Our Science – Restifo Website

Nicholas P. Restifo, M.D.

Surgery Branch Tumor Immunology Section Senior Investigator CRC/10, Room 3-5762 NCI-Bethesda Bethesda, MD 20892 Phone:   301-496-4904 Fax:   (301) 451-6949 E-Mail:   restifo@nih.gov

Biography

Dr. Restifo, a 1983 honors graduate from Johns Hopkins University, obtained his M.D. in 1987 from New York University. He held fellowships at the Memorial Sloan-Kettering Cancer Center and the NCI before becoming a principal investigator in 1993. He is a mentor for research scholars for the Howard Hughes Medical Institute.

Research

Designing Potent New Cancer Immunotherapies

Our goal is to design new immunotherapies for patients with advanced cancer. Our strategy is based on the use of animal models and human in vitro assays to test hypotheses. We then translate the most promising of these therapies into human clinical trials, which often generate new questions to be tested experimentally. The process is an iterative one that involves close collaboration with basic researchers, biotech scientists and experimental clinicians.

We also have a longstanding interest in the development of therapeutic cancer vaccines. We have found that current cancer vaccines, used alone, are insufficient to reliably induce the objective regression of established cancers in mice or patients. These findings have led us to return to basic efforts to build better vaccines and to use them in combination with other immunotherapeutic modalities. Great progress has been made in the use of vaccination in combination with immunotherapies based on the adoptive transfer of T cells. We have recently made significant advances in identifying the phenotypic and functional qualities that characterize T cells that cause tumor regression. We have also explored the use of cytokines (especially IL-15 and IL-21) to enhance the antitumor efficacy of vaccine and adoptively transferred cells. Perhaps most significantly, we have very recently found that immunodepletion prior to the adoptive transfer of T cells can greatly enhance therapeutic efficacy. These new immunotherapies have all been extensively modeled in mice. Our ongoing work, although interwoven, has been broken down into three parts in this report:

Background - Identifying the antigens - Developing the vaccines

Current therapeutic cancer vaccines used alone may be insufficient to reliably induce the objective regression of established cancers in mice or patients. Nevertheless, the identification of new tumor-associated antigens recognized by functional, high-avidity T cells remains important goals. We have identified 5 new human antigenic epitopes: Three HLA class II epitopes derived from proteins known to express class I epitopes include gp100, TRP-1 and NY-ESO-1. These epitopes are presented by class II-expressing melanoma cells and are recognized by human CD4+ T cells. We also identified two other proteins, called OA1 and P polypeptide, that had not been previously known to be targets of an antitumor response in mouse or in man.

Although the current cancer vaccines used do not reliably cause tumor regression, recombinant and synthetic immunogens targeting specific tumor-associated antigens can stimulate T cells that specifically recognize tumor targets. Our preclinical efforts have been translated into clinical trials in collaborations for preclinical work and clinical trial design between Drs. Restifo and Rosenberg, together with our clinical team. We have used epitope enhancement, vector improvement (including promoter optimization), cytokines, chemokines and co-stimulatory molecules to enhance therapeutic efficacy of anti-cancer vaccines and we have extensively studied the mechanisms involved in the immunogenicity of new vectors developed in our laboratory, including poxvirus-based vaccines and of replicon-containing 'naked' nucleic acid vaccines.

Cancer vaccines and adoptive cell transfer-based immunotherapies have been developed and tested by creating new mouse models to study the treatment of large, established cancers.

Mouse models continue to be useful tools in the development of immunotherapies for patients. We had previously used 'model' tumor antigens. Subsequently we identified important murine ortholog genes for human tumor rejection antigens and cloned them into recombinant immunogens. We have developed many new T cell receptor (TCR) transgenic mouse strains, including pmel-1 which is based on a clone we previously described several years ago. In pmel-1, virtually all (>95%) CD8+ T cells express a TCR capable of recognizing an epitope from gp100 presented both the B16 tumor and melanocytes. Because of a large worldwide demand for these mice, we have recently deposited the pmel-1 TCR transgenic strain at the Jackson Labs, and they will soon be widely available to everyone. Another useful new transgenic mouse developed in our laboratory, named JR209, is a human/mouse chimera expressing human TCR α/β variable regions spliced onto mouse constant regions that specifically recognizes the gp100 209-217 epitope in the context of a chimeric HLA-A*0201/Kb molecule.

We have used these new TCR transgenic mice and others created in our laboratory to study in vitro and in vivo the activation and proliferation of self-specific T cells and the autoimmune consequences of targeting normal self-antigens including vitiligo as well as a heretofore un-described, CD8+ T cell-mediated, steroid-sensitive uveitis in mouse and man. We have also studied the kinetics of a successful anti-tumor response including the phenotype and functional characteristics of T cells that destroy tumors.

Finally, we have investigated the genes and gene products that can be manipulated to transform an ineffective anti-tumor response into a productive one including ongoing efforts to activate anti-tumor CD4+ T cells cells, depleting regulatory T cells (Treg), and the use of .C cytokines, especially IL-2, IL-7, IL-15 and IL-21.

The importance of cytokines and T regulatory cells in adoptive transfer and vaccine models have led us to address the mechanisms of how lymphodepletion enhances the efficacy of adoptively transferred T cells

The most exciting new approach to emerge recently is the use of lymphodepletion prior to adoptive immunotherapy to treat metastatic cancer. We have been able to recently dissect the mechanisms of how immunodepletion augments the function of adoptively transferred T cells in the treatment of large, established cancer using varieties of lymphodepleted wild-type, transgenic and knockout mice.

The reasons why lymphodepletion augments antitumor immunotherapy include: i.) Lymphodepletion can ablate cellular 'sinks' for .C homeostatic cytokines, such as IL-7 and IL-15, and possibly IL-21, which are capable of activating and expanding T cells. ii.) Lymphodepletion can significantly decrease the numbers and effectiveness of CD4+CD25+ regulatory T cells (Treg), a population that can compromise the antitumor activity of adoptively transferred T cells. iii.) Although total-body irradiation and chemotherapy can reduce the number of CD11c+ dendritic cells, lymphodepleting maneuvers may enhance DC maturation and the effectiveness of tumor antigen presentation. One experimental approach developed in mice has now been proposed as a clinical trial. This involves the induction of a more complete ablation, which is made possible because hematopoetic stem cells can be used to reconstitute mice or patients.

This page was last updated on 7/15/2008.