How the Next Advance in Immunotherapy Could Impact One of the Toughest Cancers

Researchers looking for ways to leverage the next frontier in immunotherapy for pancreatic cancer discuss their work.

Jonathan Brody, PhD

George Prendergast, PhD

Set to become the second leading cause of death from cancer, pancreatic cancer is notoriously difficult to treat effectively. As advances in cancer immunotherapy provide hope to many patients, researchers at Thomas Jefferson University and Lankenau Institute for Medical Research are exploring how the newest advances in immunotherapy could benefit pancreatic cancer patients.

Here to discuss the intersection of their work are collaborators Jonathan Brody, PhD, Director of the Research Division and Professor of Surgery at Thomas Jefferson University and George Prendergast, PhD, CEO of the Lankenau Institute for Medical Research of Main Line Health. Both Drs. Brody and Prendergast are members of the NCI-designated Sidney Kimmel Cancer Center at Jefferson, which provided pilot funding support for their initial studies.  Dr. Prendergast is also Co-Leader of the Cancer Cell Biology & Signaling Program of the Sidney Kimmel Cancer Center, and serves on the Center’s Executive Committee.

Why is immunotherapy such a hot topic right now in cancer treatment?

[George Prendergast] Cancer immunotherapies known as immune checkpoint inhibitors are really the first kind of treatment that comes close to the universality of radiation or chemotherapy. It is an approach that treats the immune system, rather than the cancer cells themselves. You can think of cancers as putting the breaks on the immune system – immunotherapies release those breaks and allow the body to fight the cancer. The approach has proven immensely effective across cancer types. There are caveats – not everyone reacts to these drugs, and for some, the side effects can be quite severe – but cancer immunotherapies offer a tremendous advance in curative power for many patients.

The IDO genes you work on are relative newcomers to the immunotherapy scene. What do these genes do? 

[GP] Normally, the IDO1 and IDO2 genes help quiet the immune system under certain conditions. For example, they act during pregnancy, where they get switched on by the fetus in order to prevent the mother’s immune system from attacking the father’s “foreign” genes. A cancer will, unfortunately, co-opt this mechanism, switching on these genes to cloak itself from the immune system, which would otherwise destroy it.

How might IDO inhibitors be the next big thing in immunotherapy?

[GP] The way we understand their function, blocking IDO could help “un-cloak” cancer to the immune system. Indeed, IDO inhibitors may enhance cancer treatment across many modalities, potentially improving outcomes from radiation, chemotherapy, and checkpoint inhibitor immunotherapies. We used to think of radiation therapy and chemotherapy as simply creating toxic environments for cancers, but now we know that these therapies also work by activating immune reactions that can keep fighting cancers long after the initial treatment. That’s where IDO-inhibitors could help – they’d strengthen and possibly lengthen the immune response after these traditional therapies.

How could IDO could benefit pancreatic cancer patients in particular?

[Jonathan Brody] We think there might be a couple of ways. First, in our preclinical studies we found that mice lacking the IDO genes did not develop pancreatic cancer after it was induced in models of that disease, suggesting that IDO might be essential to drive pancreatic cancer development.

To explore that idea further, we recently tested patients who had pancreatic cancer passed down through their family, in other words, those who had a hereditary form of the disease. We saw that hereditary pancreatic cancer patients were more likely to have genetic variations in their IDO2 genes that altered their activity.  We recently published our initial findings in the Journal of the American College of Surgeons on February 7th, and will be submitting an additional study of IDO2 status in patients with non-familial forms of pancreatic cancer.

As clinical trials of IDO inhibitors proceed, we hope to learn more about how these types of genetic variations influence outcomes.

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