Exploring the landscape of novel targets & pathways in immuno-oncology
Immuno-Oncology Insights 2023; 4(8), 301–306
Could you briefly describe your past experiences in cancer research and your current role at iTeos Therapeutics?
YM: Immediately after completing my PhD in 2000, I joined the UK-based company Biovex which marked the start of my career in oncology. I started working on oncolytic viruses and dendritic cell vaccination strategies for seven years before moving to Immunocore. Here, I assumed the responsibility of re-engineering their initial anti-CD3 T cell receptor bispecific, taking it to clinical development, and successfully advancing it to phase II studies. This drug, known as KIMMTRAK, has since been launched in the market, providing a therapeutic avenue for uveal melanoma patients.
I moved from the UK to Belgium where I spent six years as the Chief Scientific Officer at Complix, and during this time, we focused on advancing a novel platform technology. I then moved to iTeos Therapeutics in 2020 and as the Chief Scientific Officer, my role encompassed building and expanding the pipeline with promising drugs for clinical trials and also shaping the scientific strategy. Given our significant emphasis on translational medicine, a key aspect involves understanding how to deploy our drugs within diverse patient populations optimally.
Could you give background on the novel targets and pathways development platform at iTeos? How do these represent an advance on previous work?
YM: We play a significant role in the adenosine pathway, emphasizing our belief in the immunosuppressive effects of adenosine. Although widely acknowledged, the successful drugging of this pathway has been quite elusive. We believe that our unique insights, built upon prior knowledge, offer a new and different approach that holds promise for the benefit of patients.
Our key insights revolve around the concentration of adenosine in the tumor microenvironment (TME). Utilizing advanced techniques such as mass spectrometry, we have surpassed previous capabilities in measuring adenosine levels within tumor tissue. Our findings reveal substantially higher levels than previously recognized. In response, we have developed a novel drug, covered by a new patent, designed to operate effectively in these elevated adenosine concentrations, interacting specifically with the major adenosine receptor, the A2A receptor
Further, we have identified a new mechanism of action related to adenosine-mediated immunosuppression. We have developed a new drug for this as well, addressing this mechanism, currently in phase I dose escalation. While details remain confidential, we anticipate sharing more information publicly next year.
Additionally, we take pride in our TIGIT drug development. Our approach, involving a fully functional IgG1, has demonstrated Treg depletion in both peripheral and, more importantly, tumor tissues. Our translational medicine efforts have successfully translated into these findings, and we believe this will significantly benefit patients by eliminating immunosuppressive regulatory T cells.
Currently, these represent our major clinical focus areas, however, our commitment extends to continually seeking novel approaches to modify the TME. Our goal is to make it more receptive to both novel therapies and standard of care treatments.
Can you tell me more about the research and development pipeline that this work fuels?
YM: We approach our research in three key ways which can best be seen in a new endeavor currently underway at iTeos. Like most, we carry out in vitro work, supported by some in vivo work, to understand what the drugs are doing to the TME before progressing to patient trials. Substantial focus is also placed on translational medicine, where we analyze extensive datasets to identify patient populations suitable for testing the drugs.
A recent and exciting initiative at iTeos involves obtaining freshly resected tumor tissue from patients undergoing standard-of-care tumor resection which requires swift handling to maintain tissue viability. Though somewhat of an art, we have been making strides in perfecting this technique. Upon acquiring the tissues, they are sliced into smaller sections and novel agent or one of our clinic-ready drugs is applied to the tissue, and the reaction to this agent is measured.
This approach opens up numerous possibilities, one of which is exploring combinations to determine which elicits the most intriguing biological responses in the tumor tissue. Moreover, the responsive tumor tissues can be analyzed to decipher the characteristics influencing their reaction versus tissues that were less responsive. This information aids in extrapolating findings to identify individual patients who might benefit from either a new therapy or a specific combination. The technique proves powerful across various tumor types.
This growing initiative is poised to become the third pillar in drug discovery and development. It promises to bridge the gap between predictions derived from preclinical studies and the realities observed in clinical trials, enhancing the understanding and efficacy in drug development.
There’s been an increased interest surrounding personalized medicine, do you think this will help with the development of personalized medicine?
YM: It undeniably provides a clear pathway for validating personalized medicine or even pioneering entirely new personalized medicine approaches. I-O, however, may not naturally align with the most specific and purest forms of personalized medicine, instead, it is viewed more in terms of patient groups or subgroups within indications.
The immune system within a particular tumor or indication may closely resemble that of a patient in a completely different indication. The perspective of iTeos is centered around tracking and mapping the TME across various patient groups. Nonetheless, this technique could serve as an incredible tool for eventually achieving and validating a pure personalized medicine approach.
What impact is being made by small-molecule targets and do you see any specific areas that require more focus?
YM: In the I-O space, the use of small molecules is not as widespread as antibodies, setting iTeos apart with the capability of employing both approaches. The in-house medicinal chemistry group, in collaboration with great suppliers, equips us to target a broad spectrum of entities that we deem crucial for modulating biology. This flexibility extends to intracellular as well as extracellular targets.
Previously, the focus in I-O has leaned toward cell-surface molecules, given the predominant role of ligand-cell-surface interactions in immunology. While this emphasis is understandable, it may have led to the underexploitation of intracellular signaling. There is potential value in delving into this, to better understand and address important biological aspects. There may be potential opportunities for developing more effective strategies to tackle specific biologies crucial in I-O.
Is there any progress in antibody targets, and how can they be further developed?
YM: For breakthroughs, it’s essential to explore biology comprehensively and consider innovative ways to harness its complexity. While anti-PD-1 breakthroughs have been monumental, duplicating similar efforts may be an inefficient use of resources. Instead, the focus should be beyond PD-1 and CD8 T cells and more on the immune system components within the TME. The key is to develop antibodies, or even small molecules, that modify their biology, creating a TME conducive to patient benefit rather than tumor growth.
I believe that significant breakthroughs occur when approaches diverge from the conventional. Reflecting on my previous roles at Biovex and Immunocore, I contributed to the development of the first oncolytic viruses and engaged in dendritic cell vaccination strategies before I-O gained widespread attention. The Immunocore team slightly later to the game developing novel I-O agents in the form of T cell receptor-based bispecifics, two of which have reached the clinic and are actively treating patients, showcasing their novelty at the time.
The next wave of breakthroughs may emerge through similar diverse approaches, whether in the form of small molecules, large molecules, bispecifics, or other inventive methods. By exploring various novel approaches, we advance scientific understanding and increase the likelihood of developing drugs that genuinely benefit patients.
What challenges are currently facing the I-O field in terms of targeted therapies and how could these be addressed?
YM: The greatest challenge in the I-O space is the inherent complexity of its operation in conjunction with other drugs. Given the intricate nature of the immune system—comprising various cell types, each with subtypes expressing different receptors—the approach necessitates a comprehensive understanding. Recognizing the immune system as a collective, where different components work together, highlights the importance of simultaneous targeting of various aspects. Achieving this involves combination therapies, a strategy filled with challenges in the clinical trial space.
Combinations are inherently difficult to execute and justify in terms of progression. Vision is crucial to proceed, especially when faced with unclear clinical data. The central challenge lies in advancing clinical development while navigating through extensive clinical trials. This challenge is then amplified when attempting to prove the added benefit of a new drug on top of what may be considered standard care.
In an ideal scenario, the next frontier would involve adding novel agents atop other novel agents. However, this presents even more significant challenges in clinical development. Within the framework of projects like Project Optimus, determining the optimal dose for each drug is essential. Simultaneously managing the intricacies of two novel agents, including understanding their specific toxicity profiles and potential interactions, further complicates matters. Overcoming these challenges anticipates the greatest benefit for patients.
Finally, what are some key goals and priorities for your role and iTeos as a whole in the future?
YM: Overall, my key priorities at iTeos involve a twofold approach. Firstly, in terms of our current clinical drugs, my focus is on determining the specific patient populations that will gain optimal benefits from these therapies. This necessitates a robust translational medicine approach, ensuring a thoughtful and comprehensive understanding. Recognizing that these drugs won’t have universal efficacy, identifying which patients stand to gain the most from a particular treatment is crucial. It aligns with the goals of oncologists and ensures that patients are not only exposed to the right drugs but are also allowed to explore alternative, potentially more beneficial treatments.
In terms of clinical space, the challenge extends to deciphering the most effective combination strategies. This involves identifying the right placement of our drugs within combination therapies to maximize benefits for the patients.
On the other front, concerning our pipeline and its growth, my second goal involves strategically considering the best approaches and searching for groundbreaking changes in the TME that can genuinely benefit patients and make a significant difference. Identifying the most promising targets and developing drugs against them to be best-in-class and first-in-class is a priority. Constructing a pipeline with innovative, promising drugs is a continual challenge. This dual focus involves not only developing the pipeline but also discerning the optimal treatment approaches for specific patient groups that will derive the most significant benefits.
Yvonne McGrath joined iTeos in 2020 as Vice-President of R&D. With more than 20 years of international experience in oncology drug discovery and development, she has taken lead candidates from early stage research into clinical trials. Immediately prior to iTeos, she served as CSO and board member in Complix, a company developing novel biologics. She has also lead R&D activities in UK based biotech companies including Immunocore and Biovex. Yvonne holds a PhD from the University of Wales, College of Medicine.
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Authorship & Conflict of Interest
Contributions: The named author takes responsibility for the integrity of the work as a whole, and has given his approval for this version to be published.
Disclosure and potential conflicts of interest: Admin support provided by current employer iTeos Therapeutics. Attendance to multiple oncology conferences including travel expenses was funded by employer iTeos Therapeutics. McGrath Y is an owner of stock options in iTeos Therapeutics.
Funding declaration: The author received no financial support for the research, authorship and/or publication of this article.
Article & Copyright Information
Copyright: Published by Immuno-Oncology Insights under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.
Attribution: Copyright © 2023 McGrath Y. Published by Immuno-Oncology Insights under Creative Commons License Deed CC BY NC ND 4.0.
Article source: Invited. This article is based on a podcast with Yvonne McGrath, which can be found here.
Revised manuscript received: Nov 28, 2023; Publication date: Dec 6, 2023.