Philip D. Greenberg
M.D. (Summa Cum Laude), University of California, San Diego, 1971.
Degree, University of California, San Diego, Biology.
Postdoctoral Training, University of California, San Diego.
Tumor and viral immunobiology
The overall goals of the laboratory are to elucidate principles underlying T cell recognition of viruses and cancer cells, determine why such responses often fail to eliminate the viral pathogen or cancer, and develop cellular and molecular approaches to manipulate cellular immunity to treat human viral and malignant diseases. Several ongoing projects are:
1. Immunobiology of malignancies.
Studies in transgenic mice are examining the requirements for inducing T cell responses to self-proteins over-expressed in tumors. The molecular basis for non-responsiveness to such potential therapeutic targets is being evaluated by studying gene expression in homogenous populations of tolerant transgenic T cells both biochemically and with microarrays, and strategies for rescuing function in such T cells are being investigated. Differential gene expression in human tumors is also being assessed to identify candidate human tumor antigens, and T cells reactive to such antigens are being generated and analyzed for the ability to selectively recognize malignant and not normal tissues. Clinical trials are currently being developed for the treatment of human leukemias by adoptive transfer of T cell clones previously expandedto large numbers in vitro that are specific for already identified over-expressed oncogenic proteins.
2. Genetic modification of T cells.
Many obstacles to generating or maintaining an effective T cell response to infections and tumors are being identified. Genetic modification of T cells via retroviral shuttle vectors provides a means to impart new functions or disrupt interfering or regulatory pathways, and expression in T cells of molecules such as chimeric receptors, homing receptors, signaling molecules, dominant-negative proteins, and siRNAs is being studied both in vitro and in vivo in murine models.
3. Immunobiology of HIV.
Studies are evaluating strategies to develop protective vaccine in a primate model, employing a hybrid SIV/HIV virus. A trial is being developed in which autologous SHIV-specific CD8+ T cell clones expanded in vitro are being administered with or without monoclonal neutralizing antibodies to uninfected macaques to determine the immunologic requirements for protection from infection and to define standards for the nature and magnitude of immune responses that must be achieved by vaccination strategies. Cellular and molecular assays are being used to monitor the persistence, function, and in vivo homing of these transferred T cells.
Joined the Fred Hutchinson Cancer Research Center and the Division of Oncology at the University of Washington in 1976
Since 1988 he has also served as the Director of the Immunology Program of the UW Center for AIDS Research.
Alpha Omega Alpha
1989, Professor, University of Washington,
1988, Professor, University of Washington,
1988, Director, University of Washington, Center for AIDS Research, Immunology
1983-1988, Adjunct Associate Professor, University of Washington
1991-present, Fred Hutchinson Cancer Research Center, Immunology, Head
1982-1988, University of Washington, Associate Professor
Durable Adoptive Immunotherapy for Leukemia Produced by Manipulation of Multiple Regulatory Pathways of CD8+ T-Cell Tolerance.. Cancer research. 73(2):605-616.. 2013.
Transferred WT1-reactive CD8+ T cells can mediate antileukemic activity and persist in post-transplant patients.. Science translational medicine. 5(174):174ra27.. 2013.
Shaping of Human Germline IgH Repertoires Revealed by Deep Sequencing.. Journal of immunology (Baltimore, Md. : 1950). 189(6):3221-30.. 2012.
Cell-Intrinsic Abrogation of TGF-β Signaling Delays but Does Not Prevent Dysfunction of Self/Tumor-Specific CD8 T Cells in a Murine Model of Autochthonous Prostate Cancer.. Journal of immunology (Baltimore, Md. : 1950). 189(8):3936-46.. 2012.
Editing T cell specificity towards leukemia by zinc finger nucleases and lentiviral gene transfer.. Nature medicine. 18(5):807-815.. 2012.
Rescued tolerant CD8 T cells are preprogrammed to reestablish the tolerant state.. Science (New York, N.Y.). 335(6069):723-7.. 2012.
Abrogation of SRC homology region 2 domain-containing phosphatase 1 in tumor-specific T cells improves efficacy of adoptive immunotherapy by enhancing the effector function and accumulation of short-lived effector T cells in vivo.. Journal of immunology (Baltimore, Md. : 1950). 189(4):1812-25.. 2012.
Single-chain VαVβ T-cell receptors function without mispairing with endogenous TCR chains.. Gene therapy. 19(4):365-374.. 2012.
Human microRNA-27a* targets Prf1 and GzmBexpression to regulate NK cell cytotoxicity.. Blood. 118 (20):5476-5486.. 2011.
Pitfalls of vaccinations with WT1-, Proteinase3- and MUC1-derived peptides in combination with MontanideISA51 and CpG7909.. Cancer immunology, immunotherapy : CII. 60(2):161-71.. 2011.
Ralph M. Steinman: A man, a microscope, a cell, and so much more.. Proceedings of the National Academy of Sciences of the United States of America. 108(52):20871-2.. 2011.
Retinoic acid as a vaccine adjuvant enhances CD8+ T cell response and mucosal protection from viral challenge.. Journal of virology. 85(16):8316-27.. 2011.
SHP-1 in T cells limits the production of CD8 effector cells without impacting the formation of long-lived central memory cells.. Journal of immunology (Baltimore, Md. : 1950). 185(6):3256-67.. 2010.
Abrogating Cbl-b in effector CD8(+) T cells improves the efficacy of adoptive therapy of leukemia in mice.. The Journal of clinical investigation. 120(10):3722-34.. 2010.
Mathematical modeling of chimeric TCR triggering predicts the magnitude of target lysis and its impairment by TCR downmodulation.. Journal of immunology (Baltimore, Md. : 1950). 184(8):4284-94.. 2010.
T cell receptor gene therapy for cancer.. Human gene therapy. 20(11):1240-8.. 2009.
Increasing functional avidity of TCR-redirected T cells by removing defined N-glycosylation sites in the TCR constant domain.. The Journal of experimental medicine. 206(2):463-75.. 2009.
Structural features of T cell receptor variable regions that enhance domain stability and enable expression as single-chain ValphaVbeta fragments.. Molecular immunology. 46(5):902-16.. 2009.