20 Oct Exploring Innovation in Cancer Therapy with Nanophysics
We find ourselves in an exciting time for innovation in the treatment of head and neck cancer. New treatments such as immunotherapy and increased precision in the delivery of radiation are examples of methods that are being evaluated in clinical trials, some of which have already shown the ability to improve therapeutic outcomes for patients.
While these advancements are encouraging, there is still room for improvement as the oncology community continually strives to maximize the efficacy of treatment while minimizing side effects that impact a patient’s quality of life. As a physicist, by education and training, my focus has always been the intersection of physics and biology. Let us examine how these areas of interest could lead to another new option for head and neck cancer patients.
Discovering Nano
As I was preparing to apply to postdoctoral programs in the mid-90s, there was an emerging subdiscipline within the physics landscape called “nanophysics.” The foundation of this area of study was the idea that the properties of physical materials could and would change if they were reduced to the “nanometric scale.” A material can be described as “nanometric” or “nano” if it is between one and one hundred nanometers in size. To put that in perspective, if you were to take a human hair and cut it 3000 times at its diameter, you would have a nanomaterial.
From my perspective, the beauty of this field was two-fold. First, once we understood that the physical properties of a material changed when reduced in scale, we could isolate the properties we wanted to apply and design “nanoparticles” with specific functional utility. Second, many biological mechanisms are at the same scale, or even larger than a nanomaterial. For example, the average human cell is 10,000 nanometers in diameter. As a result, nanotechnology applications like nanoparticles could potentially cross natural barriers within cells that are unavailable to other types of therapies and interact with DNA or small proteins in the blood, organs, tissues, or cells. This idea became the foundation for the field of study called “nanomedicine.”
The idea for my postdoctoral thesis was the question, “Can I impact the physics of a cell without touching it?” This question led me and my peers at the State University of New York in Buffalo to design a magnetic nanoparticle that could “spin” the nucleus of a cell. Even to this day, much of the nanomedicine field focuses on helping with the “delivery” of other agents within the body (i.e. the nanomaterial is used to help a drug get to where it needs to go) or for diagnostics (i.e. the nanomaterial is introduced to an area within the body so imaging tools like MRI can visualize them and researchers can better understand what is happening). The success of our magnetic nanoparticle experiment showed me that nanomaterials could take a more active role in treatment. We could use nanomaterials as an active agent, rather than purely as a vehicle for other treatments.
After the magnetic nanoparticle, we thought it would be interesting to try designing a nanoparticle that could absorb radiation. With this idea in mind, in 2003 we spun off the company Nanobiotix to bring the idea to life. We knew there was an opportunity for a company dedicated to using the principles of nanophysics to develop disruptive solutions to treat major diseases, and we wanted to lead that effort. Our radiation-absorbing nanoparticle evolved into what is now the lead product candidate for Nanobiotix: NBTXR3.
Developing Nanomedicine
NBTXR3 is designed as a novel “radioenhancer.” The technology is composed of functionalized hafnium oxide nanoparticles, administered one time via injection directly into solid tumors, and activated by radiation therapy. Hafnium oxide has high electron density and is therefore able to absorb a larger quantity of radiation than the molecules already present in the cells. After absorbing radiation, the nanoparticles cause a larger dose of energy to be deposited within the tumor cells. This mechanism of action increases the tumor-killing effect of the radiation therapy treatment. The hafnium oxide nanoparticles are biologically inert outside of the presence of radiation, so the damage only occurs in the area where the nanoparticles are present and while they are activated by radiation therapy1. It is also worth noting that because the mechanism of action of NBTXR3 is physical, rather than biological or chemical, in theory the effect should be scalable across tumor types.
Given that radiation therapy is part of the standard of care in approximately 50% of cancer diagnoses, our next step was to begin developing NBTXR3 in oncology2. The first indication we targeted was soft tissue sarcoma. Soft-tissue sarcomas (STS) are cancers that arise from different types of tissues such as fat cells, muscles, joint structures, and small vessels.
Patients with high-risk STS have a poor prognosis; they need surgery to remove their tumor, and their only therapeutic option before surgery is radiotherapy3. Treatment with NBTXR3 activated by radiation therapy aimed to destroy the tumor more efficiently, allowing for complete malignant tissue extraction during surgery.
As published in The Lancet Oncology, NBTXR3 showed statistically significant positive results in a phase II/III randomized trial4. Approximately twice as many patients with STS who received NBTXR3 activated by radiation therapy achieved a pathological complete response, which was the primary endpoint of the trial. The trial also achieved its secondary endpoint, with improvement in surgical resection margin rate for patients who received NBTXR3 activated by radiation therapy compared to patients treated with radiation therapy alone. Combined with a strong safety profile that was consistent with phase I results, these data support NBTXR3 activated by radiation therapy as an option to improve treatment outcomes for patients with STS.
Building on our proof of concept in STS, our next step was to target another solid tumor indication where radiation therapy was a major part of the standard of care. 70-80% of all patients with head and neck cancer will receive radiation therapy as part of their treatment5. While radiation remains a critical tool in combatting the disease, many patients still face limits which may prevent the therapy from improving their lives for significant periods of time. The limitations of radiation therapy are primarily driven by the inability to administer a dose that is strong enough to kill the targeted tumor without harming surrounding healthy tissue. This is compounded when the tumor is within or near sensitive organs. A large proportion of head and neck cancers are found in the oral cavity and the oropharynx, which contain structures that play a crucial role in swallowing, breathing, and speech. As a result, patients are faced with a disease that the current standard of care may not cure, and in the process of receiving treatment, they may lose function or experience trauma that will impact them for the rest of their lives. Elderly patients with head and neck cancer can be at an even greater disadvantage, as they are often ineligible for standard of care treatments like platinum-based chemotherapy due to associated toxicities6. These patients may also have other pre-existing medical conditions that further limit their treatment options. We knew that innovation might bring benefits to this group and were called to begin evaluating the potential.
As such, Nanobiotix launched Study 102 — a European phase I dose escalation/dose expansion trial evaluating the safety, feasibility and recommended dose of NBTXR3 in elderly patients (aged greater than 70 years) with locally advanced head and neck cancer, who are ineligible for cisplatin or intolerant to cetuximab. The only available treatment for these patients is radiation therapy as their condition does not allow them to receive the combination of radiation therapy and chemotherapy.
Patients recruited in the dose escalation part of the trial received doses of either 5%, 10%, 15%, or 22% of the baseline tumor volume. Results showed that there were no serious adverse events (SAEs) related to NBTXR3, and each dose showed a good safety profile. Disease control was observed at all doses and there were no dose-limiting toxicities (DLTs) observed with NBTXR37.
Given that there were no DLTs or SAEs in the dose escalation part, and that there were early signs that NBTXR3 activated by radiation therapy could improve outcomes for some patients, an additional dose expansion cohort was launched to increase the sample size and further investigate the early signs of efficacy.
The dose expansion part of the trial is ongoing and continues to evaluate NBTXR3 activated by radiation therapy in patients with locally advanced head and neck cancer ineligible for platinum-based chemotherapy. The next step in the clinical trial process will be to launch a phase III registration trial evaluating whether the product provides a clinically meaningful improvement in treatment outcomes for patients.
To Infinity and Beyond
To this day, the ambition of our team remains to use physics to expand what is possible for human beings. We will continue to develop NBTXR3 and, hopefully, prove that it can benefit patients with cancer wherever radiation therapy is a part of the treatment paradigm. We will also develop new nanotechnology applications to address other unmet needs in the treatment landscape. Most importantly, we will always champion the need for innovation to provide disruptive solutions and improve treatment outcomes for patients everywhere.
NBTXR3 is an investigational product that is currently being evaluated in several clinical trials. NBTXR3 is not available for commercial use and has not been approved as safe and effective by the U.S. Food and Drug Administration.
Editors Note: Laurent Levy is a French physical chemist, inventor, and pioneer of nanotechnology and nanomedicine. He is the co-founder of the global biotechnology company Nanobiotix, and has served as Chief Executive Officer since its inception in March 2003. He has authored more than 35 international scientific publications and owns several patents.
References:
1. Maggiorella L, Barouch G, Devaux C, et al. Nanoscale radiotherapy with hafnium oxide nanoparticles. Future Oncol 2012; 8(9): 1167-81.
2. Jaffray DA, Gospodarowicz MK. Radiation Therapy for Cancer. In: Gelband H, Jha P, Sankaranarayanan R, Horton S, eds. Cancer: Disease Control Priorities, Third Edition (Volume 3). Washington (DC): The International Bank for Reconstruction and Development / The World Bank © 2015 International Bank for Reconstruction and Development / The World Bank.; 2015.
3. von Mehren M, Randall RL, Benjamin RS, et al. Soft Tissue Sarcoma, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2018; 16(5): 536-63.
4. Bonvalot S, Rutkowski PL, Thariat J, et al. NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, phase 2-3, randomised, controlled trial. Lancet Oncol 2019; 20(8): 1148-59.
5. Ratko TA, Douglas G, de Souza J, Belinson SE, Aronson N. Radiotherapy Treatments for Head and Neck Cancer Update [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2014 Dec. (Comparative Effectiveness Review, No. 144.) Available from: https://www.ncbi.nlm.nih.gov/books/NBK269018/?report=classic.
6. Amini A, Jones BL, McDermott JD, et al. Survival outcomes with concurrent chemoradiation for elderly patients with locally advanced head and neck cancer according to the National Cancer Data Base. Cancer 2016; 122(10): 1533-43.
7. Le Tourneau C, Calugaru V, Borcoman E, et al. Hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy for the treatment of frail and/or elderly patients with locally advanced HNSCC: a phase I/II study. International journal of radiation oncology, biology, physics 2020; 106(5): 1142-3.