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.
Much of the research being conducted in immunotherapy is focused on the questions: What cells are the key players in the immune response and how do they develop and interact with other cells in their environment? We already know that T cells, a type of white blood cell, act as the immune system’s army, fighting off infections and viruses. Peter Savage, PhD, and his colleagues are studying Foxp3+ regulatory T (Treg) cells, a unique type of T cell that does not participate in host defense against pathogens and tumors. Instead, Treg cells actually suppress immunity by regulating other T cells.
A protein known as STING plays a crucial role in the immune system’s ability to “sense” cancer by recognizing and responding to DNA from tumor cells. Injection of compounds that activate the STING pathway directly into solid tumors in mice has been shown in prior studies to result in very potent anti-tumor immune responses. Justin Kline, MD, and colleagues have shown that by injecting substances that mimic tumor-cell DNA into the bloodstream, they could stimulate STING to provoke a life-extending immune response in mice with acute myeloid leukemia (AML).
Thomas Gajewski, MD, PhD, and colleagues explored how our microbiome (i.e., the bacterial flora in our gastrointestinal tract) influences responses to immunotherapy. By introducing a particular strain of bacteria into the digestive tracts of mice with melanoma, they were able to boost the ability of the animal’s immune systems to attack tumor cells. 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 injections with anti-PD-L1 antibody nearly abolished tumor outgrowth. These results provide important insights into why some people do or do not respond to immunotherapy and help identify mechanisms of drug resistance.
By combining local radiation therapy and anti-cancer vaccines with checkpoint inhibitors, Ralph Weichselbaum, MD, and colleagues, working with mice, were able to increase the response rate for these new immunotherapy agents. The findings showed this sequence of treatments could open up unresponsive pancreatic cancers to immune cell infiltration, often leading to immunologic control of tumor growth. They may eventually help physicians make better use of checkpoint inhibitors to treat many types of cancer.
Wenbin Lin, PhD, Ralph Weichselbaum, MD, and collaborators recently developed a way to spur checkpoint blockade immunotherapy into more potent action with a drug cocktail contained in a nanoparticle. The nanoparticles assemble themselves from zinc and a drug called oxaliplatin, which is widely used against advanced-stage metastatic colon cancer. A photosensitizing agent called pyrolipid forms the outer layer. When light is shined on the pyrolipid it generates molecules that can kill cancer. It also activates T-cells that can recognize cancer cells, so the nanoparticles pack a triple punch.
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.