Mesothelin is expressed by 100% of pancreatic cancers, and the more mesothelin, the worse the survival. It seems an important protein to target.— Elizabeth Jaffee, MD
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Pancreatic cancer has been notably unresponsive to immunotherapeutic approaches, but a Stand Up 2 Cancer Dream Team believes their research can change that. Team co-leader Elizabeth Jaffee, MD, Deputy Director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, described some of the key initiatives for The ASCO Post.
Dr. Jaffee’s Dream Team is using a “convergence” approach by bringing together experts in the fields of immunotherapy, genetics, informatics, biostatistics, regulatory/clinical trials, cancer biology, and pathology. They are developing strategies to identify and overcome novel immunosuppressive pathways within pancreatic cancer and to use a T-cell–activating vaccine to supercharge the immune system and make it more responsive to other immunotherapies.
“With vaccines, we are able to bring in lymphoid aggregates composed of T cells that are able to recognize cancer and other cells that help educate the T cells, such as dendritic cells (ie, antigen-presenting cells), which essentially direct the orchestra, the immune system,” Dr. Jaffee explained. “But when the T cell comes in, adaptive resistance can occur—that’s what the checkpoints do. Now we have to figure out what these checkpoints are.
“I think we will begin to see progress in cancers that do not naturally respond to one or two checkpoint inhibitors on their own. In them, you will need to induce the T cell first and then figure out how to overcome the checkpoints,” she suggested. “The opportunity is there for us to take a previously deadly disease and make it treatable—by focusing on how the immune system shapes cancer and how we can alter it so that instead of helping the cancer develop, it fights the cancer.”
Novel Vaccine Approaches
Toward this effort, Dr. Jaffee’s team has pioneered several exciting strategies, including the following:
- A vaccine that directs the immune system toward the KRAS mutation, which is common in premalignant lesions. In a mouse model, the vaccine has prevented progression to cancer in 40% of animals. This would be a pancreatic cancer prevention strategy for persons at high risk.
- A neoadjuvant vaccine that is administered 2 weeks before resection, with additional injections later. Biopsy of the surgical sample shows that the vaccine is powerful enough to draw lymphocytes into and around the tumor. Microdissection and gene analysis of the lymphoid aggregates have revealed the signals that are occurring in this environment, including downregulation of regulatory T cells, which hamper the immune response, and upregulation of T helper cells.
- The dendritic pancreas vaccine, GVAX, used in combination with other approaches in metastatic disease. GVAX is being combined with CRS-207 (described below) and with ipilimumab (Yervoy). Both approaches have demonstrated improved survival.
Studies of Immunotherapy Combinations
CRS-207 is a live but attenuated Listeria monocytogenes strain aimed to induce an immunologic response specific to the antigen, mesothelin, which is overexpressed in pancreatic adenocarcinoma. GVAX is a biologic that stimulates granulocyte-macrophage colony-stimulating factor (GM-CSF), which boosts the immune system. In a study of 90 patients with metastatic disease, the GVAX/CRS-207 immunotherapy combination improved overall survival compared with GVAX alone and showed that enhanced mesothelin-specific CD8-positive T-cell responses were associated with longer survival.1
“It is important to know what the pancreatic cancer expresses—what proteins—that are different from normal tissue. We have looked at this from the immune cells of patients who respond to the vaccine and found that the immune system is reacting to mesothelin. Mesothelin is expressed by 100% of pancreatic cancers, and the more mesothelin, the worse the survival. It seems an important protein to target. We found that patients who have long-term survival with the GVAX/CRS-207 strategy have developed a strong immune response against mesothelin and have maintained it.”
Disease-free survival has ranged from about 3 years to as long as 15 years in some of these patients, although in patients with more advanced disease, survival has not been improved over chemotherapy. “This is not unanticipated,” commented Dr. Jaffee, “since in advanced disease, we will probably also need to inhibit checkpoints.”
Vaccines for Pancreatic Cancer
- A Stand Up 2 Cancer Dream Team is evaluating the use of a GM-CSF cell-based vaccine, GVAX, in conjunction with checkpoint blockade. The combination of GVAX plus ipilimumab was shown to improve survival compared with checkpoint blockade alone.
- The team is also evaluating the benefit of combining GVAX with CRS-207, an attenuated Listeria monocytogenes strain that can induce an immunologic response specific to the antigen, mesothelin, which is overexpressed in pancreatic adenocarcinoma.
- Vaccines are being studied in the neoadjuvant setting and, at least in mouse models, as a means of cancer prevention in high-risk individuals.
Dr. Jaffee explained that, in pancreatic cancer, a one-two punch that enlists a vaccine to induce the killer T cell and one or more agents to enhance killer T-cell function will be needed. Using GVAX, CRS-207, or a checkpoint inhibitor alone does not achieve the total effect. “If you give a drug that only activates the T cell, you don’t get a great response. You must give the vaccine to induce the T cell,” she indicated.
In a study of 30 previously treated patients, ipilimumab plus GVAX led to prolonged disease stabilization in some patients and declines in CA 19-9 levels and more than tripled the rate of 1-year overall survival (27% vs 7%), compared with ipilimumab alone.2 Again, an increase in peak mesothelin-specific T cells and enhancement of the T-cell repertoire were observed with the combination. This immunotherapy combination approach has even been successful in patients whose life expectancy is 3 months or less, reported Dr. Jaffee.
“A follow-up study is ongoing, but it is too early to know the results. We also have a study with GVAX/Listeria plus anti–PD-1 [programmed cell death protein 1] that is ongoing but also too early to tell,” Dr. Jaffee said. “We are making progress, but it’s going to take another 5 to 10 years to figure out the best combinations. Ideally, the best place to use them for long-term benefit is in early disease: targeting the earliest genetic changes to prevent the additional genetic changes that occur and lead to cancer.” ■
Disclosure: Through a licensing agreement with Aduro Biotech, Dr. Jaffee has the potential to receive future royalties and has also received research funding from Aduro Biotech and Bristol-Myers Squibb.
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