Education and Professional Standing
PhD, Experimental Medicine, McGill University 1994
BSc, Biochemistry, McGill University 1991
Our group is studying the mechanisms by which the adaptive immune system recognizes and responds to viruses and tumors. Our research interests have prompted us to examine multiple aspects of immunology, oncology and virology.
We are currently involved in the following research pursuits:
1. Development of genetic vaccination for cancer therapy [Funded by OCRN, TFF, OICR]
Cancer vaccines should provide an ideal adjuvant to current therapies since immune cells have the unique capacity to circulate and “seek out” malignant cells within the body. Genetic vaccines are highly immunogenic and can readily incorporate tumor antigen cDNAs providing a very useful tool for tumor immunotherapy.
In murine models, we have observed that recombinant adenovirus vaccines are highly efficient agents for evoking immunity against cancer antigens. Interestingly, we observed that these vaccines can be administered during periods of extreme leucopenia without affecting immunogenicity demonstrating their compatibility with conventional cancer treatments, like chemotherapy and radiation (6). We have also found that genetically-modified dendritic cells provide a robust platform for immunization against cancer antigens. Interestingly, the dendritic cell vaccines appear to engage separate pathways from the recombinant adenovirus vaccines (11, 12). We are presently working to characterize the mechanisms underlying these different outcomes.
Another area of interest to my laboratory is the application of xenoimmunization to cancer vaccination where homologous proteins from different species are used for immunization. In principle, subtle non-conserved changes in protein sequence can give rise to heteroclitic epitopes that elicit T cells cross-reactive towards both the native and “xeno”antigen. To better understand the mechanisms underlying xenoimmunization, we have also employed the model melanoma antigen, dopachrome tautomerase (DCT a.ka. TRP-2) as a model antigen due to its high degree of immunogenicity (13). Identification of T cell epitopes in DCT revealed a novel mechanism of action whereby CD4+ T cells responsive to heteroclitic epitopes within the xenoantigen can elicit effector CD8+ T cells specific epitopes within the native antigen (14). Further investigation of the CD4+ T cell response to DCT also revealed that the effector epitopes recognized by anti-tumor CD4+ T cells are generated through post-translational modification of DCT suggesting a novel pathway by which these CD4+ T cells may escape negative selection in thymus.
An even more exciting finding relates to our recent discovery that the mechanisms by which CD4+ T cells mediate anti-tumor destruction and auto-immune pathology can be separated along the STAT-4/STAT-6 signalling axis. This recent result suggests that it should be possible to develop a vaccine that will selectively destroy tumor tissue without affecting healthy tissues. Our current work is targeted at further characterizing this process and testing the limits of this dichotomy.
Given the success of dendritic cell vaccines in preclinical models, we have been working with our colleagues at McMaster (Yonghong Wan, Ronan Foley, Bindi Dhesy, Graeme Fraser, Mark Levine) to evaluate dendritic cell vaccines in early phase human trials. We have successfully completed a Phase I/IIa trial in melanoma demonstrating the feasibility of this approach and we are in the midst of a similar trial for breast cancer. We have received additional support for these early phase translational investigations through research grants from the Terry Fox Foundation and the Ontario Institute for Cancer Research. These funds are directed at supporting a research program that links multiple centers across Ontario and Canada. Through these programs, we continue to advance our prototype vaccines and evaluate novel platforms for cellular vaccination, including B cells and bone marrow stromal cells (in collaboration with Dr. David Spaner @ Sunnybrook Health Sciences Center and Dr. Jacques Galipeau @ McGill University). 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. The Bramson lab has established a GLP immune monitoring facility in study anti-tumor immunity in patients undergoing these experimental treatments.
2. Investigating the immunobiology of recombinant adenovirus vaccines [Funded by CIHR]
Advances in molecular virology have provided an array of virus vectors that can be used to express heterologous coding sequences (transgenes) in mammalian cells in vivo. Since the transgenes are expressed within the context of a virus infection, their protein products are subject to immune surveillance and elicit robust cellular and humoral responses. We refer to such vectors as “genetic vaccines” since the target antigen is encoded within the genetic component of the vaccine. This approach greatly facilitates vaccine development since genes encoding putative targets can be incorporated into expression vectors with minimal knowledge of protein structure/function. Importantly, antigens from viruses such as HIV or HCV can be inserted into mildly pathogenic viruses for the purpose of immunization, eliminating the chance of inadvertently delivering the disease-causing agent to patients.
Implementation of genetic vaccination in the clinic is complicated, however, by the large number of available vectors and the absence of clear criteria for vector selection. To gain greater insight into the relationship between the vaccine vector and the resultant immune response, we have chosen to compare and contrast the cellular response elicited by 4 distinct vaccination platforms: plasmid DNA (1, 2, 3), recombinant adenovirus (4, 5, 6, 7, 8, 9), recombinant vaccinia virus and alphavirus replicons (10). We are investigating the relationship between the location of antigen expression, antigen presentation and T/B cell activation following immunization with these vaccines.
Our studies are focused on identifying the mechanisms by which the recombinant viruses trigger adaptive immunity. We are particularly interested in recombinant adenovirus vaccines which have exhibited remarkable activity in preclinical models and early human trials although results from a recent human trial were disappointing. Our investigations of CD8+ T cell and CD4+ T cell responses produced by recombinant adenoviruses discovered that although these viruses do not replicate, they elicit CD8+ T cell responses reminiscent of viruses that establish a persistent infection (7). We have since determined that the CD8+ T cell population is maintained by very low-level gene expression that persists for weeks following adenovirus infection. Although the source of antigen during this period is unknown, we have evidence to suggest that it is located in non-hematopoeitic cell suggesting a novel role for non-hematopoietic cells in the maintenance of CD8+ T cell memory. Interestingly, this low-level gene expression does not appear to influence the CD4+ T cell response. We are currently investigating how the adenovirus evokes such a response (and why other vectors/viruses do not) by examining the relationship between antigen localization and timing of antigen expression in regard to the development of CD8+ T cell, CD4+ T cell and B cell responses.
3. Studies of T cell immunity in humans naturally-infected with West Nile virus [Funded by NIH]
Rational vaccine design requires a proper understanding of the mechanisms of anti-viral immunity in naturally infected humans. We are presently taking part in a longitudinal study of patients infected with West Nile virus to determine the relationship between T cell immune reactivity to West Nile proteins and long-term sequellae following infection. Since ageing has been associated with impaired immunity, it has been hypothesized that severe illness following West Nile infection in the elderly may result from inadequate immune control following infection. Since neuroinvasive disease does not occur uniquely in the aged population, we are also considering other immune-mediated events that could underlie severe pathology. We are particularly intrigued by the possibility that neurological complications following West Nile virus infection may result from inappropriate T cell activation during infection leading to T cell-mediated destruction of CNS tissues.
We have recently completed an analysis of West Nile virus-specific CD8+ T cell immunity in a cohort of 52 patients with both mild and severe disease. Surprisingly, we did not observe any relationship between age and the magnitude or breadth of the T cell response. These results were unexpected and suggest that the relationship between age and immune function must be reconsidered. We are presently extending our investigation to characterize the functionality of the CD8+ T cells in the young and aged members of our cohort and to characterize CD4+ T cell function in these individuals.
Dr. Bramson is involved within the Faculty of Health Sciences in the following programs:
- Bachelor of Health Sciences Program
- HTH SCI 4J03: Biochemical Immunology
- Graduate Program in Medical Sciences
- Molecular Immunology, Virology, and Inflammation (MIVI)
- MS 750: Topics in Host Resistance
- MS 717: Vaccines and Vaccine Immunology
See selected publications here
See team members here