Our group is studying the mechanisms by which the adaptive immune system recognizes and responds to tumors. Our specific interest is the development of immunological strategies to fight cancer.
Cancer immunotherapy aims to augment the ability of the immune system to recognize and destroy tumors. Such an approach should provide the ideal adjuvant to current therapies since immune cells have the unique capacity to circulate and “seek out” malignant cells within the body, thereby clearing deposits of micro-metastases. Furthermore, since immune cells can eradicate quiescent cancer stem cells that are typically resistant to chemotherapy, immunotherapy offers the potential for a life-long cure. Indeed, recent clinical trials have provided unequivocal evidence that the immune system can be harnessed to mediate tumor regression in humans. However, successful implementation of immunotherapy has been restricted to a specific set of cases and further work is required to develop this as a routine and practical method of treatment.
My lab has taken a multi-modal approach to treating cancer by employing a combination of cancer vaccines, adoptive T cell therapies and oncolytic viruses. We believe that such multi-pronged strategies are the best way to attack the tumor. Our research is supported through research grants from the Terry Fox Foundation and the Canadian Institutes for Health Research.
In murine models, we have observed that recombinant vaccines were highly efficient agents for evoking immunity against cancer antigens. However, despite the robust immune response produced by these vectors, they are typically ineffective against established tumors. We have recently discovered that tumors adapt rapidly to immune attack and create an localized immune suppressive environment that shuts down the ability of T cell to elaborate their effector functions. This rapid adaptation is induced by cytokines, such as IFN-gamma, which are key effector molecules produced by T cells to suppress tumor growth. Thus, the effector molecules produced by tumor-specific T cells can be considered double-edged swords that act to both suppress tumor growth and to activate immune suppressive pathways. Further investigation revealed that the tumor adaptation can be overcome by enhancing the rate at which immune cells attack the tumor; this can be achieved by infusing the host with tumor-specific T cells prior to vaccination. We have employed transciptional analysis to investigate the microenvironment of the tumors following effective treatments (i.e. tumors regressed) and ineffective treatments (i.e. tumors did not regress). Strikingly, we found an 85-gene signature in our murine studies that was predictive of outcome in humans indicating that global changes we observe in mouse models are relevant to human disease. We are currently working to refine our signature to determine whether it can be used as a predictor of outcome following immune intervention in humans.
As stated in the previous paragraph, our studies have revealed that immune attack on tumors must be fast and furious to overcome tumor adaptation. One way to achieve a swift and overwhelming immune attack is to culture tumor specific T cells ex vivo and infuse a massive bolus injection of T cells (a process termed adoptive T cell therapy or ACT). Although naturally-occuring tumor-specific T cells are rare, clinical application of ACT can be enabled by engineering naïve T cells to express tumor-specific chimeric antigen receptors (CARs), bypassing the need to select rare tumor-specific T cells. We are currently investigating the parameters that influence optimal ACT using CAR-engineered T cells. In particular, we are examining the local effects of these T cells within the tumors to understand the reaction of the tumor to this form of treatment. We have also developed a novel tool for directing T cells to attack tumors known as a tri-functional T cell-antigen coupler (Tri-TAC), which operates through a mechanism distinct from a CAR. Our efforts are currently directed at optimizing Tri-TAC function and the development of novel costimulatory proteins that are triggereed by targets on the tumor. To enhance the activity of our ACT strategies, we are also working with oncolytic vaccines which are engineered viruses which serve the dual purpose of oncolytic agents that effectuate direct tumor killing and vaccination agents which enhance T cell function. The data generated by our research reflects a composite of multiple interacting pathways that are engaged simultaneously.
We have been working with our colleagues at the Juravinski Hospital (Ronan Foley, Mark Levine, Pierre Major) to evaluate cancer vaccines in early phase human trials. We are very excited to be a part of the Ontario Regional Biotherapeutics Program (ORBiT) that is sponsored by the Ontario Institute for Cancer Research. The ORBiT program, directed by John Bell, is focused on early phase clinical trials where cancer vaccines will be combined with oncolytic viruses and adoptive T cell transfer. This program provides a clear path for rapid translation of promising immunotherapies developed through our preclinical program.