Immune system unleashed: Immunotherapy shows promise for some of the toughest cancers

Thomas Gajewski, MD, PhD,  is leading work at UChicago to harness the immune system to fight cancer

Thomas Gajewski, MD, PhD, is leading work at UChicago to harness the immune system to fight cancer

by Piers Nash, MBA, PhD

What if our immune system could be mobilized to attack a tumor in the same way it fights the common cold or fends off an infection? This is the promise of cancer immunotherapy—to turn the remarkable power of our immune system against cancer. And the approach holds particular potential in bringing to heel the deadliest, hardest-to-treat cancers like melanoma, pancreatic cancer, mesothelioma and triple-negative breast cancer.

The historic challenge for cancer immunotherapy has been that cancer cells are virtually indistinguishable from our own healthy cells. Moreover many tumors make compounds that actively suppress our immune response against them. Accordingly, our immune system remains blind, and one of our most effective weapons against cancer is locked down, unable to act.

However recent advances—many driven by researchers at the University of Chicago Medicine—are surmounting these obstacles, suggesting cancer immunotherapy may be ready for primetime

Discoveries by investigators in the University of Chicago Medicine Comprehensive Cancer Center‘s Immunology and Cancer Program and other centers over the past 20 years have identified key proteins that regulate immune response and block the immune system from mounting an effective response to a growing cancer.

Releasing the brakes

One such regulatory system centers around the PD-1 checkpoint pathway, which acts as a brake on the immune system. This is important to bring the immune system back into check after an infection is cleared and prevent devastating autoimmune diseases such as lupus, type 1 diabetes and rheumatoid arthritis. Many tumor cells activate this brake by making a protein called PD-L1, which binds to PD-1 on immune system cells. Understanding the PD-1 checkpoint pathway offered a target for prospective new drugs that disrupt the interaction between PD-1 and PD-L1, releasing the brake and allowing the immune system to work against the cancer.

These efforts are now bearing fruit. At the American Society of Clinical Oncology annual meeting this summer, results on the first of a wave of new drugs that unleash the immune system to combat tumors were reported, with some doctors “predicting a revolution in cancer care.” A variety of cancer immunotherapies aimed at unleashing the immune system have shown promising and occasionally jaw-dropping success.

Perhaps the most intriguing and promising aspect of immunotherapy is its potential to tackle some of the toughest, most complex cancers—cancers against which progress has been haltingly slow. Melanoma, mesothelioma, and advanced cancers of the lung, breast, head and neck and many display what Thomas Gajewski, MD, PhD, describes as a “smoldering immune response”—meaning that the body attempts to mount an immune response but is thwarted by mechanisms designed to keep the immune system in check. Against these cancers, the current wave of immunotherapies may prove broadly beneficial.

Now comes news of promising early studies in Hodgkin’s Lymphoma that suggest even broader reach for these therapies.

A new generation of treatments

A clinical trial by Rita Nanda, MD, showed promising results for treating triple negative breast cancer with a new drug

A clinical trial by Rita Nanda, MD, showed promising results for treating triple negative breast cancer with a new drug

In addition to driving basic understanding of the mechanisms that affect immune response to cancer, UChicago is in the vanguard of testing the new generation of drugs being developed based on these insights from the lab.

UChicago is a lead site in a consortium of academic medical centers aiming to advance cancer immunotherapy in partnership with Bristol-Myers Squibb, and is advancing preferred trials in collaboration with Merck, Genentech, Medimmune, and Incyte. Justin Kline, MD, and his colleagues are opening an additional Merck PD-1 inhibitor trial for Hodgkin’s Lymphoma and Tanguy Seiwert, MD, fresh from a trial of the PD-1 inhibitor pembrolizumab in neck squamous cell carcinoma (HNSCC), is initiating a similar trial in malignant mesothelioma.

In parallel, Gajewski is running multiple immunotherapy trials in melanoma, and Rita Nanda just reported positive results for pembrolizumab in triple negative breast cancer. Other ongoing or recently completed trials of PD-1 checkpoint inhibitors at UChicago include advanced solid tumors and metastatic disease, pancreatic cancer, and bladder cancer.

The current batch of cancer immunotherapies may just be the beginning. New, and potentially better, drug targets may be in the pipeline. Last month, Gajewski and colleagues reported a new signaling complex called STING that promotes a robust immune response against cancer cells. New agents that activate the STING complex are under development as potential therapies. Meanwhile, work by Yang-Xin Fu, MD, PhD, and Ralph Weichselbaum, MD, has shown that radiation therapy can trigger an immune response against tumors. Combined with immunotherapy drugs, radiation therapy may become a far more effective tool against a broader range of cancers.

Despite the progress, Gajewski, for one is not resting on his laurels: “We want to know why some patients don’t respond, so we can tip them the other way,” he says. The goal, he explains, is to expand the base of patients who can benefit from immunotherapy. “This is an unparalleled opportunity to make inroads against some of the most complex cancers. It’s a really transformative moment in this field.”

Piers Nash, MD, PhD, is Senior Director, Campaign Planning for Academic Research at the University of Chicago in Medicine and Biological Sciences.

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