Persistence Paved the Path of Discovery for an Immunotherapy Pioneer

Thomas F. Gajewski, MD, PhD

For many years, no one took immunotherapy seriously, but Thomas F. Gajewski, MD, PhD, persisted in his study of how the immune system interacts with cancer. Despite the naysayers, he searched for ways to harness the body’s immune system to fight off cancer cells. His endless pursuit and study in the field of immuno-oncology paid off, and Gajewski is now hailed as a pioneer in the field of cancer immunotherapy, waving its banner even when no one else would.

That’s why The CheckPoints, a rock band that includes co-founder Gajewski on guitar, tends to close out their set with the Journey classic “Don’t Stop Believin’,” says Patrick Hwu, MD, the other co-founder and a close friend and colleague of Gajewski’s. “It is kind of our anthem to show that we’ve persisted through all of these years and now everyone understands that immunotherapy is important.”

Gajewski seems to have taken up the anthem as his own motto and never stops believing in the power of immunotherapy: “This is an exciting time for the field of cancer immunotherapy,” he said in an interview.

Laboratory Discoveries

His drive to succeed is recognized by his colleagues and friends. “[Gajewski is] one of the smartest guys I know, hands down. He has very high standards, and he has really done some spectacular work in immunotherapy,” Hwu says. “I appreciate that he makes us all better. He pushes us scientifically, and he pushes us musically.”Perhaps Gajewski is best known in the field of oncology for a discovery in his lab at the University of Chicago in 2015, when he showed that gut microbiota in mice have a role in responses to immunotherapy treatments. When Bifidobacterium was orally administered into the digestive tract of mice with melanoma tumors, it led to increased tumor control to the same extent seen with anti— PD-L1 therapies. The mechanism of action was due to enhanced dendritic cell function and CD8-positive T-cell priming and accumulation in the tumor microenvironment. The combination nearly abolished tumor outgrowth.

This discovery required keeping a watchful eye on the mice used in the research. Gajewski and his colleagues were studying mice from 2 centers, and they noticed that mice from Jackson Laboratory tended to show a greater immune response than those from Taconic Biosciences. Yet, when the mice were housed together, that difference was eliminated, which prompted the researchers to look into the types of bacteria in each mouse. Bifidobacterium stood out as having the greatest impact on outcomes.

Education and Research

A longtime resident of Chicago, Illinois, Gajewski stayed in the city to study, from his undergraduate years all the way through his residency and fellowship. In 1989, he received his PhD and in 1991 his MD at the University of Chicago Pritzker School of Medicine, where he joined the faculty in 1997. He is currently a professor of medicine and pathology and runs a laboratory investigating antitumor immunity. Many brilliant minds, as well as research, have come out of Gajewski’s laboratory. Hwu notes that Gajewski is a wonderful mentor and continues to train students and fellows at University of Chicago Medicine.

Gajewski is also well known for his study of RAS pathway signaling, which is involved in T-cell activation. He and his team identified diacylglycerol kinase-alpha (DGK-alpha) as a key negative regulator of RAS activation and T-cell function in the anergic state. Regulation of RAS activation, he thinks, could be a potential target for immunopotentiation.

He and his colleagues also identified the role of the newly discovered stimulator of interferon genes (STING) complex, which triggers an immune response when it is activated. The STING pathway induces interferon-beta, which leads to the activation of specific T cells that then target the tumor cells. “Understanding the role of the STING pathway provides insights into how we can ‘wake up’ the immune response against tumors. This can be further boosted by checkpoint therapies,” Gajewski says. New agents targeting STING could significantly augment antitumor immune responses and are currently in early-phase clinical testing.

Developing immunotherapies aimed at melanoma is of particular interest to Gajewski, and he has been involved in numerous clinical trials of experimental immuno-oncology agents for the treatment of patients with this disease. Based on preclinical data developed in his laboratory, a major focus is on combining IDO inhibitors with anti—PD-1/ PD-1 therapies to augment the effector phase of antitumor immune responses. Unfortunately, this strategy has not demonstrated improved outcomes in late-stage studies and pharmaceutical companies have scaled back development plans.

Meanwhile, Gajewski and colleagues have revealed an association between activation of the Wnt/beta-catenin signaling pathway and the absence of a T-cell gene expression signature in metastatic melanoma tumors. This signaling led to resistance to anti—PD-1/ PD-L1 and anti–CTLA-4 therapies. Gajewski continues to explore elements of resistance to checkpoint inhibition, which involves identifying oncogene pathways to target in concert with immunotherapeutic interventions. Inhibitors of Wnt/beta-catenin signaling also are in development.

Memberships and Accolades

Gajewski always tries to impart a sense of excitement about the progress being made in treating patients with this tumor type. “My job is to get both physicians and patients psyched up about what is just around the corner,” he says. “Many community oncologists are waiting [to learn] what is the best combination partner with PD-1 so that they can treat their patients and have an even greater likelihood of attaining clinical benefit from that first treatment straight out of the starting blocks. I want them to get excited that we are working hard on the problem, and I feel happy that we have discovered some of these components.”Beyond the laboratory, Gajewski maintains a steadfast loyalty to the field of immuno-oncology. He is a member of the Society for Immunotherapy of Cancer (SITC), the American Association of Immunologists, the American Association for Cancer Research, and the American Society of Clinical Oncology. He served as president of SITC from 2010 to 2012 and is active on planning committees for each of these societies. He also serves on the editorial boards for the Journal for Immunotherapy of Cancer, the official journal of SITC; Cancer Discovery; and the Journal of Experimental Medicine.

In 2013, Gajewski and 5 other immunologists— including James P. Allison, PhD (another member of The CheckPoints); Padmanee Sharma, MD, PhD; Drew M. Pardoll, MD, PhD; Robert D. Schreiber, PhD; and Louis M. Weiner, MD—helped to co-found Jounce Therapeutics, which they hope will lead to the development of lifesaving immunotherapy treatments for patients with cancer.

Gajewski is also a member of the scientific advisory board of another therapeutics company, Evelo Biosciences, which focuses on bringing microbiome-based therapeutics for cancer into clinical practice.

Last year was an unprompted congratulatory one for Gajewski, who received not only the Giants of Cancer Care® award but also the William B. Cooley Award for contributions to immunotherapy and was designated the AbbVie Foundation Endowed Professor in Cancer Immunotherapy.

Notably, Gajewski also was recognized with an Outstanding Investigator Award from the National Institutes of Health. The grant, which provides up to $600,000 per year, perpetuates an already impressive 20-year period of continuous NIH funding. The 7 years of financial support offered by this award will enable him to continue the pursuit of his favorite longterm projects, including pooling past research, and perhaps lead to his next big discovery.

“The Outstanding Investigator Award pulls together a number of separate but related projects from our lab and blends them into one, massive, cohesive undertaking,” Gajewski said. “Such funding is necessary for our lab and many others to make continual progress toward preventing and treating cancer using the host immune system. It inspires us to be even more aggressive, to move the field forward as broadly as we can.”

For Gajewski, this grant “builds on a long research path, made possible by public as well as private support.” It will be important to closely watch the future of his career to follow the developments in immunotherapy cancer treatment.

Now Gajewski believes that discovering the connection between the microbiome and clinical outcomes will enable the development of microbiota-modulating interventions to improve outcomes in patients undergoing cancer treatments. “This finding provides a novel way to exploit that connection—to improve immunotherapy by selectively modulating intestinal bacteria,” he says.