The Next Frontier
We all like a good story, and as you know, a good story has a beginning, a middle, and an end. Our apologies right up front, because the end of this story is not quite finished.
This is a story about pancreatic cancer. To be more specific, it’s a story about the efforts of scientists who are working tirelessly to develop a vaccine to prevent pancreatic cancer. Oh, and you will need to expand your concept of superheroes. In this story, our heroes wear lab coats. They are not afraid to take on the most difficult challenges, and they simply will not give up.
Our villain is pancreatic cancer. Of all types of cancer it is the most deadly, with less than 6% of patients surviving after five years. It is extremely difficult to diagnose it early, when it would be easier to treat. And, not only is it often diagnosed too late for it to be removed by surgery, but it is highly resistant to chemotherapy. So far, the villain is in the lead.
The Beginning
Not so very long ago, scientists began discovering ways to successfully fight certain kinds of cancer. They already knew that vaccines could stimulate the immune system to fight infectious entities, and they were able to create vaccines against certain viruses, such as human papilloma virus (HPV), that play a role in stimulating the growth of cancer. Yvonne Saenger, MD, Assistant Professor of Medicine at Columbia University Medical Center and a pioneer in the field of immunotherapy, explains that the HPV vaccine prevents HPV from infecting the cells in the cervix. By educating the immune system to act against that specific pathogen, the vaccine prevents the virus from taking hold and progressing to cancer.
Unfortunately, not all cancers have infectious causes that can be identified and targeted this way, and treating a full-fledged cancer is far more difficult than preventing it. One reason is that many types of cancer cells are similar enough to normal cells that the immune system cannot distinguish between them very well. Another is that cancer has the ability to suppress the immune system, effectively shutting off its normal processes. As a result, scientists found that despite their very best efforts, they were not able to develop vaccines that worked well against many types of cancer.
However, our heroes didn’t give up, and beginning in about 2005, they found success through a different approach. Rather than trying to prevent the cancer by attacking the cancer cells directly, scientists working on melanoma found they could reactivate components of the immune system, bolstering them to fight off the cancer. The approach, called tumor immunotherapy, showed dramatic success in reducing the toll of melanoma. In just ten years, long-term survival for patients with metastatic melanoma has risen from 5% to over 50%.
The Middle
Armed with encouraging results in melanoma, Dr. Saenger and colleagues at NYP/Columbia are now working to apply those successes to pancreatic cancer. If you suspected there might be more challenge or conflict, you were right; pancreatic cancer is more difficult to treat than many others, for several reasons. One is that the immune system’s response against pancreatic cancer is not very strong – there are simply fewer T cells present in pancreatic tumors, so “there is less to work with” in trying to stimulate an immune response, says Dr. Saenger. Second, pancreatic tumor cells are highly skilled at subterfuge. They protect themselves against the immune system by creating a shell of fibrous material. Third, pancreatic cancer cells have a particular talent for attracting special cells that dampen the immune response.
This is where the story becomes interesting. The general consensus among experts currently studying pancreatic cancer is that immunotherapy will eventually work. “We may need to bring the vaccine concept back in and induce immunity,” says Dr. Saenger. She and other scientists are testing several approaches at this time, including vaccines based on bacteria that could eventually be combined with immune stimulators. As she explains, “The strongest types of vaccines are pathogen-based. The immune system is designed to protect us against infectious stimuli, so vaccines using bacteria as delivery systems may be best.”
One approach under study at NYP/Columbia uses listeria bacteria combined with mesothelin, a protein that is found in excess amounts in certain cancers including pancreatic cancer. The listeria stimulates an inflammatory response, although it has been attenuated (genetically modified) so that it cannot spread from cell to cell and make patients too sick. The listeria-mesothelin combination is administered intravenously, and the hope is that the combination will penetrate into the inside of the tumor cells, where the intracellular bacteria will induce a strong immune reaction.
A study of this agent, initiated several years ago with Dr. Robert Fine and now directed by Dr. Paul Oberstein in the Division of Hematology & Oncology, is comparing listeria alone, listeria plus GVAX, and chemotherapy, to determine whether they are safe and whether they work better than chemotherapy in treating patients with advanced pancreatic cancer. For those wanting the details, the GVAX pancreas vaccine contains GMCSF, or granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells, and is designed to induce immunity to cancer antigens including mesothelin. It is administered with chemotherapy drug cyclophosphamide.
So far the team has found that patients treated with listeria combined with GVAX fared better than those who received GVAX alone; these early results were published in the Journal of Clinical Oncology in January, 2015. Additional trials opening soon will expand this line of inquiry.
In addition to investigations in immune therapy, Dr. Saenger is also tackling pancreatic cancer from another important angle, the identification of biomarkers. The goal is to identify a genetic signature that can be used to predict which patients will respond to which kinds of therapies. This approach was advanced in patients with melanoma first, and work is now underway in pancreatic cancer as well, in collaboration with Dr. Kenneth Olive. “Some pancreatic patients have more immune response than others. Finding them is important so that we can give patients better targeted therapies,” says Dr. Saenger.
Another approach under investigation is called ‘micro-satellite instability testing.’ This entails identification of patients with pancreatic cancer who have a greater number of genetic mutations due to deficiencies in DNA repair. Because their tumors are better differentiated from the native immune system, they may respond better to immunotherapies. Dr. Saenger is also planning to open a trial of oncolytic viral therapy combined with checkpoint blockade, which harnesses the power of a virus that is engineered to attack cancer by activating the T cells.
How this story ends remains a question, but Dr. Saenger is optimistic that it will, in time, have a happy ending. Stay tuned.