Stanley R. Riddell
M.D., University of Manitoba, 1979.
I. Immunobiology of graft-versus-leukemia (GVL) responses and graft-versus-host disease (GVHD).
The efficacy of allogeneic stem cell transplantation depends in large part on an immune mediated antitumor effect mediated by donor T cells. A major focus of the lab is to understand the mechanisms involved the GVL effect. The association of the GVL effect with allogeneic transplant has suggested minor histocompatibility antigens expressed on recipient cells including leukemic cells are targets for donor T cells. Several approaches including cDNA expression cloning, peptide elution and mass spectrometry, and genetic linkage analysis are being used to identify the polymorphic genes that encode human minor histocompatibility antigens recognized by T cells. The discovery of these genes permits studies of the mechanisms responsible for immunogenicity and of the expression of individual determinants on leukemic cells and tissues involved in GVHD. The goal is to identify antigens that could be targeted without causing GVHD.
II. Adoptive transfer of T cells to treat human leukemia
A model of human leukemia in NOD/SCID mice is being used to evaluate the expression of individual minor hisotocompatibility antigens on leukemic stem cells and define those that may be suitable to target in clinical trials to prevent or treat leukemic relapse in allogeneic stem cell transplant recipients. A clinical trial to evaluate the feasibility, safety, and antitumor activity of adoptive immunotherapy with T cell clones specific for minor histocompatibility antigens has been initiated. Preliminary results suggest that adoptive transfer can augment T cell responses to antigens that are expressed selectively on recipient hematopoietic cells without causing GVHD.
A second approach that is in preclinical development is to genetically modify donor T cells with a suicide gene to improve the safety of polyclonal donor lymphocyte infusions. We are working with a construct that encodes the death domain of Fas linked to the FK506 binding protein and can be conditionally activated by a synthetic chemical dimerizer drug.
III. Immunobiology of breast cancer
Recent studies have been initiated to investigate cellular and molecular strategies to manipulate the immune system for the treatment of breast cancer. This effort encompasses studies to define relevant tumor associated antigens expressed by breast cancer and recognized by T cells and studies of mechanisms that may operate at the tumor interface to impede immunologic recognition. The goal is to develop specific T cell therapy or vaccine approaches that could be applied as an adjunct to current therapy.
IV. Immunobiology of human cytomegalovirus (CMV) infection
CMV remains an important human pathogen and an ideal candidate for vaccine development. Our lab has studied the host T cell response to CMV infection in both immunocompetent and immunodeficient hosts to elucidate the requirements for protective immunity. Viruses, like tumors, have adapted by evolving evasion strategies to cope with a hostile immunologic environment. We are studying how virus immune evasion proteins operate in various subsets of infected cells in vitro and shape the host T cell response. Several novel CMV antigens that are targets for CD8+ cytotoxic T cells have recently been identified and studies of their presentation in infected cells are in progress.
A BiTE from cancer's intracellular menu.. Nature biotechnology. 33(10):1040-1.. 2015.
Adoptive cellular therapy: a race to the finish line.. Science translational medicine. 7(280):280ps7.. 2015.
Outcomes of acute leukemia patients transplanted with naive T cell-depleted stem cell grafts.. The Journal of clinical investigation.. 2015.
Engineering CAR-T Cells: Design Concepts.. Trends in immunology.. 2015.
Cytotoxic T-cell cytokines put cancer under arrest.. Cancer immunology research. 3(1):23-5.. 2015.
Safety of targeting ROR1 in primates with chimeric antigen receptor-modified T cells.. Cancer immunology research. 3(2):206-16.. 2015.
Designing chimeric antigen receptors to effectively and safely target tumors.. Current opinion in immunology. 33:9-15.. 2015.
Engineering Human Peripheral Blood Stem Cell Grafts That Are Depleted of Naïve T Cells and Retain Functional Pathogen-Specific Memory T cells.. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 20(5):705-16.. 2014.
Adoptive therapy with chimeric antigen receptor-modified T cells of defined subset composition.. Cancer journal (Sudbury, Mass.). 20(2):141-4.. 2014.
Design and implementation of adoptive therapy with chimeric antigen receptor-modified T cells.. Immunological reviews. 257(1):127-44.. 2014.
Tetramer guided, cell sorter assisted production of clinical grade autologous NY-ESO-1 specific CD8(+) T cells.. Journal for immunotherapy of cancer. 2(1):36.. 2014.
Combinatorial Antigen Recognition by Engineered T Cells. Journal of Investigative Medicine. 62:194-194.. 2014.
Receptor Affinity and Extracellular Domain Modifications Affect Tumor Recognition by ROR1-Specific Chimeric Antigen Receptor T Cells.. Clinical cancer research : an official journal of the American Association for Cancer Research. 19(12):3153-3164.. 2013.
HLA Engineering of Human Pluripotent Stem Cells.. Molecular therapy : the journal of the American Society of Gene Therapy. 21(6):1232-41.. 2013.
TCR-Ligand koff Rate Correlates with the Protective Capacity of Antigen-Specific CD8+ T Cells for Adoptive Transfer.. Science translational medicine. 5(192):192ra87.. 2013.
HLA-F and MHC-I Open Conformers Cooperate in a MHC-I Antigen Cross-Presentation Pathway.. Journal of immunology (Baltimore, Md. : 1950). 191(4):1567-77.. 2013.
Chimeric Antigen Receptor Modified T Cells - Clinical Translation in Stem Cell Transplantation and Beyond.. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.. 2012.