Philip D. Greenberg, M.D.
Professor of Medicine (Oncology) and Immunology

Department of Medicine
University of Washington
Office J-259 HSC, Box 357362
1959 NE Pacific Street
Seattle, WA 98195-6527
Tel: 206.543-8306
Fax: 206.685-3128
Email: pgreen@u.washington.edu

Greenberg Lab Members

Lecture Notes for Greenberg Tumor Immunology Talk,
AAI Advanced Immunology Course, July 2006

Dr. Greenberg graduated from Washington University with a degree in biology. He received his M.D. summa cum laude from the State University of New York, Downstate Medical Center, in 1971. After completing postdoctoral training at the University of California at San Diego, he joined the Fred Hutchinson Cancer Research Center and the Division of Oncology at the University of Washington in 1976. He is currently the Co-Director of the Immunology Program of the UW Center for AIDS Research, and the Head of the Immunology Program at the Fred Hutchinson Cancer Research Center.

Dr. Greenberg's laboratory is involved in studies elucidating the immunobiology of host T cell responses to infectious viruses and transformed cells. Analysis of T cell responses to pathogenic viral infections and tumors has demonstrated that reactive T cells are often rendered anergic or dysfunctional as a consequence of encounter with the antigen, and the basis for these defects are being explored and molecular strategies to restore and augment T cell function via genetic modification of T cells with vectors expressing novel proteins, dominant negative proteins, or RNAi are being evaluated. The mechanisms of tolerance to tumor antigens that are over-expressed pro-oncogenic self-proteins are being examined in transgenic mouse models that express tumor-derived proteins of known immunogenicity under the control of tissue-specific promoters- these models are making it possible to isolate and track antigen-specific tolerant cells, to use technologies such as gene expression arrays to identify abnormalities in tolerant T cells, and to begin testing molecular strategies for correcting defects. Immunity to human pathogenic viruses is being studied with the goal of defining methods to generate or augment protective immune responses. These studies include the development of transgenic/knock-in mice that better typify human immune responses for evaluation of candidate HIV vaccines. Studies of human CMV immunobiology led to a clinical trial in which immunosuppressed leukemia patients at high risk for fatal CMV infection were infused with CMV-specific cytolytic T cell clones. The clones had been previously selected for recognition of an immunodominant protective epitope and expanded to large numbers in vitro, and this trial demonstrated that T cell transfer can reconstitute immunity in humans and provide protection from disease. This adoptive therapy approach with cloned T cells of known function and specificity is now being pursued to elucidate the immunobiology of human malignancies and infections, and clinical trials are now underway in patients with leukemia and HIV infection. Methods to modulate the effector functions, survival, and localization of T cells, and to impart desired antigen specificity are being developed using retroviral-mediated gene transfer, and such engineered T cell clones are being evaluated in mouse models and will be tested in treatment of human disease.

Students currently training in the Greenberg Lab: Carla Fowler, Scott James, Cassie Chou

Recent publications:

Brodie SJ, Lewinsohn DA, Patterson BK, Jiyamapa D, Krieger J, Corey L, Greenberg PD, Riddell SR. In vivo migration and function of transferred HIV-1-specific cytotoxic T cells. Nat Med. 1999 Jan;5(1):34-41.

Cheng LE, Ohlen C, Nelson BH, Greenberg PD. Enhanced signaling through the IL-2 receptor in CD8+ T cells regulated by antigen recognition results in preferential proliferation and expansion of responding CD8+ T cells rather than promotion of cell death. Proc Natl Acad Sci U S A. 2002; 99:3001-6.

Ohlen C, Kalos M, Cheng LE, Shur AC, Hong DJ, Carson BD, Kokot NC, Lerner CG, Sather BD, Huseby ES, Greenberg PD. CD8(+) T cell tolerance to a tumor-associated antigen is maintained at the level of expansion rather than effector function. J Exp Med. 2002;195:1407-18.

Yee C, Thompson JA, Byrd D, Riddell SR, Roche P, Celis E, Greenberg PD. Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci USA. 2002; 99:16168-73.

Ho WY, Blattman JN, Dossett ML, Yee C, Greenberg PD. Adoptive immunotherapy: Engineering T cell responses as biologic weapons for tumor mass destruction. Cancer Cell. 2003; 3:431-7.

Topp MS, Riddell SR, Akatsuka Y, Jensen MC, Blattman JN, Greenberg PD. Related Articles, Links Restoration of CD28 expression in CD28- CD8+ memory effector T cells reconstitutes antigen-induced IL-2 production. J Exp Med. 2003 Sep 15;198(6):947-55. Epub 2003 Sep 8.

Dittmer U, He H, Messer RJ, Schimmer S, Olbrich AR, Ohlen C, Greenberg PD, Stromnes IM, Iwashiro M, Sakaguchi S, Evans LH, Peterson KE, Yang G, Hasenkrug KJ. Functional impairment of CD8(+) T cells by regulatory T cells during persistent retroviral infection. Immunity. 2004 Mar;20(3):293-303.

Blattman JN, Greenberg PD. Cancer immunotherapy: a treatment for the masses. Science. 2004 Jul 9;305(5681):200-5.

Zhang Y, Blattman JN, Kennedy NJ, Duong J, Nguyen T, Wang Y, Davis RJ, Greenberg PD, Flavell RA, Dong C. Regulation of innate and adaptive immune responses by MAP kinase phosphatase 5. Nature. 2004 Aug 12;430(7001):793-7.

Ochsenbein AF, Riddell SR, Brown M, Corey L, Baerlocher GM, Lansdorp PM, Greenberg PD. CD27 expression promotes long-term survival of functional effector-memory CD8+ cytotoxic T lymphocytes in HIV-infected patients. J Exp Med. 2004 Dec 6;200(11):1407-17.

Teague RM, Sather BD, Sacks JA, Huang MZ, Dossett ML, Morimoto J, Tan X, Sutton SE, Cooke MP, Ohlen C, Greenberg PD. Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors. Nat Med. 2006 Mar;12(3):335-41. Epub 2006 Feb 12.

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Updated July 2006