A.B., Applied Mathematics; Harvard College, 1982
Ph.D., Neurobiology; Harvard University, 1988
M.D., Harvard Medical School, 1991
Intern and Resident, Internal Medicine; Massachusetts General Hospital; 1991-1993
Fellow, Medical Oncology; University of Washington, Seattle, WA; 1993-1996
Dr. Warren is an oncologist specializing in the treatment of patients with blood cancers such as leukemia, lymphoma, and multiple myeloma. He is an Attending Physician at the Seattle Cancer Care Alliance (SCCA; a partnership between the Fred Hutch, the University of Washington, and Seattle Children’s Hospital), where he serves on both the Medical Oncology/Hematologic Malignancy and the Hematopoietic Cell Transplant Services. He has considerable experience as an investigator on clinical trials of novel agents for the treatment of blood cancers, and served as the Principal Investigator on a Phase I clinical trial of T cell immunotherapy for patients with relapse of acute leukemia or high-grade myelodysplasia after HLA-identical allogeneic hematopoietic cell transplantation (HCT).
The overall focus of Dr. Warren’s laboratory is cancer immunology. His particular interest is the mechanisms and molecules that mediate graft-versus-host disease (GVHD) and graft-versus-tumor (GVT) activity after allogeneic HCT, as well as the mechanisms that mediate tumor regression after treatment with other modes of immunotherapy such as immune-checkpoint inhibition. His lab has extensive experience with characterization and manipulation of human T and B lymphocytes, identification of antigens recognized by T and B lymphocytes, comprehensive analysis of T- and B-lymphocyte repertoires with the aid of high-throughput DNA sequencing, and assessment of adoptive cellular therapy in murine models. Dr. Warren’s laboratory also has a strong research focus on lymphomas that affect children and adults in sub-Saharan Africa, particularly Burkitt lymphoma (BL).
Ongoing effort in the Warren laboratory is centered on several interrelated areas.
1. Immunobiology of GVHD and GVT
The elimination of blood cancers such as leukemia in patients who undergo allogeneic HCT is referred to as the GVT effect. GVT was the one of the first – and remains one of the best – examples of successful “immunotherapy” for cancer. GVT is mediated primarily by lymphocytes contained in or derived from the donor hematopoietic cell graft. Research in the Warren Lab has shown that donor-derived CD4+ and CD8+ T lymphocytes that recognize a class of antigens termed “minor histocompatibility antigens” play a central and indispensable role in GVT. Current efforts are focused on understanding precisely which subsets of donor T cells make the most important contributions to GVT, what their target antigens are, and how the GVT effect can be enhanced.
A closely related area of current research is the immunobiology of GVHD, which is the most important limitation of allogeneic HCT for treating blood cancers. GVHD is the syndrome that results when lymphocytes contained in or derived from the donor hematopoietic cell graft damage a patient’s normal tissues; it is strongly associated with GVT. Severe GVHD is one of the leading causes of transplant failure. Various approaches are being studied that might reverse, reduce, or even prevent GVHD, while maintaining the critically important GVT effect.
2. Mechanisms of cancer regression after immune checkpoint inhibition
The advent of a new class of therapeutic agents collectively called “immune checkpoint inhibitors” is revolutionizing the field of oncology. These drugs, including ipilimumab, nivolumab, and pembrolizumab, are being used to treat a steadily expanding variety of cancer types. Cancer regression that occurs after treatment with these agents is attributed to the activity of tumor-reactive CD8+ and CD4+ T cells, but the antigenic specificity of these cells and their functional properties remain elusive. A current project in the Warren lab is dissecting the mechanisms that mediate tumor regression after immune checkpoint inhibition at the cellular and molecular level.
Dr. Warren was the Seattle Principal Investigator and his laboratory continues correlative analyses on a clinical trial that is now closed to patient accrual: Multi-institutional Trial of Allogeneic Bone Marrow Transplantation for Hematologic Malignancies using HLA-matched Related or Unrelated Donors with Fludarabine and IV Busulfan as Pre-transplant Conditioning followed by Post-transplant Immunosuppression with High-dose Cyclophosphamide (ClinicalTrials.gov Identifier: NCT00809276). These correlative laboratory studies are important for interpreting clinical responses and learning how best to use new therapies. The Warren lab is also doing correlative lab studies for another multicenter clinical trial led by investigators at Johns Hopkins University: Ipilimumab in Treating Patients With Relapsed or Refractory High-Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia (ClinicalTrials.gov Identifier: NCT01757639).
3. Immunology and immunotherapy of kidney cancer
Kidney cancer is diagnosed in 60,000 Americans each year and is the cause of 14,000 deaths. It is very difficult to cure once it has spread outside the kidneys, but immune therapies – such Interleukin-2 and immune checkpoint inhibitors – seem to be effective against advanced kidney cancer. To learn how use these therapies even more effectively, the Warren Lab is focused on understanding in detail how immune-based therapy can trigger regression or elimination of kidney cancer. The lab recently began developing a novel treatment strategy that is based on infusion of a patient’s own (autologous) T cells genetically engineered to recognize kidney cancer cells by expression of T cell receptors or chimeric antigen receptors that recognize the oncofetal antigen 5T4.
4. Pathogenesis, treatment, and prevention of pediatric and adult lymphomas in sub-Saharan Africa
Cancer is an increasingly important cause of morbidity and mortality in low- and middle-income countries.
The Warren Lab is actively studying several types of non-Hodgkin lymphoma (NHL) that occur with high frequency in children and adults in sub-Saharan Africa. Burkitt lymphoma is an aggressive form of B-lineage NHL, the most common childhood cancer in sub-Saharan Africa, and is the focus of intense study in the lab. It is epidemiologically associated with malaria infection, and BL cells often carry Epstein-Barr virus DNA. BL cells invariably carry clonal chromosomal rearrangements that put the C-MYC oncogene under the control of regulatory elements associated with immunoglobulin genes. Current effort is focused on the many roles that the unique B-cell antigen receptor (BCR) expressed in BL tumor cells plays in the biology of this tumor. The lab has already shown that the unique nucleotide sequences encoding the tumor-associated BCR can serve as a prognostic biomarker. Ongoing studies are exploring the BCR’s role in disease pathogenesis, and whether it might serve as a therapeutic target. Their results could ultimately inform strategies for preventing this prototypic infection-related cancer.