A.B. Biology Washington University, St Louis, MO
M.D. Medicine State University of New York, Downstate, NY
Intern and Resident Medicine University Hospital, University of CA, (UCSD), San Diego, CA
Postdoctoral Research Fellow Immunology UCSD, San Diego, CA
Clinical and Research Fellow Oncology Fred Hutchinson Cancer Research Center, Seattle WA
Dr. Greenberg was a founding member of the University of Washington (UW) Department of Immunology and of the Fred Hutch Program in Immunology, helping guide their coordination to 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 30 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 focused on how immune T cells can recognize and eliminate malignant cells in the context of progressing tumors. First using small animal models, Dr. Greenberg’s lab has developed technologies to isolate and expand functional, target (antigen)-specific T cells to numbers large enough to be effective when given to patients as “adoptive” immune-boosting therapy.
In the early 1990s, Dr. Greenberg and colleagues showed that T cells collected from human peripheral blood could be used as a source for generating, purifying and expanding antigen-specific T cells in the lab, and that such T cells could then be reinfused into patients to seek and destroy diseased cells. He was a member of the first group to formally demonstrate that 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 tumor. 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 a CD8+ T cell response.
Their findings suggested that it would be possible to generate potent T cells in the lab that could then be administered to patients to establish very strong immune responses in their bodies. This initially led to approaches to protect immune-compromised patients from CMV infection and to enhance control of HIV infections, which are major causes of morbidity and mortality worldwide. More recently, these advances in concert with efforts to identify and validate tumor antigen targets, led to the development of anti-cancer therapies using naturally isolated and expanded or genetically-engineered T cells.
Dr. Greenberg’s laboratory continues to focus on both basic immunology and cancer immunobiology, and on 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 T cells that can be effectively therapeutics. These include technologies that are now widely employed, such as for the rapid expansion of selected T cells in the laboratory and the 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 high affinity 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 naturally isolated and expanded or genetically-engineered T cells for patients with melanoma or leukemia, or lung, ovarian or pancreatic cancers. For example, WT1 and Cyclin A1 antigen-specific TCRs are being engineered to create high avidity CD8+ T cells. Such engineered T cells are being tested for their ability to eliminate acute myeloid (AML) cells, and TCRs specific for the Mesothelin protein are being developed and tested for their ability to eliminate pancreatic and ovarian cancer cells. Clinical trials with some of these TCRs have already resulted (see below).
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, collectively known as graft-versus-host-disease. To address this serious limitation, CD8+ cell-killing T cells were produced with specificity for the Wilms’ tumor antigen 1 (WT1), a protein that can promote malignancies and is abnormally abundant in many cases of AML, myelodysplastic syndromes (MDS) and chronic myeloid leukemia (CML). Dr. Greenberg and his clinical colleagues previously treated leukemia patients who had relapsed after allogeneic HCT, using WT1-specific CD8+ T cells expanded from each patient’s normal HCT donor. The treatment had a very acceptable safety profile, but limited efficacy in part due to poor persistence and/or low T cell avidity for leukemia targets in some patients. Therefore, in the ongoing phase I/II clinical trial, patients are being treated with T cells enriched for the subset of “central memory” CD8+ T cells, which have longer post-transfer persistence; in addition, these T cells are engineered to carry a well-characterized, high affinity WT1-specific TCR. Patients who are at high risk of relapse after transplantation are eligible for this trial. Dr. Greenberg’s laboratory is 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 2727: Phase I/II study in WT1-expressing non-small cell lung cancer and mesothelioma, comparing the biologic activity and therapeutic efficacy of adoptive immunotherapy with polyclonal autologous CD8+ T cells derived from either the central memory or naïve T cell subset that have been transduced to express a WT1-specific T cell receptor. WT1 is also highly expressed on a wide variety of other tumor types, including lung cancers. As part of a multicenter collaboration, Dr. Greenberg and colleagues are assessing potential strategies to improve therapeutic efficacy, including monitoring the transferred T cells for increased levels of immune inhibitory “receptor” molecules, such as PD-1, and monitoring tumor samples for up-regulation of inhibitory, receptor-binding “ ligand” molecules, such as PD-L1. Next generation trials will include the administration of specific antibodies that can disrupt these inhibitory processes and overcome this established mechanism of immune escape.