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To say that immunotherapies have been a game-changer for cancer feels like an incredible understatement.  

These powerful treatments, which work by bolstering the immune system’s ability to detect and kill cancer cells, have saved countless lives since the first immunotherapy was approved for cancer in 2011.1 Today, more than 1,000 immunotherapy clinical trials are underway, each exploring different cancers and contexts.2

Van Andel Institute Fellow Dr. Josh Jang is one of the scientists at the forefront of developing ways to improve immunotherapies. His work focuses on a specific class of these treatments called immune checkpoint inhibitors, which supercharge the immune system’s cancer-fighting powers.

Dr. Josh Jang, Van Andel Institute

“Immunotherapies have helped so many people, but not every person or every cancer responds to them,” Jang says. “We want to change that.”

Jang is uniquely positioned to pursue solutions. He is a scientist who works with the Van Andel Institute–Stand Up To Cancer© (SU2C) Epigenetics Dream Team, a multi-institutional collaboration that evaluates promising combinations of cancer therapies through clinical trials. The initiative is unique because it pairs epigenetic agents, which work by fixing errors in how our genetic instructions are used, with other treatments such as immunotherapies.

“The idea is that epigenetic drugs might prime cancer cells to be more vulnerable to immunotherapies and other cancer-fighting therapies,” Jang said.

Cancers — and people — vary widely. What works for one type of cancer (or one person) may not work in another. That’s why Jang and his colleagues are carrying out high-tech molecular, genetic and epigenetic analyses of samples from the people who participate in the trials. This critical work gives scientists an inside look at how combination therapies affect cancers on a molecular level, insights that could help them fine-tune treatments and find ways to identify people who will best respond to certain treatments.

This latter point is of particular importance to Jang. In very rare cases, some people treated with immunotherapy may experience a phenomenon in which their cancer progresses rather than recedes.

It’s a problem that Jang and his VAI–SU2C Epigenetics Dream Team colleagues are keen to solve — and, thanks to their recent findings, they’re well on the way toward finding answers.

A wrench in the gears

In science, a single observation can have a major impact.

For Jang and his collaborators, this moment arrived when reviewing bladder cancer data gathered by the VAI–SU2C Epigenetics Dream Team. They noticed a small subset of these cancers progressed more quickly in response to immunotherapy.


Related: Learn more about the VAI –SU2C Epigenetics Dream Team here ➔


But why? What made them different? And could that difference be fixed?

They dug into the data and there it was — a clue found in the form of a gene called CYP1A1. In tumors that progressed after immunotherapy, the team found CYP1A1 was selectively and highly expressed — a signature that may differentiate cancers that progress versus those that don’t. Importantly, CYP1A1 also is part of a wider network known as the AHR pathway.3

“Pathways” are interconnected networks of molecules and reactions that carry out specific tasks within cells. Our health is based on all our molecular pathways working well and in concert. But when something goes wrong — when a wrench is thrown into the gears or a part breaks — the results can lead to disease. This can happen for many different reasons, such as genetic mutations, which scramble the instructions required to produce key pathway components called proteins.

Scientists are deeply interested in pathways because they offer opportunities to treat diseases like cancer. Much like an engineer figuring out why a production line went haywire, scientists seek out errors in pathways and try to find ways to fix them.

This is the approach Jang and his colleagues are taking with the AHR pathway. When something in the AHR goes awry, it can interfere with the immune system and contribute to cancer development.  

Their initial findings led to Jang being awarded a prestigious Pathway to Independence Award from the National Cancer Institute, which will fuel further research into the role of AHR in bladder cancer. Jang is hopeful their findings also might inform a better understanding of this critical pathway in other cancers.

“Understanding why some cancers progress after immunotherapy and finding ways to prevent it is a massive unmet need,” Jang says. “I’m so fortunate to be part of such an excellent team of clinicians and scientists who are working together to solve this problem and help people battling cancer.”

Mining for markers

Fixing problems with AHR and CYP1A1 is only half of the equation. The other part lies in identifying people at risk for progression after immunotherapy.

Enter biomarkers.

Biomarkers are measurable, biological indicators of disease. For example, temperature is a biomarker used to evaluate fever, HbA1c is a biomarker that measures blood sugar levels, and prostate-specific antigen (PSA) is used to diagnose and monitor prostate cancer. Jang and the team are hopeful that CYP1A1 or other parts of the AHR pathway may serve as biomarkers, which would enable doctors to identify people at risk for accelerated cancer progression before they undertake immunotherapy. 

If successful, Jang envisions a future in which a person with cancer is screened for susceptibility for progression after immunotherapy. Those who are not at risk would be cleared for immunotherapy. Those at risk would receive a different course of treatment that would minimize or eliminate the risk by fixing problems with AHR. Ideally, these folks would then be eligible for immunotherapy.

AHR inhibitors — medications that interact with the AHR pathway — already are being evaluated as possible treatments for other cancers. Jang is hopeful that the team’s research might shed light on how to best repurpose existing medications toward uses in a wider range of cancers.

“We’re not there yet but we’re well on our way,” Jang said. “This work would not be possible without the people who participate in clinical trials, the outstanding physicians and health care staff that treat them, and our incredible VAI–SU2C Epigenetics Dream Team. Finding better treatment strategies for cancer isn’t something a single person can do — it takes a dedicated community and we are so fortunate to have that here.”

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award no. K99CA286742. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Research reported in Jang et al. was supported by a Stand Up To Cancer Catalyst© Research Team Award with support from Genentech (SU2C-AACR-CT08-17) and the National Cancer Institute of the National Institutes of Health under award no. P30CA006927 (Chernoff). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Image Credit: In very rare cases, some cancers progress more quickly after treatment with immunotherapy. Dr. Josh Jang and colleagues on the Van Andel Institute–Stand Up To Cancer Epigenetics Dream Team pursue answers to this problem by investigating differences between cancers that progress versus those that don’t. They hope pairing epigenetic drugs with immunotherapies may better tackle these tough-to-treat cancers. This image shows bladder cancer cells from a tumor that progressed, with the different colors representing the different types of cells that compose the tumor. Image courtesy of Dr. Josh Jang, Van Andel Institute.

Sources

1 Johns Hopkins inHealth. n.d. Immunotherapy: Precision medicine in action. https://www.hopkinsmedicine.org/inhealth/about-us/immunotherapy-precision-medicine-action-policy-brief

2 ClinicalTrials.gov. 2024. Search: “cancer” and “immunotherapy”. https://clinicaltrials.gov/search?cond=cancer&intr=Immunotherapy

3 Jang HJ, Hostetter G, Macfarlane AW, Madaj Z, Ross EA, Hinoue T, Kulchycki JR, Burgos RS, Tafseer M, Alpaugh RK, Schwebel CL, Kokate R, Geynisman DM, Zibelman MR, Ghatalia P, Nichols PW, Chung W, Madzo J, Hahn NM, Quinn DI, Issa JPJ, Topper MJ, Baylin SB, Shen H, Campbell KS, Jones PA, Plimack ER. 2023. A phase II trial of guadecitabine plus atezolizumab in metastatic urothelial carcinoma progressing after initial immune checkpoint inhibitor therapy. Clin Can Res 29(11):2052–2065.