Addressing Adenosine: Immunotherapy in the Tumor Microenvironment
In our bodies, cells are constantly communicating with each other through complex signaling pathways. A signaling pathway is a series of steps in which groups of proteins work together to control cell function and respond to environmental changes. Pathways can be thought of as a step-by-step baking recipe, where adding or removing certain ingredients can change outcomes drastically. These changes or disruptions are what often lead to disease.
Adenosine is a naturally occurring molecule, essential in many biological processes such as wound healing, communication between brain cells and regulation of blood flow — but it can also be involved in many diseases.1,2,3 Specifically, it is found at high levels inside tumors, making it an attractive target in cancer research.4
Targeting the Adenosine Axis
Adenosine is found at high levels inside tumors because the conditions of their microenvironment promote its presence — low oxygen levels can lead to increased adenosine production and high levels of adenosine precursor molecules are generated by dying cells.5,6 Once produced, adenosine binds to and suppresses immune cells, inhibiting their ability to kill cancer cells. Adenosine can also turn other cells known as fibroblasts, a type of stromal cell, into tumor-protecting cells.7
Today, there remains a significant need to develop new approaches to cancer immunotherapy, treatments that harness the body’s own immune system to attack and destroy the cancer. Targeting the adenosine axis – components that contribute to the production of adenosine and its subsequent impact – is a promising option. This approach has the potential to release the brakes on a broad range of immune cells to fight cancer naturally. 11,12 At Arcus, we are exploring multiple ways to inhibit this well-established biological pathway.
The molecules we engineered against the adenosine axis and brought to clinical trials were only possible through close collaboration between our research and clinical teams. At Arcus, we rely on the joint expertise of both teams to ensure the molecules we develop are guided by disease biology from the outset. In other words, our clinical and research strategies are linked by clear therapeutic hypotheses, so new molecules are specifically studied in combination regimens and clinical settings that are consistent with such hypotheses.
Molecular Architects
Etrumadenant is an investigational treatment that is designed to simultaneously block two adenosine receptors (A2aR/A2bR) on the surface of immune cells and other cells within the tumor microenvironment, such as fibroblasts. Etrumadenant is thought to work by preventing adenosine from acting on these cells. It was specifically made to bind to both adenosine receptors because different types of immune and stromal cells have one or both of these, so a molecule that could inhibit A2aR and A2bR was essential for its use in cancer.7,12
Building a new treatment required the expertise of our Medicinal Chemistry team. Medicinal chemists are the architects that design new molecules. To do their job successfully, they need to consider every variable that could affect how well the molecule binds to its target so it has the potential to elicit the strongest anti-tumor activity, while also limiting side effects.
Designing a Discerning and Strong Molecule
In designing any molecule, selectivity is essential — a molecule should be discerning and only bind to its intended target to avoid unwanted effects on other biological pathways. Non-selective binding can also reduce the amount of a molecule that is available to bind to the correct target and perform the intended function.
Additionally, because there’s a high concentration of adenosine in many tumors, any molecule must bind strongly, or potently, to its target and not immediately let go. If the molecule is not bound strongly enough, this could open the door for adenosine to bind to its receptors and enable a tumor-supportive environment.
To build a structure that was both highly selective and potent, our Medicinal Chemistry team fine-tuned etrumadenant by swapping out atoms and changing the size of certain building blocks to get the ideal form, much like an architect might swap out fixtures or change the size of a room. They collaborated with colleagues in the Biology, Pharmacology, Drug Metabolism and Pharmacokinetics (DMPK), and Lead Discovery and Optimization (LD&O) teams to design and use laboratory tests to assess how structural changes made the molecule more potent and selective, while ensuring these properties were maintained in a tumor-like microenvironment. The iterative process resulted in a molecule that is highly selective and potent for A2aR and A2bR.
Refining for Combining
Beyond creating treatments that appropriately act on the intended target, one of our central goals is to make molecules that can be used in combination with others — so that patients can receive treatments that shut down cancer cells in multiple ways. But the combination of multiple treatments creates the potential for more side effects. So it is vitally important that our molecules are designed with safety in mind to minimize potentially harmful side effects when used in combination regimens. This was particularly important for adenosine receptor inhibitors, given their past clinical histories.
Adenosine receptor inhibitors were previously developed for use in neurological disorders and therefore structured to cross the blood-brain barrier (BBB), a highly protected environment, to reach their target.14 For cancer treatments, however, entering the BBB can lead to unwanted side effects. To avoid this, our medicinal chemists made meticulous changes in etrumadenant’s structure to reduce the chances of it entering the brain, akin to how an architect ensures the structural integrity of a building to keep people safe.
Additionally, to create treatments intended to be combined, we look critically at the biology to develop combination strategies for cancer types in which blocking more than one pathway could improve anti-tumor activity. In certain cancers, chemotherapy and other immunotherapies can increase adenosine production, creating an environment where immune cells can be silenced even with treatment.7,15 So, a combination regimen with an adenosine receptor inhibitor could increase the number of ways cancer cells are killed.
From the Lab to the Clinic: Meaningful Early Results for Patients
All the work done by the Medicinal Chemistry team, in collaboration with Biology, Pharmacology, DMPK, LD&O and others, provided compelling evidence that etrumadenant was a strong candidate with the potential to activate the immune system against cancer. Specifically, colorectal cancer is a tumor type where the biology of disease aligns with using an adenosine receptor inhibitor because this cancer is believed to be associated with high levels of adenosine.16
Within just one year after its identification, etrumadenant was moved into human trials — a testament to the power of combining efficient and meticulous medicinal chemistry with biological insights from the research and clinical teams from the beginning.
At the American Society of Clinical Oncology (ASCO) Annual Meeting in 2024, a Phase II clinical trial in people with metastatic colorectal cancer showed improvements in both progression-free and overall survival for those receiving etrumadenant combined with chemotherapy and another immunotherapy, compared to the standard of care. No unexpected safety signals were observed in the etrumadenant arm of the clinical trial.
The innovative work of our Medicinal Chemistry team has opened the door to potential novel treatments for patients in need. These results show that etrumadenant has the potential to treat metastatic colorectal cancer and validates the importance of continued clinical research on the adenosine axis.
Etrumadenant is an investigational molecule. Arcus has not received approval from any regulatory authority for any use globally, and its safety and efficacy for the treatment of colorectal cancer has not been established.
Dr. Jaen has been engaged in all aspects of drug discovery and development for more than 30 years, and in 2015 he co-founded Arcus.
Dr. Nuyten is a physician-scientist with over 15 years of experience across all phases of drug development, with expertise in immuno-oncology.
References:
1. Feoktistov, Igor, Italo Biaggioni, and Bruce N. Cronstein. “Adenosine receptors in wound healing, fibrosis and angiogenesis.” Adenosine Receptors in Health and Disease (2009): 383-397.
2. Liu, Ying‐Jiao, et al. “Research progress on adenosine in central nervous system diseases.” CNS neuroscience & therapeutics 25.9 (2019): 899-910.
3. Guieu, Régis, et al. “Adenosine and the cardiovascular system: the good and the bad.” Journal of clinical medicine 9.5 (2020): 1366.
4. Bai, Yu, et al. “Overcoming high level adenosine-mediated immunosuppression by DZD2269, a potent and selective A2aR antagonist.” Journal of Experimental & Clinical Cancer Research 41.1 (2022): 302.
5. Ohta, Akio. “A metabolic immune checkpoint: adenosine in tumor microenvironment.” Frontiers in immunology 7 (2016): 186112.
6. Gilbert, S. M., et al. “ATP in the tumour microenvironment drives expression of nfP2X7, a key mediator of cancer cell survival.” Oncogene 38.2 (2019): 194-208.
7. Vigano, Selena, et al. “Targeting adenosine in cancer immunotherapy to enhance T-cell function.” Frontiers in immunology 10 (2019): 925.
8. Kim, Seong Keun, and Sun Wook Cho. “The evasion mechanisms of cancer immunity and drug intervention in the tumor microenvironment.” Frontiers in pharmacology 13 (2022): 868695.
9. Thompson, Elizabeth A., and Jonathan D. Powell. “Inhibition of the adenosine pathway to potentiate cancer immunotherapy: potential for combinatorial approaches.” Annual review of medicine 72 (2021): 331-348.
10. Morello, Silvana, et al. “Myeloid cells in the tumor microenvironment: Role of adenosine.” Oncoimmunology 5.3 (2016): e1108515.
11. Sun, Changfa, Bochu Wang, and Shilei Hao. “Adenosine-A2A receptor pathway in cancer immunotherapy.” Frontiers in immunology (2022): 1195.
12. Chen, Siqi, et al. “The Expression of Adenosine A2B Receptor on Antigen-Presenting Cells Suppresses CD8+ T-cell Responses and Promotes Tumor Growth.” Cancer immunology research. 8.8 (2020): 1064-1074.
13. Wang, Longsheng, et al. “The inhibitory effect of adenosine on tumor adaptive immunity and intervention strategies.” Acta Pharmaceutica Sinica B (2023).
14. Fredholm, Bertil B., and Per Svenningsson. “Why target brain adenosine receptors? A historical perspective.” Parkinsonism & Related Disorders 80 (2020): S3-S6.
15. Zahavi, David, and James W. Hodge. “Targeting immunosuppressive adenosine signaling: a review of potential immunotherapy combination strategies.” International journal of molecular sciences 24.10 (2023): 8871.
16. Hajizadeh, Farnaz, et al. “Adenosine and adenosine receptors in colorectal cancer.” International immunopharmacology 87 (2020): 106853.
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