T cell function as a determinant of blinatumomab efficacy in B-ALL
- Research Opportunity
- PhD students, Masters by Research, Honours students
- Number of Honour Places Available
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- Department / Centre
- Royal Melbourne Hospital
|Professor David Ritchiefirstname.lastname@example.org||Personal web page|
|Dr Rachel Koldejemail@example.com||Personal web page|
Summary The CD3/CD19 bispecific T cell engager blinatumomab (blin) is effective for the treatment of relapsed or refractory B cell acute lymphoblastic leukaemia (B-ALL). Total CD8 T cell numbers at the time of treatment have been associated with a higher likelihood of response. However, studies have not explored if patient T cell function has an impact on therapeutic efficacy. We hypothesise that response to blin will be dependent on pre-treatment T cell function.
B-cell acute lymphoblastic leukaemia (B-ALL) is a malignancy of CD19+ B-precursor cells. The CD3/CD19 bi-specific T cell engager blinatumomab had demonstrated remarkable efficiency in attaining deep, minimal residual disease (MRD) negative, remissions in relapsed/refractory B-ALL and is currently being explored in the frontline setting.
To date, low tumour burden and high percentage of CD8 T cells at treatment initiation have been identified as predictive biomarkers of MRD response. We hypothesise that rather than total T cell number, it is the quality and functional capacity of the T cells to respond to blin and subsequently kill tumour cells that determines therapeutic outcome. To explore this, we have collected samples from patients that are embarking on blin therapy in the ALL08 clinical trial. Our initial analysis has demonstrated that there is an association between and increased ability to form immune synapses between T cells and CD19-expressing tumour cells in patients who subsequently achieve MRD negative remission.
Our laboratory, located within the Victorian Comprehensive Cancer Centre, has significant experience in the analysis of T cell fitness in patients with haematologic malignancies undergoing treatment with novel therapies (Wong et al 2020, Cooke et al 2020 and Davis et al 2020) and the assessment of T cell synapse formation (Davenport et al 2018). In this project, advanced immunologic (including spectral flow cytometry, proliferation/degranulation/cytokine assays) and live video microscopy techniques will be used to analyse the impact of T cell fitness in primary patient samples on the therapeutic efficacy of blin.
Opportunities exists to explore how T cell defects that lead to a lower efficacy of blin may be corrected therapeutically to improve B-ALL control.
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PhD students, Masters by Research, Honours students
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Research NodeRoyal Melbourne Hospital
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