Frontiers in Basic Immunology: Celebrating the NCI Investment in Basic Immunology Research

The Center of Excellence in Immunology (CEI) is one of five Centers of Excellence in the NCI intramural research program (IRP). The mission of the CEI is to foster discovery, development, and delivery of novel immunologic approaches for the prevention and treatment of cancer and viral diseases associated with cancer. The CEI is headed by a steering committee that oversees a faculty of approximately 100 principal investigators and staff scientists. Membership spans 20 different CCR laboratories, programs, and branches and also includes representatives from the Division of Cancer Biology and the Division of Cancer Epidemiology and Genetics. CEI faculty members include a variety of accomplished researchers, including seven members of the National Academy of Sciences, five of whom are also members of the academy’s Institute of Medicine. This multidisciplinary organization represents a means to create the critical mass of basic, clinical, and translational scientists necessary to rapidly define new areas of opportunity and accelerate high-impact research in immunology and the development of immune-based approaches to preventing and treating cancer and cancer-associated viral diseases.

An important goal of the CEI is to facilitate information exchange and foster collaborations among NCI investigators, as well as other NIH scientists and the extramural research community. Consequently, the CEI has initiated an annual series of meetings on cancer-related immunology research. The first of these, “Translational Immunology Related to Cancer,” was held in 2005. On September 28–29 of this year, more than 700 scientists attended the second meeting in this series, “Frontiers in Basic Immunology.” This event represented a celebration of NCI’s long-standing support for basic immunology. Al Singer, MD, headed the scientific organizing committee, which included Jon Ashwell, MD, Larry Samelson, MD, Ron Gress, MD, Joost Oppenheim, MD, Scott Durum, PhD, Bill Farrar, PhD, and John Ortaldo, PhD. All of the speakers were outstanding scientists doing innovative research in basic immunology. A complete list of the presentations at the meeting can be seen at http://web.ncifcrf.gov/events/basicimmunology/program.asp and the talks can be viewed at http://videocast.nih.gov/PastEvents.asp?c=998.

Basic research in the CEI includes work being performed in several internationally renowned laboratories dedicated to understanding the development and regulation of the cellular components of immunity. Collectively, studies by CEI faculty have led to the identification of novel molecules and molecular pathways important for the normal development and function of lymphoid cells. Some of these discoveries include activation-induced T-cell apoptosis; identification of the role of DNA damage in thymocyte and B-lymphocyte survival and transformation; critical advances in protein ubiquitination and its role in inflammation; mechanisms mediating costimulatory signals between the T-cell receptor (TCR) and CD28; and the means to visualize TCR-induced signaling in single, living cells.

Members of the CEI are also leaders in the field of cytokine research. These powerful molecules are critical in the development of the immune system, as well as in host defense and tumor biology. Therefore, the identification of cytokines, defining their biological activities, and understanding their mechanisms of action are important components of the efforts of the CEI to reduce the burden of cancer. CEI investigators have contributed groundbreaking work in the discovery, characterization, and immunotherapeutic potential of numerous cytokines. For example, interleukin (IL)-1, IL-2, IL-3, IL-6, IL-8, IL-15, transforming growth factor-β (TGF-β), and monocyte chemotactic protein-1 (MCP-1) were all discovered/co-discovered by CEI scientists. Cytokines with rich clinical potential that are currently distinct areas of emphasis in the research of CEI faculty include IL-2, IL-7, IL-15, TGF-β, as well as several chemokines. The bench-to-bedside progression of IL-2 is an outstanding illustration of the integration of basic, translational, and clinical research by faculty of the CEI. IL-2 and components of its receptor were discovered by NCI researchers Frank Ruscetti, PhD, and Thomas Waldmann, MD, respectively. Work from the laboratory of Steve Rosenberg, MD, PhD, established the value of this cytokine in the treatment of advanced kidney cancer and melanoma, while Dr. Waldmann’s group demonstrated that antibodies blocking the α-chain of the IL-2 receptor are useful in treating T-cell leukemia, autoimmune disease, and graft-versus-host disease (GVHD).

Another bench-to-bedside project in the CEI deals with IL-15. Dr. Waldmann and co-workers in the Metabolism Branch are currently engaged in efforts to bring this promising molecule to the clinic. His group co-discovered this cytokine and have made several landmark discoveries and other advances in the field. These include discovery of two of the three components of the IL-15 receptor; demonstration that IL-2 and IL-15 share receptor components; development of mice transgenic for IL-15; demonstration that IL-15 enhances effectiveness of therapeutic cancer vaccines and increases survival in some murine models of cancer; developing new treatments for graft rejection, rheumatoid arthritis, and multiple sclerosis using antibodies to a subunit of the IL-15 receptor; as well as development of inter-institute collaboration (NCI with the National Institute of Allergy and Infectious Diseases [NIAID]) for GMP (good manufacturing practices) production of IL-15 for clinical trials. To facilitate efforts to bring IL-15 to the clinic, the CEI co-sponsored a meeting with the NIH Cytokine Interest Group entitled “IL-15: Basic Research and Clinical Applications.” This meeting, chaired by Dr. Waldmann and Howard Young, PhD, was held in Lipsett Auditorium on October 30, 2006. The speakers included leading IL-15 researchers from the NIH and the extramural research community. The program can be found at http://web.ncifcrf.gov/events/IL15/program.asp.

Other examples of CEI faculty translating advances in basic research into the clinic include development of a human papillomavirus (HPV) vaccine that could save up to 150,000 lives a year, a recombinant immunotoxin that has proved very effective against refractory hairy cell leukemia, and a cell-based therapy for the treatment of refractory metastatic melanoma that has resulted in improvement in 51% of patients involved in clinical trials. In addition, Dr. Rosenberg and colleagues recently demonstrated the potential for using a gene-therapy approach to re-educate a cancer patient’s immune system to treat refractory metastatic melanoma. Thus, work from scientists within the CEI has shown that strong basic research in immunology can fuel the translational and clinical advances that contribute to the NCI mission of reducing death and suffering from cancer and diseases such as AIDS.

Those interested in learning more about the current activities and future plans for the CEI are encouraged to attend a steering committee meeting, held the third Monday of each month. More information on the CEI can be found at http://home.ccr.cancer.gov/coe/immunology or by contacting Diana Linnekin, PhD, at dlinnekin@ncifcrf.gov.

Robert H. Wiltrout, PhD
Director

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