The Fellows Grants support innovative research by a meritorious young investigator by presenting the Fellow with research funds to pursue an independent line of investigation within the context of his/her current Fellowship placement. By allowing a Fellow to acquire the equipment and supplies needed to pursue a new direction in his/her research program, the Fellows Grant assists the Fellow in developing preliminary data to support a future project or investigating a new technique that otherwise would not be possible in the absence of this funding.
2009-2010 AACR-Colorectal Cancer Coalition Fellows Grant, in memory of Lisa Dubow
Jeffrey Chou, M.D., Ph.D.
Fred Hutchinson Cancer Research Center, Seattle, WA
Project: Epigenetic Modulation of Colorectal Cancer Stem Cells for Immunotherapy
"Colorectal cancer (CRC) is one of the most common malignancies. Most patients with advanced or metastatic disease ultimately die from their cancer. Treatments may fail due to incomplete eradication of the CRC stem cell, which has the capacity to initiate and sustain tumor growth. Thus, an urgent need exists for effective systemic therapies that target and eliminate the CRC stem cell. Although promising for some cancers, immunotherapy for CRC has been hindered by a poor understanding of targets expressed on the CRC stem cell. The cancer/testis antigens (CTAs) are ideal targets for immunotherapy since they are restricted to expression in either cancer cells or in germline tissues which are inaccessible to the immune system. Furthermore, they can elicit robust immune responses. Although CTAs are not normally expressed by CRC cells, preliminary data demonstrate that expression of certain CTAs such as the highly immunogenic NY-ESO-1 can be induced by the drug decitabine in established CRC cell lines. This induction then allows for recognition and lysis of the CRC cells by cytotoxic T cells specific for NY-ESO-1. My project will determine whether decitabine induces NY-ESO-1 expression in CRC stem cells and whether this leads to their recognition and destruction by cytotoxic T cells. This will be evaluated in cell culture and mouse models. Results from my proposed studies may potentially provide pre-clinical data supporting a novel therapy using a combination of decitabine and immunotherapy for metastatic CRC. I am honored by and grateful for the generous support provided by AACR, the Colon Cancer Coalition, and the Lisa Fund, and I would like to thank my mentor Dr. Edus Warren, who has been invaluable in fostering my development as a cancer researcher."
2009-2010 AACR-FNAB Fellows Grant for Translational Pancreatic Cancer Research
Eric R. Lutz, Ph.D.
Johns Hopkins University, Baltimore, Maryland
Project: Tregs and the Pancreatic Cancer Immunotherapy Induced T Cell Repertoire
"Immunotherapy is an innovative approach being developed for the treatment of pancreatic cancer, a relatively chemotherapy-resistant disease. The goal for tumor immunotherapy is to train the immune system to see tumor cells as foreign, ultimately resulting in their destruction. This depends on the activation of immune effector cells capable of specifically recognizing antigens derived from proteins expressed by the tumor. Since most tumor antigens are self-antigens derived from proteins also expressed by normal cells, effective immunotherapy must also overcome natural mechanisms of immune tolerance that are necessary for preventing autoimmunity. We have developed a vaccine for the treatment of pancreatic cancer that consists of whole tumor cells genetically modified to enhance their ability to activate anti-tumor immune responses. So far, this vaccine has been tested in 3 completed clinical trials. These studies have shown that the vaccine is safe and capable of inducing tumor-specific immune responses. Importantly, these studies led to the identification of a new pancreatic tumor antigen, mesothelin, and have suggested that the post-vaccination induction of mesothelin-specific immune responses is associated with improved survival. These early studies have begun to increase our understanding of the quality of immune responses associated with improved clinical responses. Specifically, our results have suggested that the diversity and avidity of immune cells recognizing mesothelin are important parameters for predicting improved survival. More recently, data from our lab and others have suggested that selectively depleting regulatory T cells (Tregs), a T cell population present within the tumor microenvironment that can suppress tumor-specific immune cells, can enhance the efficacy of the vaccine. Currently, there are 2 therapeutic options capable of selectively inhibiting Tregs, a single intravenous dose or daily oral doses of the drug cyclophosphamide (Cy). In this study, we will compare the effects of both forms of Cy given in sequence with vaccine on both Tregs and mesothelin-specific immune responses. Specifically, we will assess how changes in the number and function of Tregs are associated with the post-vaccination induction of mesothelin-specific immune responses. Furthermore, we will correlate these changes with clinical responses. Results from this study will directly impact the design of future clinical trials. This study will also build on our prior studies evaluating mesothelin-specific immune responses and help determine which parameters of the immune response most accurately differentiate clinical responders from non-responders. Ultimately, these data will provide new insights into the development of improved vaccines for the treatment and prevention of pancreatic cancer. I am truly honored to receive the AACR-FNAB Fellows Grant for Translational Pancreatic Cancer Research during this early stage of my career. This award not only provides significant support for this project, but also serves as a foundation for my developing career as a tumor immunologist. I am also grateful to my long-time mentor Dr. Elizabeth Jaffee who's continued support has been invaluable throughout my training."
- View the list of previous AACR Fellows Grant Recipients