University of Manitoba; MD, Medicine; 1979
University of Manitoba; Resident, Internal Medicine; 1983
University of Manitoba; Fellow, Hematology; 1985
University of Washington and Fred Hutchinson Cancer
Dr. Riddell’s research focuses on 1) understanding the roles of distinct T cell subsets in protective immunity to pathogens and tumors and 2) the development and clinical application of adoptive T cell therapies for viral diseases and cancers, including with genetically modified antigen-specific T cells. His early studies demonstrated the potential to augment T cell immunity by the adoptive transfer of antigen-specific T cells and uncovered mechanisms by which virally-infected cells evade immune recognition. These findings provided insights into similar mechanisms that tumors use to escape T cell immunity and that might be therapeutically targeted to improve patient outcomes.
Dr. Riddell’s lab has developed critical techniques for isolation, expansion, genetic modification and reinfusion of therapeutic T cells, and for monitoring patient safety, T cell persistence, migration and function post-infusion. These include state-of-the-art ways to identify the tumor cell “antigens” recognized by T cells. Many are now broadly employed in adoptive immunotherapies for cancer that use natural targeting molecules called T cell receptors (TCRs) or use synthetic TCR- and antibody-related molecules known as chimeric antigen receptors (CARs).
In the clinic, Dr. Riddell is an expert at treating patients with leukemias, lymphomas and other blood-related cancers using bone marrow transplantation, also known as hematopoietic (blood-forming) stem cell transplantation (HCT). He is also an expert in treating graft-versus-host disease (GVHD) that can occur after allogeneic HCT when a donor’s T cells, which are transferred to the patient along with the blood-forming stem cells, attack normal tissues.
Dr. Riddell also has world-recognized expertise in using adoptive transfer of T cells to treat various cancers, and in the immunobiology of human cytomegalovirus (CMV) and human immunodeficiency virus (HIV) infections. He was principal investigator on the first human trial of adoptively transferred T cell clones, used to prevent CMV infection after allogeneic HCT, and on four subsequent FDA-approved human trials of T cell therapy, including the first efforts to treat relapsed leukemia after HCT with leukemia-reactive T cells and the first human trial of CAR-T cells of defined subset composition.
Dr. Riddell’s lab has contributed to our understanding of the mechanisms involved in beneficial graft-versus-leukemia (GVL) effects of donor T cells, as well as potentially dangerous GVHD, in order to increase the safety and relapse-preventing efficacy of allogeneic HCT. They uncovered a key role in GVHD for a family of proteins on leukemic cells and normal tissues, known as human minor histocompatibility antigens.
The Riddell lab also led in learning how viruses can evade T cell immune responses and how these mechanisms can be overcome to achieve beneficial immunity. CMV remains an important human pathogen, including in patients who undergo transplantation. Several novel CMV antigens have recently been identified in the Riddell lab and are being studied as potential targets for novel anti-viral T cell therapies.
Other recent studies are focused on cutting-edge cellular and molecular strategies to manipulate the immune system for the treatment of various cancers, defining relevant tumor-associated antigens and mechanisms that may impede immunologic recognition but could be therapeutically targeted to improve patient outcomes. The goal is to develop specific T cell therapy or vaccine approaches that could be applied as adjuncts to standard therapy.
The Riddell team is working to identify tumor antigens that can be recognized by T cells through engineered TCRs or CARs. He and his colleagues recently designed the first CARs to target the tumor antigen, ROR1, which is expressed on chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia/lymphoma (ALL), mantle cell lymphoma (MCL) and many epithelial cancers, including subsets of breast and lung cancers.
Dr. Riddell and colleagues are also developing laboratory models in which they can clarify specific tumor “microenvironments” that may interfere with the efficacy of CAR and/or TCR therapy. They are identifying intrinsic T cell properties that are important for effective adoptive T cell therapy, including intrinsic qualities of particular T cell subsets. Powerful cell selection methods have been developed to rapidly isolate these specific cell populations for clinical trials of adoptive immunotherapy. They are also developing approaches to genetically modify donor T cells with a suicide gene so the engineered cells can be removed if they prove dangerous.
Findings from Dr. Riddell’s laboratory have led to multiple clinical trials, including the first human trial of CD19 CAR-T cells of defined T cell subset composition and the current phase I/II study of CD19 chimeric antigen receptor (CAR)-modified T cells for patients with advanced CD19+ CLL, ALL or non-Hodgkin lymphoma.