Translational Immunology Related to Cancer: Meeting Highlights

he Center of Excellence in Immunology (CEI) is one of four Centers of Excellence in the NCI Intramural Research Program (IRP). The mission of the CEI is to foster the discovery, development, and delivery of novel immunologic approaches for the prevention and treatment of cancer and cancer-associated viral diseases. To create opportunities for immunologists to exchange information and to facilitate collaborations, 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 September 22 and 23, 2005, in the Masur Auditorium in Building 10. Dr. Jeffrey Schlom headed the Scientific Organizing Committee, which included Drs. Steven Rosenberg, Tom Waldmann, Ron Gress, and Jay Berzofsky. Speakers included scientists in the CCR and distinguished invitees from the extramural community. More than 600 scientists attended, and approximately half were from outside the NIH. Highlights of presentations by senior CEI members are described below.

Introductory Comments

Dr. Robert Wiltrout, head of the CEI, introduced the center, describing a faculty of approximately 200 scientists with expertise in the fields of immunology, virology, and epidemiology. Dr. Wiltrout emphasized the importance of this venue for integrating basic and clinical research and accelerating the translation of research into treatments for cancer. Dr. Andrew von Eschenbach next welcomed participants and described his vision of the NCI IRP as an organization that “serves, catalyzes, and leads the scientific field with research and rapid translation.”

Monoclonal Antibodies and Cytokine Session

Dr. Tom Waldmann of the Metabolism Branch provided an overview of his pioneering work on interleukin-2 (IL-2) and IL-15. He discussed his work in defining the contrasting role of these cytokines in regulating the immune response, developing humanized antibodies to components of the receptors, arming the antibodies with toxins or isotopes, and using them as treatments for cancer and other diseases of the immune system.

Dr. Wiltrout presented translational studies on the use of IL-2 in combination with either IL-12 or antibodies to CD40. He showed data from phase I studies in which IL-12 and IL-2 were administered to patients with advanced solid tumors. As part of studies directed toward identifying potential mechanisms of cytokine action, his group in the Laboratory of Experimental Immunology investigated the role of interferon-γ (IFNγ) induction in the antitumor effects of various cytokines. He shared intriguing findings that indicate contrasting roles for IFNγ in tumor growth and metastases, as well as antitumor immunity.

Dr. Ira Pastan of the Laboratory of Molecular Biology discussed his work targeting specific antigens on cancer cells, including CD22, mesothelin, and the epithelial growth factor (EGF) receptor, with recombinant immunotoxins (RITs). In phase I trials, treatment with an immunotoxin targeting CD22 has resulted in complete remissions in a high percentage of patients with refractory hairy-cell leukemia. He indicated that phase II trials using RITs to treat hairy-cell leukemia, other B-cell malignancies (BL22), mesothelioma, ovarian cancer (SS1P), and glioblastoma (TP38) are in progress or will open soon. He also showed follow-up work identifying new targets on the surface of malignant cells, as well as approaches to increase the potency and reduce the immunogenicity of RITs.

Cell-Based Therapy Session

This session began with Dr. Nick Restifo of the Surgery Branch discussing innovative, preclinical studies of adoptive cell therapy in murine models of melanoma. Dr. Steven Rosenberg, head of the Surgery Branch, followed, demonstrating how information from these animal studies has been successfully translated into treatments for patients with advanced melanoma. He showed exciting results of a cell-based therapy of refractory metastatic melanoma: In brief, there has been a 50% response rate using this approach. Dr. Rosenberg also described work in using this approach to treat lung, breast, and prostate cancer.

Vaccine Session

Dr. Jay Berzofsky of the Vaccine Branch talked about improving vaccine design by blocking inhibitory pathways in the immune system. He described elegant basic research demonstrating natural killer T cell (NKT)–dependent increases in secretion of transforming growth factor-β (TGF-β) by myeloid cells that suppress induction of CD8-positive cytotoxic T lymphocytes. He then followed up with a discussion of translational work showing the role of this pathway in tumor immunosurveillance in animal models and the ability to improve cancer vaccine efficacy by blockade of this pathway.

Dr. Jeffrey Schlom of the Laboratory of Tumor Immunology and Biology spoke about comprehensive studies with vaccines developed in his laboratory. He described bench-to-bedside work with TRICOM vaccines, a class of vaccines designed to enhance immune response through inclusion of genes for three T-cell costimulating molecules and tumor antigens into viral vectors. He showed data illustrating a dramatic increase in avidity of cytotoxic T lymphocytes in response to TRICOM vaccines and also reported exciting new work that combines primary vaccination with intratumoral vaccination, or targeted radiation. Dr. Schlom concluded with the suggestions that sole dependence on reduction in extensive tumor burden in early clinical trials could be inappropriate to monitor vaccine efficacy and that increased survival in patients with limited disease might be a more appropriate paradigm.

Dr. James Yang of the Surgery Branch gave a provocative overview of the challenges in developing cancer vaccines to successfully treat solid tumors. He noted the low percentages of objective responses (3.9%) of patients receiving tumor vaccines in the published literature and described a number of strategies his group is pursuing, aimed at increasing successful outcomes. He also cautioned that while an increase in antigen-specific T cells is an important component of vaccine response, tumors often recur despite this increase. He emphasized that understanding how to induce existing tumor-reactive T cells to reject tumor cells is another important milestone in designing effective vaccines for cancer.

Dr. Doug Lowy of the Laboratory of Cellular Oncology described the bench-to-bedside progression of a vaccine designed to prevent infection with human papillomavirus (HPV). Cervical cancer is the third most common cancer among women worldwide and is caused by infection with a subset of HPVs. Phase II trials with commercially produced versions of this vaccine have demonstrated a high level of protection against HPV infection. Phase III trials, directed by Dr. Allan Hildesheim in the Division of Cancer Epidemiology and Genetics, are under way.

Transplantation and Antitumor Therapies

Dr. Ron Gress of the Experimental Transplantation and Immunology Branch presented studies that provide new insight into mechanisms mediating production and maintenance of T lymphocytes of thymic and peripheral origin. These include advances in understanding regulation by cytokines such as TGF-β, IL-7, IL-15, insulin-like growth factor-1 (IGF-1), and keratinocyte growth factor (KGF). He provided compelling evidence underscoring how this information is contributing to clinical strategies that use immunotherapies such as tumor vaccines and adaptive cell transfer to treat T-cell lymphopenia associated with transplantation, cancer, HIV, and chemotherapy.

Dr. Crystal Mackall of the Pediatric Oncology Branch spoke of her work on homeostasis of T regulatory cells during chemotherapy-induced lymphopenia. She demonstrated that lymphopenic patients can have enrichment, of relative frequency, of CD4-positive, T regulatory cells and showed that IL-2 increased T regulatory cells, particularly during lymphopenia. In contrast, IL-7 increased CD4 and CD8 cells, but did not increase CD4-positive, T regulatory cells. She concluded with the suggestion that depleting T regulatory cells while treating lymphopenia could be a useful tool to amplify antitumor response.

Additional Information and Plans for Future Meetings

Information on the CEI can be found on the CEI Web site. Dr. Diana Linnekin can be contacted at dlinnekin@ncifcrf.gov for additional information on CEI activities.

The next meeting in the CEI series on Cancer and Immunology is tentatively planned for the fall of 2006 and will deal with “Basic Immunology Related to Cancer.”

Figure 1. The poster session, held on the afternoon of September 22nd, drew a large crowd and fostered a lively scientific exchange.

Figure 2. Dr. Doug Lowy presents work on vaccines to prevent infection with human papillomavirus at the Translational Immunology Related to Cancer Meeting.

Diana Linnekin, PhD