The central idea of my research is that appropriate stimulation of the immune system will provide an effective strategy for the treatment and prevention of childhood cancers. Our research, therefore, seeks to understand the influence of the immune system during cancer progression and to use this knowledge to develop approaches to induce therapeutic anti-cancer immune activity. In addition to evaluating the impact of immune responses on established disease, our research seeks to identify the influence of the immune system before cancer is detected. To achieve these goals we use a range of experimental systems, including transgenic mice, adoptive transfer models, human xenograft models, and ex vivo and in vitro analysis of patient samples and human cell lines. It is hoped this broad approach will expedite the development of effective new treatments for children with cancer.
The TLR9 agonist (GNKG168) induces a unique immune activation pattern in vivo in children with minimal residual disease positive acute leukemia: Results of the TACL T2009-008 phase I study.
Pediatric hematology and oncology
TLR9 limits enteric antimicrobial responses and promotes microbiota-based colonisation resistance during Citrobacter rodentium infection.
CD47-ligation induced cell death in T-acute lymphoblastic leukemia
Cell Death & Disease
Pascal Leclair and Chi-Chao Liu and Mahdis Monajemi and Gregor S. Reid and Laura M. Sly and Chinten James Lim
Tailoring the homing capacity of human Tregs for directed migration to sites of Th1-inflammation or intestinal regions.
The non-motor adaptor HMMR dampens Eg5-mediated forces to preserve the kinetics and integrity of chromosome segregation.
Combination therapy with proteasome inhibitors and TLR agonists enhances tumour cell death and IL-1ß production
Cell Death & Disease
Anthony C Tang and Seyed M Rahavi and Shan-Yu Fung and Henry Y Lu and Hong Yang and Chinten J Lim and Gregor S Reid and Stuart E Turvey
Absolute lymphocyte counts at end of induction correlate with distinct immune cell compartments in pediatric B cell precursor acute lymphoblastic leukemia.
Cancer Immunology, Immunotherapy
Cell Cycle-dependent Tumor Engraftment and Migration are Enabled by Aurora A
Generation of a multi-antigen-directed immune response for durable control of acute lymphoblastic leukemia.
IFN-¿ directly inhibits murine B-cell precursor leukemia-initiating cell proliferation early in life
European Journal of Immunology
Mario Fidanza and Alix E. Seif and Sumin Jo and Amina Kariminia and Nina Rolf and Laura M. Sly and Stephan A. Grupp and Gregor S. D. Reid
Y-box-binding protein 1 contributes to IL-7-mediated survival signaling in B-cell precursor acute lymphoblastic leukemia.
Altered Toll-like receptor 9 responses in circulating B cells at the onset of extensive chronic graft-versus-host disease
Biology of Blood and Marrow Transplantation
CpG stimulation of precursor B-lineage acute lymphoblastic leukemia induces a distinct change in costimulatory molecule expression and shifts allogeneic T cells toward a Th1 response
The cationic antimicrobial peptide LL-37 modulates dendritic cell differentiation and dendritic cell-induced T cell polarization
Journal of Immunology
TAP expression provides a general method for improving the recognition of malignant cells in vivo
TRANSPORT AND EXPRESSION IN HUMAN MELANOMAS OF A TRANSFERRIN-LIKE GLYCOSYLPHOSPHATIDYLINOSITOL-ANCHORED PROTEIN
Journal of Biological Chemistry
Immune influence on ALL development. Infection has long been postulated to play a role in the progression of childhood ALL. Using novel models of this disease we are actively identifying the influence of the immune system during a pre-leukemic state on the onset of ALL. Our research indicates that the immune system may exert considerable control over early pre-leukemic cell expansion, but other mechanisms, such as growth factor availability, may also be important. Our long-term goal is to identify the growth constraints on pre-leukemic expansion, understand the influence of infection on these constraints, and use this knowledge to develop targeted strategies to reduce the incidence of primary disease and relapse.
Immune therapy for acute lymphoblastic leukemia (ALL). This research addresses the issue of ALL immunogenicity and the induction of anti-ALL immune activity as a strategy to eradicate residual disease after chemotherapy. Our work has described the ability of immunostimulatory DNA (CpG ODN) treatment both to enhance the immunogenicity of primary human ALL blasts and to stimulate significant anti-ALL immune activity resulting in T cell-mediated protection against disease progression. This work provided the first report of immune-mediated killing of primary human ALL in vivo in the absence of adoptive transfer of lymphocytes or stem cell transplantation, and indicates that toll-like receptor signaling may provide a clinically feasible strategy for augmenting immune responses against ALL. A clinical trial based on this approach is aboout to commence. The next major step in our development of CpG ODN as an immune therapy for ALL will involve the examination of their ability to induce anti-leukemia immune activity after chemotherapy in a spontaneous mouse model of ALL, and to generate ALL-specific T cells against autologous leukemia blasts from patients. By using such models, in which immune tolerance must be overcome, this ongoing work will be the most stringent pre-clinical testing yet of an immune therapy for pediatric leukemia. The goal of these studies is to provide insights that will optimize the clinical application of this approach.Grants
Canadian Institutes of Health Research
Canadian Cancer Society
Leukemia & Lymphoma Society of CanadaResearch Group Members
Maryam Aletaha, Volunteer
Tanmaya Atre, Graduate Student
Ali Farrokhi, Postdoctoral Fellow
Arnawaz Kaleem, Technician
Nina Rolf, Postdoctoral Fellow
Mohammad Sharghi, Volunteer
Brenda Tse, Research Coordinator