Cancer Immunotherapy Research
Immunotherapies are revolutionizing the way we treat cancer. These promising and potent drugs aim to harness the body’s immune system, directing it to attack tumors. From basic science to clinical trials, Comprehensive Cancer Center researchers are conducting innovative studies to optimize the use of current immunotherapies, such as checkpoint inhibitors, predict who will respond, and identify new immune targets for therapy by dissecting the underlying mechanisms of antitumor immunity and immune tolerance.
The University of Chicago Medicine was among the first sites in the Midwest certified to offer breakthrough CAR T-cell therapy for select cancers in adults and children. Used to supplement forms of cancer treatment like chemotherapy, radiation and stem cell transplants, CAR T-cell therapy works by using modified versions of a patient’s own blood cells to target and destroy cancer cells.
Sam Tinaglia was just five years old when he was diagnosed with cancer.
And at the time we had another son and a baby on the way. I was eight weeks pregnant. So he was not even in kindergarten yet.
Sam fought cancer with multiple treatments over 12 years. He had chemo and even a bone marrow transplant. The cancer came back each time.
And at this point, the doctors really tell you, if you had a transplant that didn't work and you've had all of this chemo, there's a real chance that your child may not ever get rid of the cancer.
He went in for another round of chemo, and then, right before his junior year of high school, his family got the devastating news.
The doctor called, and my grandma was over and everything, right when I came home from school. It was like a weird moment because everyone was there. It looked like a hard time. And then my parents told me that it had come back for the fifth time that afternoon. And we thought that, well, if the chemo can't do it after three times, and a bone marrow can't do it after one time, yeah, we thought it would never go away.
So now at this point, we thought that this might be the end. We celebrated as a family, we traveled, and we just said, we need to make the most of life because we really don't know what's ahead.
Sam needed something special. Fortunately, there was a new experimental treatment called CAR T cell therapy. Dr. John Cunningham worked to get Sam into a clinical trial at Children's Hospital of Philadelphia.
We had no hope. But then, when we heard about CAR T, there was hope again.
What CAR T cell therapy does is it induces the immune system to attack the leukemia cells and kill them.
In the first part of the process, t-cells, the workhorse of the immune system, are collected from the patient's blood. Then scientists insert instructions that enable these t-cells to find specific cancer cells. While the t-cells multiply in the lab, the patient receives chemotherapy to reduce the number of cancer cells. And finally, the engineered t-cells are returned to the patient's bloodstream, where they seek out and kill the remaining cancer cells.
We'd been looking for a treatment like this for over 30 years. In fact, I came to the United States to work on therapies like this 30 years ago. And so it's the culmination of many people's work, both at the University of Chicago, the University of Pennsylvania, and elsewhere that has resulted in this new therapy that we were able to provide.
We never thought this would be possible after five times. So the CAR T cell really did the job.
It has given Sam and his family another chance. In fact, he's going away to college at the University of Illinois, where he hopes to use his love of sports to build a career.
I'm studying broadcast journalism, looking to become a sports broadcaster for any baseball team, football team. I just love sports. Sports is my life.
Susie says she is thankful for the care Sam has received at many places, including the University of Chicago Comer Children's Hospital.
We really needed to find a place that had the most intense research, the most updated studies, and the doctors who were really on the forefront of what treatments were available. So when we came to Comer, we knew we were in the right place.
CAR T cell therapy has given Sam another chance and an exciting outlook ahead, something his family is grateful for.
We have learned to live one day at a time and really make the most of life because we never thought we'd have this chance with him with a future. He has hope for a future.
Predicting Immunotherapy Response
Understanding how to overrule a signaling pathway that can cause treatments to fail in metastatic melanoma patients should help physicians extend the benefits of recently approved immunity-boosting drugs known as checkpoint inhibitors to more patients. Thomas Gajewski, MD, PhD, and colleagues showed how these tumors shield themselves from T cells—the immune system’s front-line anti-cancer weapon—by producing high levels of beta-catenin, an intracellular messenger (Spranger et al., Nature 523:231-5, 2015; Luke et al., Clin Cancer Res Epub ahead of print, 2019).
Justin Kline, MD, and colleagues have identified a subset of diffuse large B-cell lymphoma (DLBCL) with alterations in the PD-L1 gene and high levels of infiltration with T cells. Patients with these gene alterations generally had inferior outcomes following frontline chemo-immunotherapy but for those in which the cancer relapsed or did not respond to this therapy, these alterations were actually associated with better anti-PD1 immunotherapy response (Godfrey et al., Blood Epub ahead of print, 2019). These studies suggest that the more we know about the molecular events in tumors, the better we can predict how patients will respond to immunotherapy.
Optimizing Immunotherapy
Thomas Gajewski, MD, PhD, and colleagues have explored how our microbiome (i.e., the bacterial flora in our gastrointestinal tract) influences responses to immunotherapy. In pioneering preclinical animal studies, they boosted the ability of the immune systems of mice with melanoma to attack tumor cells by introducing a particular strain of bacteria into their digestive tracts. These gains were comparable to treatment with anticancer drugs known as checkpoint inhibitors, such as anti-PD-L1 antibodies. The combination of oral doses of the bacteria and anti-PD-L1 antibody nearly abolished tumor outgrowth (Sivan et al., Science 350: 1084-9, 2015). Subsequent work demonstrated that the commensal microbiome is associated with anti-PD-1 responsiveness in metastatic melanoma patients (Matson et al., Science 359: 104-8, 2018). These results have set the stage for clinical trials and provide important insights into why some people do or do not respond to immunotherapy and help identify mechanisms of drug resistance.
Wenbin Lin, PhD, Ralph Weichselbaum, MD, and collaborators are developing ways to spur checkpoint blockade immunotherapy into more potent action with drug cocktails contained in nanoparticles. For example, combination of anti-PD-L1 immunotherapy with nanoparticles containing oxaliplatin and other anti-cancer agents were effective in stimulating the immune system and eradicating colorectal tumors in animal models (Duan et al., Nat Commun 10:1899, 2019). Other studies by the team are combining radiotherapy with nanotechnology to overcome some limitations of checkpoint inhibitors (Lu et al., Nat Biomed Eng 2:600-10, 2018). These strategies may eventually help physicians make better use of checkpoint inhibitors to treat many types of cancer.
Clinical Trials
Our researchers are leading immunotherapy clinical trials in multiple types of cancer, including melanoma and bladder cancer.