Division of Surgical Oncology, Massachusetts General Hospital
Harvard Medical School
Dr. Wargo runs a translational research laboratory studying the genetics of melanoma and other cancers with the goal of understanding what makes them able to grow, spread, and evade the immune system. Based on the findings from her laboratory, she is now studying the role of the tumor microenvironment and the immune system in targeted therapy. She is currently developing clinical trials incorporating what she has learned in the laboratory to treat patients with cancer. Her efforts in this regard have been nationally recognized, and she has several research grants for this work.
In addition to her important work in the laboratory, Dr. Wargo has focused on minimally-invasive surgical techniques for the treatment of pancreatic diseases, including pancreatic cancer. As part of the pancreatic surgery group at the Massachusetts General Hospital, she has contributed to improving the improving management for patients with pancreatic cancer and other pancreatic disease.
Among Dr. Wargo's awards are:
Zachary A Cooper, PhD
Dennie Tompers Frederick, MS
As part of the Surgical Oncology Research Laboratory, the Wargo Lab focuses heavily on Melanoma. Our lab is helps maintain the new MGH Melanoma Tissue Repository which currently, as of January 2013, holds over 550 frozen tumor samples and hundreds of PBL and serum samples of patients with melanoma. This growing repository is currently linked to a web-based clinical database. The efficiency and maintenance of this tumor bank has gained international notoriety for the quantity and variety of unique clinical samples.
Melanoma remains a major world health problem though recent advances in targeted therapy against oncogenic BRAF for melanoma have shown some promising results. Somatic mutations in the BRAF oncogene occur in over half of melanomas, with the vast majority of these harboring an activating point mutation (V600E). This oncogenic mutation leads to constitutive activation of the MAPK signaling pathway and increased oncogenic potential through a variety of mechanisms including reduced apoptosis, increased invasiveness, and increased metastatic behavior. Our lab has recently shown in vitro data also suggest that BRAFV600E could also contribute to immune escape. Targeted therapy against oncogenic BRAF for metastatic melanoma results in objective responses in the majority of patients whose tumors harbor BRAFV600E. Despite this, resistance to therapy remains a significant issue, with a median duration of response between 6 and 7 months. There is a great deal of ongoing research to determine mechanisms of resistance and strategies to overcome resistance. Multiple distinct mechanisms of resistance have already been identified in recent months.
Combination of BRAF-targeted therapy with other signal transduction inhibitors has been proposed based on evidence that other pathways become activated upon emergence of resistance and such clinical approaches are already underway. Another potential approach involves combining BRAF-targeted therapy with immunotherapy. This strategy is supported by data demonstrating that treatment of melanoma cells with BRAF-targeted therapy results in increased expression of melanocyte differentiation antigens (MDAs) and increased recognition by antigen specific T cells. We corroborated the results in tumor biopsies from patients with metastatic melanoma receiving BRAF-targeted therapy and CD8+ T cell infiltrate correlated with response to therapy.
We also demonstrated that BRAF-targeted therapy is associated with improved melanoma antigen expression and an enhanced immune response in patients with metastatic melanoma. We also assayed immune-modulatory cytokines and markers of T cell cytotoxicity as well as T cell exhaustion markers and the immunosuppressive ligand PDL1 to gain insight into potential means to modulate the immune response to BRAF inhibition.
We are currently expanding our studies to further characterize the tumor microenvironment to help understand potential way to modulate the immune system to improve responses to targeted therapies.
In our laboratory, we are currently studying several methods to improve pancreatic cancer treatment.
One method involves a better understanding of the mutations that develop in cancer cells in an effort to develop personalized cancer therapy. Once a mutation is identified, we can determine how that mutation affects the cancer and helps it survive despite treatment. We can also use drugs or medicines that specifically target that mutation to cripple the cancer and make it more responsive to treatment.
Another way to treat pancreatic cancer is through the use of immunotherapy. This type of therapy takes advantage of a person’s own immune system to fight their cancer. The immune system is made up of white blood cells that can recognize foreign invaders such as bacteria and viruses. These white blood cells, specifically the T cells, use a T cell receptor to identify foreign proteins (antigens) on the surface of invading organisms. T cells can also recognize and kill cancer cells, such as pancreatic cancer and melanoma, through this interaction.
We can capitalize on the power of the immune system to treat melanoma and other cancers. Non-specific forms of immunotherapy for melanoma are currently in use, though are not effective in all patients. One very effective treatment for patients with metastatic melanoma involves the use of tumor-infiltrating lymphocytes (TIL). This type of therapy involves removal of a tumor with the goal of growing the immune cells and re-infusion them into the bloodstream, causing shrinkage or disappearance of tumors in over half of treated patients. In addition, we have developed methods to genetically engineer T cells to express receptors targeting proteins on pancreatic cancer and melanoma, essentially giving them a “license to kill” the cancer cells.
At Mass General, I am currently working with other investigators to develop a Program for Immunotherapy for Cancer. Mass General has all of the critical components necessary for such a program, which will extend this promising form of therapy to many of our patients. Our efforts will initially focus on immunotherapy for pancreatic cancer and melanoma but our goal is to quickly bring this form of therapy in the treatment of other types of cancer. In addition, we are actively working on combining genetic approaches with immunotherapy to improve the care for patients with cancer.
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