Project 467036

Glioblastoma multiforme (GBM) is the most common and aggressive primary adult brain tumour. Despite multimodal management patients currently face a median survival of 15 months and disease recurrence is virtually 100% certain. Development of novel therapeutics is desperately needed. Adoptive cell transfer of T cells engineered with synthetic receptors targeting GBM offers the promise of achieving durable tumour control through the ability of immune cells to persist within the host and destroy malignant cells as they re-emerge. Modern engineered T cells have shown limited success in treating GBM due, in part, to the fact that GBM is a heterogeneous disease and the therapeutic cells evaluated thus far have been directed at single tumor targets. These engineered T cells also bear significant financial and technical burden as they are manufactured on a per-patient basis. We propose to overcome these challenges by developing an off-the-shelf engineered T cell product that can attack multiple GBM targets. To this end, we have chosen a non-canonical T cell population, known as γδ T cells, as a platform for this off-the-shelf approach given their ability to be transferred to unrelated hosts without risk of lethal graft-versus-host disease. While γδ T cells are capable of directly attacking GBM, we are augmenting that capacity by engineering the T cells to express a series of synthetic receptors against multiple GBM targets. We hypothesize that engineering T cells with multi-target specificity will increase therapeutic potency. Addressing this hypothesis using an off-the-shelf platform is expected to facilitate clinical translation of the outcomes by offering an affordable solution that can be manufactured in a controlled fashion and made available across Canada.