Member & Head, Program in Immunology
Clinical Research Division, Fred Hutch
Dr. Phil Greenberg is an internationally-recognized expert in cancer immunotherapy, a form of therapy that aims to harness the power of immune cells to eliminate cancer. Dr. Greenberg's early discoveries showed how to target diseases with immune T cells and helped drive this now burgeoning field. In the lab and the clinic, Dr. Greenberg's team continues to develop and test new strategies to genetically reprogram a patient's T cells to even more effectively target cancers. They are creating new T-cell therapies for patients with acute myeloid leukemia, ovarian cancer, pancreatic cancer and several other cancers, and advancing these therapies to clinical trials for patients.
Professor of Medicine & Immunotherapy
University of Washington
Parker Institute for Cancer Immunotherapy
A.B. Biology Washington University, St Louis, MO
M.D. Medicine State University of New York, Downstate, NY
Intern and Resident in Medicine, University Hospital, University of CA, (UCSD), San Diego, CA
Postdoctoral Research Fellow in Immunology, UCSD, San Diego, CA
Clinical and Research Fellow in Oncology, Fred Hutchinson Cancer Research Center, Seattle, WA
Dr. Greenberg was a founding member of the UW Department of Immunology and the Fred Hutch Program in Immunology, helping develop productive training and research environments for investigators involved in basic immunology and translational cancer immunology research. Internationally recognized as a leader in the cancer immunology field, he has trained more than 40 investigators who have gone on to develop independent research careers, including many who have also become leaders in immunology fields. His laboratory performed some of the earliest studies on how immune T cells can recognize and eliminate malignant cells in the context of progressing tumors.
First using small animal models, the Greenberg lab developed technologies to produce functional, protein target (antigen)-specific T cells.
In the early 1990s, Dr. Greenberg and colleagues showed that T cells collected from human peripheral blood can be used to generate antigen-specific T cells in the lab, and that such T cells can then be reinfused into patients to seek and destroy diseased cells. He was a leader of the first group to formally demonstrate that such ‘adoptively’ transferred antigen-specific T cells can recognize and eradicate disseminated cancer cells. Dr. Greenberg’s team went on to clarify the requirements for T cells to persist and completely eliminate tumors. These early studies also revealed what was then a very surprising finding; i.e., that one type of tumor antigen-specific T cells (CD4+) can not only help the type of T cells (CD8+) that are best known for directly killing tumor cells but can also help eradicate disseminated tumors even without CD8+ T cells.
Dr. Greenberg’s findings initially led to approaches to protect immune-compromised patients from cytomegalovirus infections and to enhance control of HIV infections, which are both major causes of disease and mortality worldwide. More recently, his team has developed anti-cancer therapies using naturally isolated or genetically-engineered T cells. His lab continues to innovate using molecular strategies to create T cells that can show sustained function despite obstacles posed by progressive tumors.
Protocol 2498: Phase I/II Study of Adoptive Immunotherapy with Virus Specific CD8+ T Cells that have been Transduced to Express a WT1-Specific T Cell Receptor for Patients with High Risk or Relapsed AML, MDS, or CML
The success of donor (allogeneic) hematopoietic stem cell transplantation (HCT) in part reflects anti-cancer immunity mediated by transferred donor T cells, but these cells are generally not leukemia-specific and thus can also have harmful side effects. To address this serious limitation, CD8+ killer T cells were produced with specificity for the Wilms’ tumor antigen 1 (WT1), a cancer-promoting protein that is abnormally abundant in most cases of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and chronic myeloid leukemia (CML). This ongoing phase I/II clinical trial is designed to treat patients at high risk of post-transplant relapse. The generated therapeutic T cells are enriched for the subset of highly persistent “central memory” CD8+ T cells and engineered to carry a well-characterized, high affinity WT1-binding molecule (known as a T cell receptor). Dr. Greenberg and collaborators are performing extensive laboratory tests to monitor any changes in the leukemia and/or in the engineered T cells at various time points after therapy.
Protocol 9296: Phase I/II study of Autologous (Central Memory / Naive) CD8+ T cells that have been Transduced to Express a WT1-specific T cell Receptor for Treatment of AML
This trial is evaluating the activity of particular subsets (central memory and naïve) of CD8+ T cells that can be especially effective in mounting anti-leukemia immune responses. T cells are collected from high-risk patients with newly diagnosed acute myeloid leukemia or soon after initial chemotherapy, genetically modified with a WT1-recognizing T cell receptor to impart specificity for killing leukemia cells, and then given back to the patient with the goal of preventing relapse.
Protocol 9245: Study to Evaluate Cellular Adoptive Immunotherapy Using Polyclonal Autologous CD8+ Antigen-Specific T Cells for Metastatic Merkel Cell Carcinoma in Combination with MHC Class I Up-regulation and the Anti-PD-L1 Antibody Avelumab
This trial is evaluating the use of localized radiation therapy or recombinant interferon beta as means to increase the ability of transferred T cells to find and kill Merkel cancer cells. The immune T cells are collected from a patient's blood and selected and expanded in the laboratory, based on their ability to specifically recognize Merkel cell polyoma virus antigens. An antibody drug, known as avelumab, is also administered to abrogate an inhibitory signal and help the anti-cancer T cells kill remain active long enough to eliminate the tumor cells.
Dr. Greenberg’s laboratory continues to make advances in both basic immunology and cancer immunobiology, and in the development and assessment of adoptive therapies with antigen-specific T cells targeting human malignancies and chronic infections. They remain leaders in the development and optimization of methods to efficiently generate and modify therapeutic T cells. These include technologies that are now widely employed for the rapid expansion and genetic engineering of T cells to carry antigen-specific T cell receptor (TCR) molecules. Currently, the Greenberg team is developing methods to 1) engineer tumor-reactive T cells with optimally binding TCRs and 2) genetically re-program therapeutic T cells so they can eradicate even large tumors and overcome often immune-suppressing tumor microenvironments.
Ongoing efforts also include identifying and validating new tumor antigen targets and developing therapies with natural or genetically-engineered T cells for patients with melanoma or leukemia, or with lung, ovarian or pancreatic cancers. Beyond WT1, Cyclin A1 antigen-specific TCRs are being engineered to create CD8+ T cells that are being tested preclinically for their ability to eliminate AML cells as well as several solid tumors. TCRs specific for the Mesothelin protein are being developed and tested for their ability to eliminate pancreatic and ovarian cancer. Clinical trials employing some of these TCRs are being planned.
— Dr. Philip Greenberg
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