Development and application of comprehensive T-cell receptor reactivity profiling technologies to aid in the discovery of novel immune cell therapies

The success of chimeric antigen receptor (CAR)-T cell therapy in the treatment of leukemia has spurred significant effort into developing similar “living medicines” for other cancer types. A large component of this effort is to discover new immune cell receptors that can be engineered into T cells, a specialized subset of immune cells, to function as the guidance system needed to attack and kill specific tumors. However, the difficulty associated with this lies in finding immune receptors that effectively target cancer cells but do not damage healthy tissues. Indeed, multiple clinical trials to-date have resulted in patient deaths due to catastrophic and unanticipated autoimmune reactions. We have developed an innovative laboratory screening method that profiles the reactivity, up front, of candidate T cell therapies against very large sets of possible targets. With this capability, our technology can comprehensively screen candidate cell therapies and predict which ones represent an unacceptable safety risk early in the discovery phase of development. As a result, our platform will increase the likelihood of T cell-based therapies achieving success in clinical trials and becoming approved treatments.

The Impact of COVID-19 on Cancer Diagnosis and Outcomes in British Columbia (BC)

Diagnosing cancer early is critical to achieve positive patient outcomes. The COVID-19 pandemic has had an unprecedented impact on cancer diagnosis in BC, suspending screening programs and drastically reducing diagnostic services. The patient and population health impact of a prolonged reduction in these services is unknown. Further, as COVID-19 restrictions ease, the expected demand for these services will exceed the system’s capacity, significantly increasing wait times. It is now critical for BC Cancer to establish priorities for the re-introduction of services to reduce negative impacts of delays. Our research will quantify the impacts of reductions in cancer diagnostic services on patient outcomes and develop effective strategies for re-introduction.

Investigating noncoding RNA networks in hematopoiesis

The genetic material of cells is DNA. The popular notion in biology for a long time was that DNA makes RNA which in turn makes proteins. But over the past two decades, research has shown that not all types of RNA are converted to protein. These RNAs which do not make (or do not code for) proteins are called noncoding RNAs. Long noncoding RNAs (lncRNAs) belong to one of the classes of noncoding RNAs. Based on various studies, we know that lncRNAs are crucial during different biological contexts including embryonic development as well as disease. The importance of lncRNAs in blood stem cells and blood cancer is not yet studied in detail. We will study how lncRNAs can help blood stem cells to either remain as stem cells (maintain stemness) or convert into different blood cell types (differentiate) and how they control the blood stem cells from forming cancer.

One of the very recently studied modes of action for lncRNAs is the binding of long noncoding RNAs to other class of noncoding RNAs called microRNAs and blocking the action of microRNAs. By using several techniques, we will systematically decipher lncRNAs acting by the microRNA mechanism to the blood stem cells in maintaining stemness or differentiation. The knowledge from this project will improve our understanding of the biology of blood stem cells and can be helpful in future for treatment of disorders of the blood system, bone marrow failure and cancer.

Targeting stress granules: A novel strategy to inhibit Ewing sarcoma metastasis

Metastatic disease remains the single most powerful predictor of adverse outcomes in Ewing sarcoma (ES) and other childhood sarcomas (malignant connective tissue tumours). High risk ES appears to be characterized by uninhibited outgrowth of neoplastic clones that have acquired additional genomic or epigenomic alterations, which facilitate the spread of the cancer cells. 

Considerable research has focused on understanding the genetic and biomolecular alterations that underlie ES, including drug resistance. The challenge is to identify targetable events that can be used to characterize metastatic disease, which is widely held as an inefficient process, with only a tiny fraction of primary tumour cells surviving. 

Emerging evidence suggests that a largely overlooked component of the spread of tumour cells is the impact of stress adaptation, occurring through acute changes in mRNA translation and protein synthesis. It is likely that specific ribonucleoprotein complexes known as stress granules (SG) are intimately connected to cancer biology, and even resistance to chemotherapy. However, targeting these structures in cancer cells has not been widely pursued. Dr. El-Naggar’s research will focus on understanding the link between stress granules  and conditions that promote the spread of cancer cells. 


Role of allergen-experienced Group 2 Innate Lymphoid Cells in allergic lung inflammation

Allergic asthma is an incurable respiratory disease that affects more than 300 million people worldwide. Asthmatic patients first become sensitized by inhaled substances that trigger an allergic reaction (allergens). Repeated exposures to the same allergens cause allergic inflammation in the lung because allergen-specific cells of the immune system called lymphocytes acquire memory: they react when they re-encounter the same allergen.

Another set of cells, the recently identified Group 2 Innate Lymphoid Cells (ILC2s), can also trigger allergic lung inflammation. Unlike regular lymphocytes, ILC2s do not recognize specific allergens. However, experienced ILC2s can vigorously react to new allergens, causing a stronger allergic lung inflammation than they did on their first exposure to unrelated allergens. Therefore, ILC2s can acquire memory that is not specific to particular antigens.

We believe that upon allergen encounter, different subsets of memory ILC2s are generated. The goal of this research is to characterize memory ILC2s in the chronic phase of allergic lung inflammation.

The results obtained in this research would explain why sometimes the causative allergen is not identified and why asthma vaccines are not always effective. This research may lead to the development of novel therapies for chronic asthma.

Co-registered optical coherence tomography and autofluorescence imaging

Lung cancer is the most common cause of cancer death with more than 1.3 million mortalities annually. Autofluorescence (AF) bronchoscopy is an established clinical technique that has proven to be extremely effective for early detection and staging of cancer by identifying high-risk areas where biopsies should be collected.

Currently, AF imaging is the most sensitive means of lung cancer detection. However, the improved sensitivity of AF broncoscopy comes at the cost of a decrease in specificity due to false-positive fluorescence in areas of inflammation or an increase in epithelial thickness. Moreover, performing biopsies and conducting histology on the removed tissue are costly and time-consuming.

The efficacy of the treatment would be significantly enhanced by differentiating carcinoma from other non-dangerous anomalies. OCT, the optical equivalent of ultrasound, enables high resolution in vivo imaging of airway morphology to study the high-risk tissue sites without performing biopsy and removing tissue. Therefore, when used in combination, AF-OCT imaging can provide rich biochemical information. The aim of Dr. Pahlevaninezhad’s research is to combine AF imaging and optical coherence tomography (OCT) to manage this disease through earlier detection. Dr. Pahlevaninezhad’s research method begins with combining the two modalities in free space to test ex vivo samples and to calibrate the system. The next step will be to build a fibre-based system for in vivo imaging of lung and to test the system on a small number of consenting patients.

Through the combination of these imaging techniques, Pahlevaninezhad’s research will provide both architectural and biochemical information which will aid in avoiding unnecessary biopsies. Significantly, the applications of the proposed device are not just limited to lung cancer; it also could target other applications like the oral cavity, considerably enhancing the ability to detect cancers effectively and efficiently.

Evolutionary dynamics and driver mutations underlying histological transformation and treatment resistance in follicular lymphoma

Lymphoid cancers arise from lymphocytes, a subset of white blood cells, and represent the fifth most common cause of cancer. Follicular lymphoma (FL) is a common subtype of lymphoid cancers. For ten percent of FL patients, the disease either does not respond to primary therapy or progresses early after treatment. These patients have poor outcomes and often require aggressive therapeutic interventions.

With regards to its origin, FL demonstrates how cancers arise through the successive acquisition of changes in their genomes. In his research, Dr. Kridel’s group has identified highly recurrent mutations in certain genes which delineate disease-initiating mechanisms. Yet, the biological underpinnings of treatment resistance and transformation in FL are only partially understood.

Dr. Kridel hypothesizes that both resistance to therapy and transformation can be explained by genetic alterations that are either present at diagnosis and get selected for during therapy, or that arise during the course of the disease. Thus, Dr. Kridel’s team will apply high-throughput genome sequencing technology to paired FL and progressed/transformed lymphoma samples. Dr. Kridel will leverage the availability of tumour specimens from the tissue repository of the Centre for Lymphoid Cancer at the BC Cancer Agency and collaborate with the Computational Biology group of Dr. Sohrab Shah, who has developed cutting-edge tools to examine genome-wide mutational changes.

The goal is to improve patient outcomes by understanding the genetic mechanisms that drive treatment resistance, early progression and transformation in FL.

The role of histone methyltransferase SETD2 in the development of acute myeloid leukemia

Acute myeloid leukemia (AML) results from genetic defects. Recurrent  variations in chromosomal structures are common in AML, and several genes have been identified to be recurrently mutated in AML. Identification of these genetic defects in AML patients has improved diagnosis and treatment. However, more than twenty-five percent of AML patients carry no mutations in the known leukemia-associated genes, and the heterogeneity of AML and various survival outcomes suggest that as yet, undiscovered genes and pathways contribute to AML.

Dr. Gerben Duns performed high-throughput RNA sequencing and resequenced whole exomes, a portion of the genome, on 92 AML clinical samples to discover novel genes involved in AML. Mutations were identified within a gene called SETD2 in 7.6 percent of samples, suggesting a role for SETD2 in a subset of AML samples. The nature of the identified mutations suggests that these mutations are inactivating, which is in concordance with the recent identification of inactivating SETD2 mutations in several other cancer types.

Through in vitro and in vivo studies, Dr. Duns will examine the effects of the inactivating and mutating gene SETD2 as it contributes to AML development. Bioinformatic approaches are also used to investigate the potential association between the presence of SETD2 mutations and the response to therapy and disease outcome.

This study will provide insights into the mechanisms of AML pathogenesis, and will potentially reveal novel diagnostic and prognostic markers, as well as therapeutical targets.