Pipeline Insights

Targeting AhR: A promising new approach to cancer immunotherapy

How an oral inhibitor has the potential to reactivate the immune system and tackle tumor growth

It infiltrates, learns, adapts and grows. Cancer is a clever disease that has pushed the limits of medicine – and the human body – for centuries. Current estimates show that there will be 27.5 million new cases of cancer each year by 2040.

Typically, when an infection strikes the body, our immune system deploys T cells to target and destroy invading pathogens. But cancer stays one step ahead, using mechanisms to hide and sending mixed signals to avoid an attack. About a decade ago, first-generation immunotherapies, called immune checkpoint inhibitors (ICIs), brought a breakthrough in cancer therapy. Targeting a pathway that cancer uses to suppress the immune system, they can reactivate the body’s defense with significantly improved outcomes for patients, even in the metastatic setting.

For most, however, the effects are not realized: roughly 70% of patients with various tumors do not respond to treatment at all. Cancer seems to have found yet more ways to out-smart the immune system. But now, Bayer is targeting what appears to be a key conductor in orchestrating immune escape: the arylhydrocarbon receptor (AhR).

Expert insights: immunity through innovation

Dr Ilona Gutcher, Group Leader Immuno-Oncology Research at Bayer, is the leading pharmacology expert on the AhR. She reveals, “More and more research suggests that AhR, once activated, triggers events that suppress immune response and promote tumor progression. The AhR appears to be a central mediator in the whole process, so inhibiting it may re-activate immune response and provide a new therapeutic strategy for cancer."

As part of a strategic research alliance between Bayer and the German Cancer Research Center (DKFZ), scientists have developed a selective AhR inhibitor that has now started a first clinical trial with patients harboring advanced solid tumors. It aims to enforce therapy where first-generation IO drugs alone may not be sufficient.

The AhR inhibitor is intending a powerful double-act on the immune system. First, to activate the immune response by stimulating the production of cytotoxic T cells and natural killer cells, and enhancing dendritic cells that are activating even more T cells. Second, to decrease immune suppressive processes by blocking the function of regulatory T cells.

Implications and outlook: A two-way treatment path

AhR is a prognostic marker for aggressive disease progression. High levels have been detected in T-cell leukemia/lymphoma, as well as in solid tumors such as glioblastoma, ovarian cancer, lung cancer and more. “Cancer cells constantly fuel the AhR pathway, as they produce kynurenine, the most prominent activator of AhR, which results from the metabolism of the amino acid tryptophan,” says Gutcher. "In the tumor environment, we see high amounts of kynurenine binding to and activating AhR."

And it does not stop with the suppression of immune response: research indicates that the AhR might also have a direct effect on cancer that is driving various stages of tumorigenesis, including cell proliferation, tissue invasion, angiogenesis, inflammation and metastasis.

"The AhR is found in different immune cells, from dendritic cells to professional antigen-presenting cells,” Gutcher continues. "Unlike checkpoint inhibitors, which predominantly target T cells, targeting AhR, therefore, may allow us to affect more of the immune cell population in the tumor – diminishing the options of cancer cells evading the body’s immune response.”

Moving ahead: Small solution, big impact

As a small molecule (SMOL), the AhR inhibitor may also give additional advantages: SMOLs are able to cross cell membranes and reach targets such as the AhR located inside the cells. A SMOL is also administered orally and has a shorter half-life in the body. “This allows for a more flexible treatment regimen as compared to or in combination with antibodies, including the approved antibody ICIs,” says Gutcher.

Scientists from both Bayer and the DKFZ are excited to see if the AhR inhibitor can translate promising preclinical results to the clinic and help patients in their battle against cancer. With the start of the phase 1 clinical trial, Bayer is now solely responsible for its clinical development. Gutcher concludes: "We believe eliminating the bad guy, AhR, could be a promising new approach to cancer immunotherapy.”