PharmaShots Interview: In Conversation with Leonard A. Farber and James Welsh, Where they Share Insights on How Nanoparticle can Trigger an Immune Priming Effect

Shots:

Leonard spoke about the newly developed radiotherapy-activated nanoparticle and other cancer therapies developing in Nanobiotix’s pipeline
James shared his views on the data presented at the 2022 Annual Meeting of the American Association of Cancer Research
The interview provides a core understanding of Nanobiotix’s outlook to expand the utility of nanoparticles in cancer treatment

Smriti: Tell us about NBTXR3 and its MoA, and formulation details.

Leonard: NBTXR3, a potential first-in-class radio enhancer, is an aqueous suspension of functionalized crystalline hafnium oxide nanoparticles that are delivered via one-time, intratumoral injection and activated by radiotherapy. The NBTXR3 mechanism of action is universal and physics-based. While the nanoparticles are biologically inert outside of the presence of radiation, when exposed to radiation therapy the nanoparticles absorb more radiation within the tumor than the tumor cells would alone, and then delivers up to 9 times the dose within the tumor cells where it is present. This reaction triggers significant cell death within the tumor through the destruction of DNA by free electrons, without increasing the damage to surrounding healthy tissues beyond what you would expect from radiotherapy alone. Subsequent to the tumor cell destruction triggered by NBTXR3's physics-based MoA, the product has also shown a potential to "prime" the immune system by activating several adaptive and innate immune pathways within the body. Given that immune checkpoint inhibitors require active immune pathways to deliver efficacy, our hypothesis is that the priming effect of NBTXR3 could make the radio enhancer a fundamental combination therapy with these and potential other immunotherapy agents.

The local effect of NBTXR3 has been confirmed in a randomized European phase III trial evaluating the radio enhancer for patients with soft tissue sarcoma, and the subsequent immune priming effect is currently being evaluated in a US phase I study.

Smriti: Give us the background behind the preclinical study evaluating multiple combinations of NBTXR3 and Immune Checkpoint Inhibitors.

James: In an attempt to improve the therapeutic outcome of radioimmunotherapy (RIT) in αPD1 resistant tumors, we previously incorporated NBTXR3 in our RIT regimen, which consists of localized radiation and systemic αPD1 injection for treating an αPD1 resistant lung cancer (344SQR) in mice. We found that NBTXR3 enhanced the control of both the irradiated primary tumor and unirradiated distant tumor, thereby extending the survival of the mice. We also found that triple therapy of NBTXR3, XRT, and αPD1 upregulated the expression of Lymphocyte Activation Gene 3 (LAG3) and Tyrosine-based inhibitory motif domain (TIGIT) in both irradiated and unirradiated tumors. LAG3 and TIGIT can deliver inhibitory signals that regulate immune cell homeostasis, T cell activation, and proliferation. Substantial evidence supports the notion that both LAG3 and TIGIT contribute to the exhaustion of CD4+, CD8+ T cells, and NK cells and limit the adaptive and innate immune response against tumors. Therefore, to further improve the treatment efficacy of NBTXR3-mediated RIT in αPD1-resistant lung cancer, αPD1, αLAG3, and αTIGIT monoclonal antibodies were co-injected into mice.

Smriti: Throw some light on the data that were presented at the annual meeting of the American Association of Cancer Research 2022 (What were the highlights?)

James: The addition of αLAG3 or αTIGIT alone to the combination of NBTXR3+XRT+αPD1 improved the control of both the primary and secondary tumors. More profoundly, the co-blockade of LAG3 in tandem with TIGIT affected additional tumor control and improved survival rate in mice. In the unirradiated tumors, triple blockade of PD1, LAG3, and TIGIT in combination with NBTXR3+XRT produced elevations in multiple immune-related pathways.

Smriti: Which combination therapy showed a better outcome in which indication model?

James: The combination therapy of NBTXR3+XRT+ αPD1+ αLAG3+ αTIGIT showed a better outcome in 344SQR anti-PD1 resistant lung cancer model than other combinations of NBTXR3, XRT, αPD1, αLAG3, αTIGIT.

Smriti: Can we discuss in detail which indication and combination your team is planning to assess in the clinic?

Leonard: Our team is already assessing NBTXR3 in combination with either pembrolizumab or nivolumab through Study 1100, an ongoing phase I clinical trial in the United States evaluating the combination for patients with locoregional recurrent or recurrent/metastatic head and neck cancer, liver metastases, and/or lung metastases. We recently received feedback from the FDA that we believe helps clarify the next steps for late-stage development of NBTXR3 in combination with anti-PD-1, and this feedback is currently under discussion as we outline our future plans. Additionally, our NBTXR3 radio enhancer is also being evaluated in parallel by our collaborators at The University of Texas MD Anderson Cancer Center in combination with pembrolizumab for patients with inoperable locoregional recurrent head and neck cancer. Moreover, we believe the results of this preclinical study could provide the rationale for ample development opportunities combining NBTXR3, anti-PD-1, anti-LAG3, and anti-TIGIT.

Smriti: Can you tell us more about other therapies developing in your pipeline for oncology indications?

Leonard: Given the universal mechanism of action of NBTXR3, combined with its intratumoral delivery and activation by radiotherapy, we are developing NBTXR3 as an agent that can integrate across all solid tumor indications where radiotherapy is part of the treatment regimen and intratumoral injection is feasible. Currently, Nanobiotix is prioritizing the development of NBTXR3 for elderly and frail patients with locally advanced head and neck cancer who are ineligible for platinum-based chemotherapy through our ongoing pivotal phase III study, NANORAY-312, and in combination with anti-PD-1 checkpoint inhibitors (pembrolizumab and nivolumab) for patients with locoregional recurrent head and neck cancer, liver metastases and/or lung metastases in a phase I study. Our collaborators at MD Anderson are evaluating the radio enhancer in parallel, with several active clinical studies including:

1. NBTXR3 as a single agent activated by radiotherapy for patients with locoregional recurrent non-small cell lung cancer that are amenable to re-irradiation

2. NBTXR3 as a single agent activated by radiotherapy for patients with locally advanced or borderline resectable pancreatic cancer

3. NBTXR3 in combination with concurrent chemoradiation for patients with esophageal cancer

4. NBTXR3 in combination with anti-PD-1 immune checkpoint inhibitors (pembrolizumab) for patients with inoperable locoregional recurrent head and neck cancer that are amenable to re-irradiation

5. NBTXR3 in combination with anti-PD-1 immune checkpoint inhibitors for patients with recurrent/metastatic head and neck cancer.

Nanobiotix has already achieved clinical proof of concept for NBTXR3 in a randomized phase III study evaluating the radio enhancer as a single agent activated by radiotherapy patients with soft tissue sarcoma that led to the product's first European market approval (CE mark), under the brand name Hensify

Smriti: Are you looking for any collaborations for the further development of combination therapy?

Leonard: With our hypothesis about the broad applicability of NBTXR3 across tumor indications, therapeutic combinations, and lines of therapy, we see ample potential opportunity for industry collaboration. As previously noted, we are currently in a preclinical and clinical development collaboration with MD Anderson, and we also have a development collaboration in Asia with LianBio. The potential immune priming effect of NBTXR3 that is being evaluated in the clinical studies listed above, could also lend to collaborations with several different types of immune checkpoint inhibitors.

Source: Canva

About Authors:

Leonard A. Farber

Leonard A. Farber is the MD, Chief Clinical and Medical Affairs Officer at Nanobiotix. He has extensive executive experience in developing and growing centers and departments within the oncology sector. Dr. Farber is a board-certified radiation oncologist who completed his residency in radiation oncology at the Hospital of the University of Pennsylvania where he served as chief resident.

James Welsh

James W. Welsh, MD, is a Tenured Professor and Physician-Scientist at The University of Texas MD Anderson Cancer Center, Houston, Texas. At the MD Anderson Cancer Center, he is the director of the immune radiation program. His major interests and goals are the use of radiation to turn the tumor into an “in-situ” vaccine to prime T cells and subsequently turning radiation into a systemic therapy.