Philip D. Greenberg
M.D., (Summa Cum Laude), State University of New York (Downstate, NY), 1971
A.B., Washington University (St. Louis, MO), 1967
Senior Fellow, Division of Oncology, University of Washington and Fred Hutch, 1976–1978
Postdoctoral Research Fellow, Immunology, University of California, San Diego, 1974-1976
Internship and Residency in Internal Medicine, University of California, San Diego, 1971-1974
Member and Head, Program in Immunology, Fred Hutch, 1991-present
Professor of Medicine and Immunology, School of Medicine, University of Washington, 1989-present
Professor of Medicine, Division of Oncology, School of Medicine, University of Washington, 1988-present
Adjunct Professor of Microbiology, School of Medicine, University of Washington, 1988–2004
Director, Program in Immunology, UW Center for AIDS Research, University of Washington, 1988-2003
Adjunct Associate Professor of Microbiology and Immunology, University of Washington, 1983–1988
Associate Professor of Medicine, Division of Oncology, School of Medicine, University of Washington; Associate Member, Fred Hutch, 1982–1988
Assistant Professor of Medicine, Division of Oncology, School of Medicine, University of Washington; Assistant Member, Fred Hutch, 1978–1982
The overall goals of the Greenberg laboratory are to 1) elucidate principles underlying T cell recognition of viruses and cancer cells, 2) determine why such responses often fail to eliminate the viral pathogen or malignancy, and 3) develop cellular and molecular approaches to manipulate cellular immunity and thereby effectively treat human viral and malignant diseases. Ongoing projects include:
1. Immunobiology of malignancies
My lab very early began using small animal models to investigate the requirements for and mechanisms by which T cells can recognize and eliminate malignant cells in the context of established, progressing tumors. I was a member of the first group who formally demonstrated that adoptively transferred, antigen-specific T cells can recognize and eradicate disseminated cancer cells. In the early 1990s, my colleagues pursued initial translation of these studies, and showed that T cells could be collected from human peripheral blood, purified and expanded in the lab, and reinfused into patients to seek and destroy diseased cells. We have since spent many years improving the in vitro conditions for generating T cells, clarifying the requirements for tumor elimination including the necessity for T cells to persist to completely eliminate tumor, and developing the technologies necessary to continue advancing our findings to clinical trials for patients.
Ongoing studies in transgenic mice are elucidating the requirements for inducing T cell responses to self-proteins that support the malignant phenotype and are overexpressed 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 by biochemical, transcriptional and epigenetic analyses. Based on our findings, strategies for rescuing T cell function are being investigated.
Differential gene expression in human tumors is also being assessed to identify candidate human tumor antigens. Methods for generating antigen-reactive T cells in vitro have been developed, and such cells are being analyzed for the ability to selectively recognize malignant versus normal tissues. Clinical trials for the treatment of leukemia patients by adoptive transfer of T cell clones specific for validated over-expressed oncogenic proteins have already been performed, with evidence of safety and therapeutic activity. These trials have utilized T cells isolated and grown using methods that we developed to rapidly expand selected T cells in vitro. In fact, these methods are now widely employed for T cell therapy trials.
2. Genetic modification of T cells
There are many obstacles to efficiently targeting and eradicating tumors with T cells and many can be addressed by genetically modifying the T cells prior to transfer. Retroviral and lentiviral shuttle vectors have made it possible to introduce genes that can impart new specificities, enhance functions, or disrupt interfering or regulatory pathways. Successful transfers include expression in T cells of high affinity T cell receptors, chimeric receptors that can bind to tumors and provide costimulatory signals, as well as particular homing receptors, signaling molecules, dominant-negative proteins and siRNAs. The molecular consequences of these genetic changes and the function of these modified T cells are being evaluated both in vitro and in vivo in murine models that recapitulate human disease settings.
3. Preclinical studies
We are utilizing preclinical animal models that mimic most aspects of human disease as a means to develop new and/or improved therapies for human malignancies. These models are providing insights into the obstacles that must be resolved for T cells to be effective at eliminating tumors, and providing a platform for testing genetic T cell modifications and modulations of the tumor microenvironment designed to enhance anti-tumor activity. Currently, we have genetically engineered and transplantable models for disseminated leukemia, pancreatic cancer, ovarian cancer and non-small cell lung cancer.
4. Clinical trials
We already have several ongoing clinical trials in which cancer patients are being treated with genetically engineered T cells. The trials are based on insights derived from and reagents generated by our preclinical and basic research efforts. Active trials include treatment of patients with myeloid leukemias, non-small cell lung cancer and mesothelioma. Several additional trials are being developed, which should begin enrolling within the next year, including for patients with pancreatic cancer and ovarian cancer.
Dr. Greenberg has served on the editorial boards of multiple journals, including Journal of Immunology, Gene Therapy, Clinical Cancer Research and Molecular Therapy, and currently serves on the boards of Cancer Immunology and Immunotherapy and Cancer Cell and is Editor-In-Chief of Cancer Immunology Research.
Dr. Greenberg currently also serves on multiple Scientific Advisory Boards, including for the University of Chicago Cancer Center, the MD Anderson Cancer Center, the Johns Hopkins Cancer Center, the Cancer Research Institute, and the Ludwig Institute for Cancer Research.
Alpha Omega Alpha (elected 1970)
American Association for Cancer Research (Charter Member)
American Association for the Advancement of Science (elected 2007)
American Association of Immunologists (1982-present)
American College of Physicians (elected 2008)
American Society of Clinical Investigation (elected 1987)
Association of American Physicians (elected 1998)
New Strategies in Engineering T-cell Receptor Gene-Modified T Cells to More Effectively Target Malignancies.. Clinical cancer research : an official journal of the American Association for Cancer Research. 21(23):5191-5197.. 2015.
TCR contact residue hydrophobicity is a hallmark of immunogenic CD8+ T cell epitopes.. Proceedings of the National Academy of Sciences of the United States of America. 112(14):E1754-62.. 2015.
Editorial overview: Tumour immunology.. Current opinion in immunology. 33:ix-xi.. 2015.
Ontogeny of recognition specificity and functionality for the broadly neutralizing anti-HIV antibody 4E10.. PLoS pathogens. 10(9):e1004403.. 2014.
T-cell immunotherapy: looking forward.. Molecular therapy : the journal of the American Society of Gene Therapy. 22(9):1564-74.. 2014.
Molecular Pathways: Myeloid Complicity in Cancer.. Clinical cancer research : an official journal of the American Association for Cancer Research. 20(20):5157-70.. 2014.
MicroRNA-150 regulates the cytotoxicity of natural killers by targeting perforin-1(⋆). The Journal of allergy and clinical immunology.. 2014.
Stromal re-engineering to treat pancreas cancer.. Carcinogenesis. 35(7):1451-60.. 2014.
Re-adapting T cells for cancer therapy: from mouse models to clinical trials.. Immunological reviews. 257(1):145-64.. 2014.
Tolerance and exhaustion: defining mechanisms of T cell dysfunction.. Trends in immunology. 35(2):51-60.. 2014.
Antigen-specific activation and cytokine-facilitated expansion of naive, human CD8(+) T cells.. Nature protocols. 9(4):950-66.. 2014.
Correction: Shaping of Human Germline IgH Repertoires Revealed by Deep Sequencing. The Journal of Immunology. 192(1):534-534.. 2014.
Characterizing the Functional Autoreactivity and Polyspecificity of the MPER-Specific bNAb 4E10 and an Ensemble of Its Germline-Encoded Precursors. AIDS Research and Human Retroviruses. 29:A48-A48.. 2013.
Engineering recombinant reoviruses with tandem repeats and a tetravirus 2A-like element for exogenous polypeptide expression.. Proceedings of the National Academy of Sciences of the United States of America. 110(20):E1867-76.. 2013.
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.