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.
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.
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.