Research
High-throughput Sequencing of T- and B-Cell Antigen Receptor Repertoires
In collaboration with Drs. Harlan Robins and Christopher Carlson of the Public Health Sciences Division at Fred Hutch, our lab developed molecular and computational techniques that exploited the power of high-throughput DNA sequencing to define more comprehensively than ever before the diversity and complexity of antigen-receptor repertoires carried in populations of T- and B-lymphocytes. These efforts led to US and international patents as well as the formation of Adaptive Biotechnologies, a Seattle biotech company that is rapidly commercializing this technology. High-throughput antigen receptor sequencing to define the composition of T- and B-cell populations at the clonal level has provided valuable insights into the immunobiology of tumors, autoimmune disease, vaccinology, and infectious diseases, and is currently being used by our group and others to dissect the complex immune interactions that underlie GVT and GVHD as well as those that mediate tumor regression after immune checkpoint inhibition. Much of the current effort in our lab is focused on malignancies that are common in sub-Saharan Africa (SSA), particularly pediatric Burkitt lymphoma (BL), HIV-associated non-Hodgkin lymphoma, and Kaposi sarcoma (KS). A primary objective of these studies is to develop more effective therapies for what are now largely fatal cancers. We have applied our high-throughput DNA sequencing methods to characterizing BCR and TCR diversity in African lymphomas and Kaposi sarcoma, and made the surprising discovery of high levels of tumor-infiltrating T cells in these cancers, supporting immunotherapy approaches.
Mechanisms of Cancer Regression After Immune Checkpoint Inhibition
The advent of a new class of cancer therapeutic agents collectively referred to as “immune checkpoint inhibitors” is revolutionizing the field of oncology. This class of agents – which includes FDA-approved ipilimumab, nivolumab, and pembrolizumab – is being used to treat a steadily expanding variety of cancer types. These agents are thought to work by enhancing 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 cellular and molecular mechanisms that mediate tumor regression after immune checkpoint inhibition.
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. Increasing evidence suggests, however, that immune therapies – such as infusion of Interleukin-2 or treatment with immune checkpoint inhibitors – can be effective against advanced kidney cancer. Research in the Warren Lab is focused on understanding the activities in detail, which is essential to making these therapies even more effective. A recently initiated effort in the lab is developing a novel strategy that uses infusion of 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.
Pathogenesis, Treatment and Prevention of Pediatric and Adult Lymphomas in Sub-Saharan Africa
Cancer is an increasing 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 frequently occur in children and adults in sub-Saharan Africa. Burkitt lymphoma (BL) is the most common type of childhood cancer in this region, and is the focus of intense study in the Lab. BL is an aggressive form of B-lineage NHL that is epidemiologically associated with Plasmodium falciparum (malaria) infection. The tumor cells in this disease often carry Epstein-Barr virus DNA, and 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 played in BL biology by the unique B-cell antigen receptor (BCR) that is expressed in BL tumor cells. Our studies to date have demonstrated that the unique nucleotide sequences encoding the tumor-associated BCR in individual patients can serve as a prognostic biomarker. Ongoing studies are exploring whether the tumor-associated BCR has potential as a therapeutic target. The results of these studies could ultimately inform the design of strategies for prevention of this prototypic infection-related cancer.
Immunobiology of Graft-versus-Host Disease and the Graft-versus-Tumor Effect
The elimination of blood cancers, such as leukemia, in patients who undergo allogeneic HCT is referred to as the “graft-versus-tumor” effect (GVT). 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 HCT graft. The Warren Lab has shown that donor-derived CD4+ and CD8+ T lymphocytes that recognize a class of “minor histocompatibility antigens” play a central and indispensable role in GVT. Current effort is focused on understanding precisely which donor T cell subsets make the most important contributions to GVT, which are the target antigens and how GVT can be enhanced.
A closely related area of current research is the immunobiology of graft-versus-host disease (GVHD), which is the most important limitation of allogeneic HCT for treating blood cancer patients. 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.
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.
The Uganda Cancer Institute (UCI) and Fred Hutchinson Cancer Research Center host a weekly lymphoma tumor board at which the evaluation and management of adult and pediatric patients presenting to the UCI with hematologic malignancies are discussed.
The mission of the weekly tumor board is to enhance the quality of care for patients diagnosed with blood cancers, foster productive interactions between providers and other medical professionals at the UCI and at the Fred Hutchinson Cancer Research Center, and educate all participants about state of the art diagnosis and care for all types of blood cancer.
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