AACR Highlights: Saturday, September 7
The tumor microenvironment. Genomics. Immunology. These interrelated topics were the focus of the first three plenary sessions of the AACR special conference on pancreatic cancer held Saturday, September 7.
In terms of pancreatic cancer treatment, these areas of research potentially hold many of the answers to unraveling current barriers to more effective therapies. Here are just a few highlights of the incredible research presented.
One question confounding researchers and clinicians is why do approximately 80% of patients have a recurrence of the disease after undergoing surgery for pancreatic cancer? One way to potentially find an answer and to improve those odds is by studying the evolutionary mechanisms underlying the disease, which was the focus of the presentation by Christine A. Iacobuzio-Donahue, M.D., Ph.D. (Memorial Sloan Kettering Cancer Center, New York), “Multimodal evolutionary dynamics of pancreatic cancer.” It seems that some mutations pre-exist in a subset of cells within the primary tumor and are characteristic of recurrent pancreatic cancer. By tracking these mutations in patient samples, her research shows that metastases can lead to a local recurrence in the pancreas, and metastases can seed other metastases.
Breaking Down Drug Resistance
The tumor microenvironment, or TME, confers resistance to many cancer treatment regimens, especially that of immunotherapy which, very simply, is using the body’s own natural immune defenses—T cells and other immune cells—to fight the cancer. So far, pancreatic tumors, as well as other so-called “cold”tumors, have been tough to treat with current immunotherapy approaches. One problem often cited is that of the pancreatic cancer stroma, a dense matrix of cells surrounding the pancreas, which doesn’t allow current treatments to reach the malignancy. In a presentation titled the “Immune contexture of human pancreatic cancer,” Lisa Coussens, Ph.D. of Oregon Health Sciences University (Portland), theorized the physical barrier of the stroma isn’t completely to blame. Rather, part of the issue may be due to an acquired network of oncogene (a gene that can transform a normal cell into a tumor cell) and microenvironmental-driven immunosuppressive networks that minimize effective T cell responses. Very simply, it seems the microenvironment of early stage pancreas cancer has a very distinct immune cell composition compared to late stage disease. And the microenvironment of late stage primary disease is also distinct from the microenvironment of metastatic pancreas cancer. For patients, it’s these distinctions that will provide deeper insight into ways immune system response can be improved at these different stages, potentially making immune treatment more effective.
Finding Immunotherapy Targets
One highlight of the many interesting immunology presentations was “Targeting pancreatic cancer with TCR-engineered T cells” given by Phil Greenberg, M.D., of the Fred Hutchinson Cancer Research Center, Seattle, Washington. His presentation focused on mesothelin-specific T cells and CAR T-cell therapy. CAR T-cell therapy is one potentially promising immunotherapy strategy to treat pancreatic cancer. It involves engineering a patient’s own T cells to fight their cancer. But finding a target is key, which is why researchers are interested in one so-called tumor-associated antigen called mesothelin, which is overexpressed in pancreas and other cancers. In pre-clinical work, Greenberg showed these T cells can enter the pancreas of a genetically-engineered mouse model, essentially remodeling or changing the tumor stroma, improving vessel patency (the likelihood that a vessel will remain open) and inducing tumor cell apoptosis or cell death. He also outlined ongoing work to identify the best targets in the tumors so that the engineered T cells can be most effective.
Stay tuned for highlights from Sunday, September 8, the second day of plenary sessions . .