The last day of the ASCO meeting featured talks on immunotherapy for pancreatic cancer, one of the deadliest and hardest-to-treat cancers. Unlike many other cancer types discussed at the meeting, pancreatic cancer is one of the few that has so far resisted checkpoint blockade therapy. Drugs targeting the CTLA-4 and PD-1 checkpoints do not appear to have any effect in this disease, at least when used by themselves. “Largely futile,” was how Tanios Bekaii-Saab, M.D., of The Ohio State University, described the approach.
The reason for that lack of effectiveness stems from the fact that pancreatic cancer is a highly immunosuppressive tumor: very few of the immune system’s attack cells called T cells are found within the tumor. In the parlance of scientists, they are “excluded.” Checkpoint inhibitors, which release the brakes on T cells, can only work if T cells are present in the first place.
For that reason, much work in the field is focused on reducing the immunosuppressive environment in pancreatic cancer and jumpstarting an immune response. One way that researchers are trying to accomplish these twin aims is by combining chemotherapy with cancer vaccines. The chemotherapy helps to kill off immunosuppressive cells in the tumor, while the cancer vaccine tries to get an immune response started.
As Dr. Bekaii-Saab discussed, a phase II trial is currently testing the combination of cyclophosphamide, a chemotherapy, with two different cancer vaccines called GVAX and CRS-207. GVAX is made up pancreatic cells that have been genetically modified to express a cytokine called GM-CSF, which stimulates antigen-presenting cells to start an immune response. CRS-207 is a modified version of a Listeria bacterium that has been genetically engineered to produce a cancer antigen called mesothelin, which is found in nearly 100% of pancreatic cancer tumors. By combining these three therapies, it is hoped that the immune system will be empowered to attack the cancer. CRI Scientific Advisory Council member Elizabeth Jaffee, M.D., of Johns Hopkins, is leading the trial.
Another approach, being pursued by CRI-funded investigators Carl June, M.D., and Gregory Beatty, M.D., Ph.D., both of the University of Pennsylvania, as part of a jointly funded CRI and Lustgarten Foundation grant, is to use chimeric antigen receptor (CAR) T cells directed at mesothelin. CARs are genetically engineered receptors that join the antigen-binding region of an antibody to the signaling domain of a T cell receptor; they turn a patient’s own T cells into powerful weapons against cancer. Dr. Beatty presented the results of a phase I trial using this approach at ASCO yesterday. On the whole, the approach seems safe, and demonstrated some efficacy, although the effect was modest—especially when compared to the dramatic results obtained with CAR T cells directed at the CD19 antigen found on B cell leukemias.
There is clearly more work to be done on developing immunotherapies for pancreatic cancer.
So concludes the annual meeting of ASCO—with high notes of optimism for the applicability of checkpoint blockade in multiple tumor types, and clearly articulated calls for further research to understand why some patients respond to these therapies while others do not.
I’m looking forward to the next big scientific meeting in cancer immunotherapy, the inaugural International Cancer Immunotherapy Conference: Translating Science Into Survival, sponsored jointly by the Cancer Research Institute, the Society for the Immunotherapy of Cancer, the European Academy of Tumor Immunology, and the American Association for Cancer Research. The four-day conference takes place September 16-19, 2015, at the Sheraton New York Times Square Hotel in New York City. I’ll be sharing updates from what is sure to be a deeper dive into the latest science underpinning this important new approach to treating cancer.