Phase I Trial first appeared on Nano Publications.

2021 – Phase I study of functionalized hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy in cisplatin-ineligible locally advanced HNSCC patients

nano-pub — Fri, 27 May 2022 13:29:37 +0000

Authors

Christophe Le Tourneau, Valentin Calugaru, Zoltan Takacsi-Nagy, Xavier Liem, Zsuzsanna Papai, Jacek Fijuth, Victor Moreno, Jordi Giralt, Sébastien Salas, Gilles Poissonnet, Emiliano Calvo, Bernard Doger, Olivier Choussy, Xavier Mirabel, Samar Krhili, Katell Bernois, Nicolas Fakhry, Stéphanie Wong-Hee-Kam, Edith Borcoman, Caroline Hoffmann

Institut Curie, Saint-Cloud, France; Institut Curie, Paris, France; Center of Radiotherapy-National Institute of Oncology, Budapest, Hungary; Centre Oscar Lambret, Lille, France; State Health Center, Hungarian Defense Forces, Oncology Department, Budapest, Hungary; Provita Prolife, Tomaszów Mazowiecki, Poland; START Madrid-FJD, Fundación Jiménez Díaz Hospital, Madrid, Spain; Vall d’Hebron University Hospital, Barcelona, Spain; CEPCM Assistance Publique des Hôpitaux de Marseille, Aix-Marseille Université, Marseille, France; Antoine-Lacassagne Anticancer center, Nice, France; START Madrid-CIOCC, Madrid, Spain; Hospital Universitario Fundacion Jimenez Diaz – START Madrid, Madrid, Spain; Oncology, Oscar Lambret Center, Lille, France; Nanobiotix, Paris, France; Hôpital Timone, AP-HM, Marseille, France; INSERM Unit U932 Immunity and Cancer, Institut Curie, Paris, France

Summary

Background: The non-surgical standard of care (SOC) for the treatment of locally advanced head and neck squamous cell carcinoma (LA HNSCC) patients is concurrent chemoradiation with high dose cisplatin or cetuximab in case of contra-indication to cisplatin. However elderly patients, and those with poor performance status, comorbidities, and/or intolerance, may not benefit from these SOC treatments and represent a high unmet need. New approaches are thus needed to improve clinical outcomes without adding toxicity. NBTXR3, a novel radioenhancer, composed of functionalized hafnium oxide nanoparticles, is injected once intratumorally and activated by radiotherapy (RT).NBTXR3 increases the RT energy deposit inside tumor cells and subsequently increases tumor cell death compared to RT alone, while sparing healthy tissues. We present here the results of the dose expansion part of the phase I study evaluating NBTXR3 plus intensity modulated radiation therapy (IMRT) in this population.

Methods: Patients with stage III-IVA or T3/T4 (AJCC/UICC TNM staging system 8th ed.) HNSCC of the oropharynx or oral cavity, ineligible to cisplatin or cetuximab and amenable for RT, received a single intratumoral injection of NBTXR3 and IMRT (70 Gy in 35 fractions /7 weeks). A classical 3 + 3 dose escalation design has tested four doses of NBTXR3, equivalent to 5, 10, 15, and 22% of baseline theoretical tumor volume. The RP2D established as 22% of baseline tumor volume is further tested in the dose expansion part. The primary endpoints of the dose expansion part are objective response rate (ORR) and complete response rate (CRR) of the primary tumor, by imaging according to RECIST 1.1. Safety is also evaluated.

Results: As of August 13, 2020, 43 patients have been treated in the phase I dose expansion part. The median age was 70.7 years old (range: 50.7- 89.9), 70% of patients had cardiac disorder risk, 44% had gastrointestinal disorder risk and 44% metabolic and nutrition disorder risk. The median tumor volume was 42.8 mL (range: 1.3 – 222.3). At a median time of 7.8 months after NBTXR3 injection, the ORR of the primary lesion was 83.9% and the CRR 67.7% in the evaluable population for efficacy (N = 31). Three patients (7%) experienced at least one serious adverse event (AE) related to the injection procedure and/or NBTXR3 which represented less than 1% of all reported AEs. RT-related toxicity was as expected with IMRT. Three deaths due to AEs related to RT and other causes were reported. The recruitment is ongoing and updated efficacy and safety results will be presented.

Conclusions: NBTXR3 intratumoral administration followed by IMRT may represent an option in elderly patients or patients with multiple comorbidities with LA-HNSCC who have limited therapeutic options. NBTXR3 activated by RT showed promising anti-tumor efficacy, supporting further evaluation in a phase III randomized trial. Clinical trial information: NCT01946867.

The post 2021 – Phase I study of functionalized hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy in cisplatin-ineligible locally advanced HNSCC patients first appeared on Nano Publications.

2021 – NBTXR3 Activated by Radiotherapy in Combination With Nivolumab or Pembrolizumab in Patients With Advanced Cancers: A Phase I Trial

nano-pub — Fri, 27 May 2022 09:46:14 +0000

Authors

Summary

The post 2021 – NBTXR3 Activated by Radiotherapy in Combination With Nivolumab or Pembrolizumab in Patients With Advanced Cancers: A Phase I Trial first appeared on Nano Publications.

2021 – Phase I Study of Novel Radioenhancer NBTXR3 Activated by Radiotherapy in Cisplatin-Ineligible Locally Advanced HNSCC Patients

nano-pub — Fri, 27 May 2022 09:36:15 +0000

Authors

C. Le Tourneau1, V. Calugaru2, Z. Takacsi-Nagy3, X. Liem4, Z. Papai5, J. Fijuth6, V. Moreno Garcia7, I. Brana Garcia8, S. Salas9, G. Poissonnet10, E. Calvo7, B. Doger7, O. Choussy11, X. Mirabel12, S. Krhili13, K. Bernois14, N. Fakhry15, S. Wong Hee Kam16, E. Borcoman13, and C. Hoffmann13

1 – Department of Medical Oncology, Institut Curie, Paris, France
2 – Department of Radiation Oncology, Institut Curie, Paris, France
3 – National Institute of Oncology, Budapest, Hungary
4 – Université Montreal, Montreal, QC, Canada
5 – Magyar Honvedseg Egeszsegugyi Kozpont, Budapest, Hungary
6 – Medical University of Lodz, Lodz, Poland
7 – START Madrid, Madrid, Spain
8 – Vall D’Hebron Institute of Oncology, Barcelona, Spain
9 – Assistance Publique Hopitaux de Marseille, Timone Hospital, Marseille, France
10 – Unicancer – Antoine Lacassagne Center, Nice, France
11 – Department of head and neck surgery, Institut Curie, Paris, France
12 – Centre Oscar Lambret, Lille, France
13 – Institut Curie, Paris, France
14 – Nanobiotix, Paris, France
15 – Hopital Timone

Summary

Purpose/Objective(s): Concurrent radiotherapy (RT) with high-dose cisplatin, or cetuximab in case of intolerance to cisplatin, are the non-surgical standard treatment for locally advanced head and neck squamous cell carcinoma (LA HNSCC). However, elderly patients, patients with poor performance status, comorbidities, and/or intolerance may not benefit from these treatments and represent a high unmet medical need. New approaches are thus needed to improve the patient clinical outcomes without adding toxicity. NBTXR3, composed of functionalized hafnium oxide nanoparticles, is injected once intratumorally and activated by RT. NBTXR3 increases the RT energy deposit inside tumor cells and subsequently increases tumor cell death compared to RT alone, without adding toxicity to healthy tissues. We present here current results of the dose expansion part of the phase I study evaluating NBTXR3 plus intensity modulated radiation therapy (IMRT) in this population (ClinicalTrials.gov: NCT01946867).

Materials/Methods: Patients with stage III-VA or T3/T4 (AJCC/UICC TNM staging system 8th ed.) HNSCC of the oropharynx or oral cavity, ineligible to cisplatin or cetuximab and amenable for RT, received a single intratumoral injection of NBTXR3 and IMRT (70 Gy in 35 fractions /7 weeks). A classical 3 + 3 dose escalation design has tested four doses of NBTXR3, equivalent to 5, 10, 15, and 22% of baseline theoretical tumor volume. The RP2D established as 22% of baseline tumor volume is further tested in the dose expansion part of the study. The primary endpoints of the dose expansion part are objective response rate (ORR) and complete response rate (CRR) of the primary tumor, by imaging according to RECIST v1.1. Safety is also evaluated.

Results: As of August 13, 2020, 43 patients have been treated in the dose expansion part of the study. The median age was 70.7 years old (range: 50.7-89.9), 70% of patients had cardiac disorder risk, 44% had gastrointestinal disorder risk and 44% metabolic and nutrition disorder risk. The median tumor volume was 42.8 mL (range: 1.3-222.3). In the evaluable population for efficacy (N = 31), the ORR of the primary lesion was 83.9% and the CRR 67.7% at a median time of 7.8 months after NBTXR3 injection. Three patients (7%) experienced at least one serious adverse event (AE) related to the injection procedure and/or NBTXR3 which represented less than 1% of all reported AEs. RT-related toxicity was as expected with IMRT. Three deaths due to AEs related to RT and other causes were reported. The recruitment is ongoing and updated efficacy and safety results will be presented.

Conclusion: NBTXR3 intratumoral administration followed by IMRT may represent an option in elderly in elderly patients or patients with multiple comorbidities with LA-HNSCC who have limited therapeutic options. NBTXR3 activated by RT showed promising anti-tumor efficacy, supporting further evaluation in a phase III randomized trial.

The post 2021 – Phase I Study of Novel Radioenhancer NBTXR3 Activated by Radiotherapy in Cisplatin-Ineligible Locally Advanced HNSCC Patients 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 — Fri, 27 May 2022 09:25:22 +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.