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Honors (Ottawa Hospital Research Institute, Cancer Therapeutics Program) – Investigated the mechanism and immunogenicity of a Maraba virus infected cell vaccine (ICV), specifically within the context of immunogenic cell death and antigen presenting cell recruitment/activation.
Masters (current) – Developing a novel CAR-T based therapy with improved safety, flexibility, and targeting ability for leukemia and lymphoma.
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Antibody-based therapeutics are playing an ever increasing role in the arsenal of treatments of many diseases.
Complex membrane receptors are considered key therapeutic targets in many of these pathologies, yet targeting them with antibodies has proven to be a major challenge. This project is dedicated to the development of approaches that would enable efficient discovery of rare antibodies that bind to the difficult epitopes on the surface of membrane proteins. A novel Microencapsulation-based method for screening and recovery of B-cell clones specific for the membrane protein target of interest will be employed to fish out rare antibodies. This approach will be applicable to many targets that have so far evaded the efforts of drug discovery.
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Developing a panel of K562 cells expressing different HLA molecules (A02-03, A03-01, A11-01, A11-02, A34-02) to screen antigen presentation and T-Cell recognition.
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A substantial portion of the cancer burden worldwide is attributable to infectious agents such as viruses or bacteria. Some of these can directly cause cancers, others can facilitate cancer development, and still others may have no causative role but their existence can indicate the presence of a cancer or risk of developing one. Recently, Fusobacterium nucleatum (Fn) has been found to be highly elevated in a subset of colorectal cancer. Fn is a well recognized benign resident of mucosal surfaces often present in the absence of pathogenicity. The reason why Fn may in some cases be pathogenic and at other times an apparently benign, commensal organism is not yet completely understood. So far we have only a rudimentary idea of Fn gene expression, especially during host infection. Therefore the overall goal of my work is to identify genes associated with Fn virulence, and to determine how expression levels of these genes are modulated during infection of the bacterium into host cells using RNA-Seq. I hypothesize that Fn virulence is directly linked to its invasive capacity, and that invasive Fn isolates require select sets of genes that endow these strains with this (and perhaps other) pathogenic properties, setting them apart from commensal isolates. An alternative hypothesis is that there is no difference in the virulence gene repertoires of commensal and invasive strains, but genes associated with pathogenicity are upregulated under certain circumstances to promote invasion and tumorigenesis. Successful identification of gene targets will allow for the subsequent development of neutralizing antibodies against identified virulence determinants in vaccination strategies. Targeted vaccination against specific virulence genes, as opposed to a general anti-Fn vaccine, will avoid the potential problem of vaccine inefficiency caused by tolerisation to commensal Fn.
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Determination of patient-specific epitopes arising from tumor mutations is a promising strategy to identify patient-specific targets for T cell-based cancer immunotherapy. Such neo-epitopes could be specifically targeted by personalized therapeutic vaccines or by adoptive T cell therapy. However, little is known about optimal methods to identify relevant neo-epitope targets. One possible approach is to analyze both tumor mutations and CD8+ T cell repertoire, in order to identify an existing but weak immune response that can be boosted. Recent results have suggested it is possible, at least on a limited scale, to link specific T cell receptor (TCR) complementarity determining region 3 (CDR3) sequences to specific neo-epitopes based on their correlation in large cohorts of tumors.
At DTU we have developed a tool that enables neo-epitope prediction from tumor sequencing data. The Holt group has optimized a method for determining CDR3 sequences from RNAseq data. We will explore the possibility of using patient-specific CDR3s identified in tumor-infiltrating lymphocytes (TILs) from renal cell carcinoma (RCC) samples, to help prioritize predicted neo-epitopes.
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With their ability to sense and integrate a wide range of signals, actively move to specific tissue compartments, and actuate context-dependent responses, engineered cell-based therapeutics are emerging as promising alternatives to pharmaceuticals and biologics in complex diseases such as cancer and autoimmunity. Cytotoxic lymphocytes (CLs) are cells of the human immune system that are primarily responsible for killing tumor or virally infected cells. CLs are an ideal chassis for developing cell based therapies due to several unique characteristics: (i) they have a secretion pathway that specifically delivers molecules from a CL to a targeted cell; (ii) T-cell receptors (TCRs), or chimeric antigen receptors (CARs), endow CLs with an exquisite level of specificity in selecting a target cell population defined by its surface molecule profile; and (iii) CLs traffic throughout the body and actively home to target sites.
I am exploiting these properties to develop delivery lymphocytes with an engineered secretory pathway that transfers a defined protein payload from delivery cell to target cell. This represents a completely novel approach to molecular delivery, which, when combined with antigen receptor-mediated targeting, would pave the way to a new class of cell-based therapeutics. If combined with emerging complex genetic circuits being developed in the field of mammalian synthetic biology, as well as the clinical protocols of adoptive cell therapy, this work could begin to truly leverage the in vivo computational capacity of cells to sense their environment, and then select and effect an appropriate response.
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The accumulation of mutations (or changes in the genetic code) is a hallmark of cancer. With the advent of next generation sequencing (NGS), it is now possible to rapidly identify all mutations in a patient’s tumour. Recent NGS studies have revealed that cancers contain tens to hundreds of coding mutations, the vast majority of which are unique to individual patients. I am interested in developing personalized vaccines that that target the unique mutations in individual tumours. If used in the clinic, this treatment would provide every cancer patient with a unique vaccine based on the mutational profile of the patient's own tumour.
To investigate this novel treatment, I am using a mouse model of ovarian cancer. In the Holt lab at the Michael Smith Genome Sciences Centre, I performed exome and RNA sequencing on four murine mammary tumours to identify somatic, tumour-specific mutations. In the Nelson Lab in the Deeley Research Centre in Victoria I optimized a novel vaccination approach involving long peptide antigens, the adjuvant poly(I:C), and multiple inoculations that elicits massive proliferation and activation of immune cells called T cells. I use this new vaccination protocol to activate T cells that can recognize unique, tumour-specific mutations in the mouse tumor that I sequenced. I anticipate that the vaccines will cause immune mediated regression established tumours.
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My project is Metagenomic analysis of lung infiltrates in patients with leukemia. The goal is to sequence samples of genomic DNA obtained from DNA isolation from the brochoalveolar lavage (BAL) fluids of patients with leukemia. This metagenomic sequencing will allow us to identify with a greater degree of certainty the exact nature of the bacterial or fungal infilitrates in the lungs, instead of using culturing methods. I will be processing the BAL samples to isolate the genomic DNA, and aliquoting and tracking the remaining patient samples for storage by the biospecimens core.
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