Immunotherapy is no longer a treatment of the future. At City of Hope, researchers are now advancing immunotherapy as an approach to treat and cure devastating illnesses — conducting innovative research in the laboratory, even while improving lifesaving standard treatments in the clinic.
Researchers in the Cancer Immunotherapeutics Program are pioneering this science to harness the power of the human immune system and create more powerful, less toxic cures. In recent months, these scientists have made great strides that will change the way in which people with cancer and other diseases are treated — and ultimately, cured.
Here are synopses of some of their work.
One step closer to the clinic: A targeted approach to cancer treatment
The immune system is a powerful, largely untapped force for fighting tumors. City of Hope’s scientists have developed a number of revolutionary therapies that harness immune cells to block the growth and proliferation of cancers.
Hua Yu, Ph.D., and her colleagues have devised a novel biologic-based drug called CpG-STAT3 siRNA that strikes a dual blow against cancer. It blocks the growth of tumor cells directly, and activates surrounding immune cells to attack the tumor. This drug takes advantage of two components, which block production of the cancer-promoting and immunosuppressive protein STAT3, and direct the therapy specifically to immune and tumor cells.
Of note, CpG-STAT3 siRNA overcomes the limitations of small molecule drugs, which are difficult to design against proteins such as STAT3 that have no enzymatic activity. It also serves as a unique therapeutic platform, as the siRNA can be designed to block virtually any protein of interest that is important for cancer growth and proliferation.
In preclinical studies, CpG-STAT3 siRNA effectively stymied growth of aggressive lymphomas and the brain cancer glioma, two deadly cancers with no current viable therapies. A clinical grade CpG-STAT3 siRNA is scheduled to begin production at City of Hope’s facilities this year, and Yu and her colleagues are poised to take this leading-edge therapeutic strategy to first-in-human clinical trials within two years.
Refining the promising CpG-siRNA approach
In a related effort, Marcin Kortylewski, Ph.D., is studying the intracellular processing of CpG-siRNA to identify molecular mechanisms needed to make the silencing of cancer-causing genes more effective. As a part of this effort, Kortylewski is broadening his understanding of TLR9, the protein responsible for recognizing pathogens and infectious agents like cancer cells, and then, activating the body’s immune cells against those pathogens.
In mouse studies, Kortylewski demonstrated that the TLR9 protein helps the foreign siRNA therapeutic escape endosomes (which are responsible for moving and sorting proteins throughout the body, specifically, plasma) and reach cytoplasm. There, the therapeutic silences overexpressed STAT3 proteins.
Kortylewski now seeks to verify whether TLR9 perform the same function for siRNA in human immune and cancer cells. The results of this investigation will ultimately help improve the CpG-siRNA therapeutic for clinical use.
Identifying the connection between STAT3 and diabetes
It has long been established that obesity is a major cause of type 2 diabetes, due in part to specific cells in fat tissue that promote pathogenic T cells and blunt the activity of insulin. Yu is exploring the connection between STAT3 and the development of diabetes.
In efforts to learn more about this potential link, her lab has used genetically-engineered mice whose T cells lack the STAT3 gene. When these mice became obese through forced consumption of a fatty diet, they showed better glucose tolerance compared with comparably overfed normal mice, as well as a shift in the balance of pathogenic T cells toward regulatory T cells. These intriguing findings suggest that STAT3 is common to both cancer and diabetes and suggest that anti-STAT3 therapies, which have thus far been considered primarily for cancer, might also be effective against type 2 and perhaps type 1 diabetes.
Seeing the invisible
Andrew Raubitschek, M.D., continues to develop intraoperative optical imaging (IOOI), a tumor-mapping technique that can visualize tumors to subcellular resolution in real-time.
Prior to robotic surgery, patients are given an optically tagged antibody that fluoresces. The fluorescent antibody is engineered to target the tumor — to locate and attach to specific molecules such as those found on cancer cells. Once it arrives, the antibody attaches to all cancerous cells and fluoresces to “color” the tumor. Then, specially designed lasers and optics attached to the surgical robot illuminate and detect the glowing cells. This shows the surgeon exactly what to take out.
Raubitschek is partnering this technique with a microscope attached to a fiber optic cable to allow for enhanced images of specific areas of tissue. Typically used for scoping procedures, the microscope is attached to one arm of the surgical robot. This allows surgeons to identify cancerous cells with the fluorescent imaging, then zoom in with the scope to find and remove all remaining cancer, no matter how small.
The fluorescent antibody has been produced and animal toxicity studies of the agent commenced this summer. Raubitschek and his team are also working on the investigational new drug application to the Food and Drug Administration. Although this approach will be first studied in patients with prostate cancer, Raubitschek aims to extend this technique to patients diagnosed with breast, lung, ovarian and colorectal cancers.
City of Hope will be the only surgical center in Southern California offering patients IOOI with tagged antibodies — pioneering a new approach to surgery here and across the nation.
Reclaiming the immune system
Peter P. Lee, M.D., seeks to utilize immunotherapy as a less toxic approach to treating patients diagnosed with breast cancer.
Many researchers focus on attacking the cancer cell itself, but Lee aims to target the cancer cell as well as its ‘co-conspirators’ — support cells within the tissue stroma and tumor microenvironment. In order to survive, cancer cells recruit and manipulate these support cells, and as a result, a patient’s immune system is destroyed.
Right now, Lee is studying these co-conspirator cells to broaden his understanding of their interactions. By gaining a better understanding of the ways they help feed cancer cells, he may be able to develop therapeutics that target both malignant cells and their supporting cells — thereby, restoring and enhancing the immune function in patients with breast cancer.
Through their efforts, these researchers are creating better treatments and cures for millions of people worldwide.