Sabra Salim is an Undergraduate Science Student at McMaster University
Sabra’s project has been generously supported by a gift from the Taite Boomer Foundation
About the research
Project title: « Improving the safety of CAR-T cells using inducible caspase-9 safety switch”
Glioblastoma (GBM) is the most common primary malignant brain tumour in adults. Despite current standard of care involving surgical resection, radiotherapy and high-dose chemotherapy with the alkylating agent temozolomide (TMZ), disease relapse is inevitable. Numerous studies have implicated CD133+ brain tumour initiating cells (BTICs) as drivers of chemo- and radio-resistance in GBM. CD133 expression correlates with disease progression, recurrence, and poor overall survival of GBM patients. This treatment resistance underscores an urgent need for exploring other treatment options including immunotherapy. Among different immunotherapeutic modalities, chimeric antigen receptor (CAR) technology holds great promise. The CAR strategy is an adoptive T cell therapy that uses T cells with genetically modified antigen-recognizing receptors to recognize tumour cells and induce cell death upon T cell activation. However, this CAR Technology is checked by safety concerns, highlighted by the prevalence of off-target toxicities that can be lethal. To mitigate this effect, we propose to construct a cellular safety switch, inducible caspase 9 (iCasp9) CAR-T vector targeting CD133+ BTICs that has the potential to eliminate GBM BTICs as well as mitigate the risks of T-cell therapy by enabling the elimination of transferred T cells when required.
About Sabra, in her own words…
Glioblastoma Multiforme (GBM) is the most common and aggressive form of malignant primary brain tumours in adults. Despite scientific advances in our understanding of its development, there remains much to learn about the intricacies of this disease. My interest in neural diseases piqued after volunteering at an Alzheimer’s clinic. Upon coming to McMaster, I learned about brain cancer and was reminded of the deterioration of Alzheimer’s patients I saw first-hand. Ultimately, these experiences lead me towards furthering my knowledge of brain cancer research in hopes of developing a viable therapy option for GBM patients.
Being awarded a Brain Tumour Research Studentship means that I can pursue my interests while learning from a dedicated community of patients, volunteers, students and scientists. As we learn more about GBM, being able to participate in developing adaptive therapies is an opportunity that I am grateful for. Even more, this award reaffirms my hopes of continuing a lifelong career in cancer biology.
For the next two summers, I am honoured to explore a novel therapeutic option for patients with glioblastoma. I am indebted to Brain Tumour Foundation of Canada and the Boomer Family, who have graciously funded this award in loving memory of Taite.
Progress Update – January 2019
Over the past summer, I have had the opportunity to make some advancements in my project. The first component of my project is to assess the efficacy of CD133 CAR-Ts in targeting patient-derived human GBM. Over this time, I worked on optimizing a luciferase-based assay to see how CAR-Ts can directly induce cytotoxicity in GBMs. In addition to optimizing this assay, I also assisted in the in vivo experimentation of CAR-Ts using humanized mice models where we found that CAR-T treatment significantly prolonged survival and reduced tumour burden. We also assessed some other properties of the CD133 CAR-T that include their ability to become activated and proliferate when incubated with an antigen-presenting cell. Overall, this past summer, we have been able to characterize and profile various properties of our CD133 CAR-T which cumulatively show its efficacy as a therapeutic modality for patients with GBM. In addressing the safety concerns of the CAR-T, I also briefly profiled the ability of a chemical dimerizer to induce apoptosis in a safety-switch system. One primary problem we have with the safety switch is the low transduction efficiency of the vector which we are in the process of optimizing. While much of the summer was focused on assessing the isolated CD133 CAR-T, I hope to further optimize the inducible apoptotic system in the iCASP9 CAR-T to back some of the safety concerns associated with the CAR-T therapy.
Final report – December 2019
I would like to thank Brain Tumour Foundation of Canada and the Taite Boomer Foundation for this award. While I am grateful that this award has allowed me to further my scientific career, it has been equally an honour to join this passionate community of scientists, donors, families and patients in the fight against brain cancer.