Recipient immunity as a determinant of long term outcome in bone marrow transplantation
Allogeneic stem cell transplantation (alloSCT) is an effective therapy in haematological malignancies, but is associated with significant rates of relapse, infection and graft versus host disease (GVHD). High intensity myeloablative conditioning results in the highest rate of disease eradication, but is associated with the greatest toxicity. Conversely, reduced intensity conditioning (RIC) is safer, but less effective due to lower rates of engraftment and induction of a less potent graft-versus-tumor (GVT) effect. In order to improve the safety and efficacy of alloSCT, novel ways to achieve less toxic regimens that maintain GVT whilst lessening GVHD are desperately required. Also required are treatments that improve donor bone marrow function in recipients with poor marrow function post alloSCT. We have previously identified that residual recipient immunity after RIC impacts on the efficacy of donor engraftment (Davis et al 2015 BBMT; Jiao et al 2019 CDD) which can be targeted to improve alloSCT outcomes.
We are currently undertaking investigator initiated clinical trials to translate these findings into the clinic (VICTORY and RESELECT). The VICTORY study incorporates velectoclax into standard RIC to reduce residual immunity in patients prior to alloSCT while the RESELECT study uses N-Acetyl Cystine and Avorstatin to increase marrow function post alloSCT. Both studies incorporate significant correlative analyses to examine the immunological impact of these therapies. Complementary to this, we have an ongoing prospective sample collection protocol to collect samples from patients undergoing standard alloSCT (currently at 200+ patients). These samples, along with the comprehensive patient outcome database, offer a rich resource for translational studies into alloSCT.
In this project, advanced immunological techniques to assay peripheral blood (including spectral flow cytometry, proliferation/degranulation/cytokine assays) and bone marrow immunity (including flow cytometry and Digital Spatial Profiling (Koldej and Ritchie 2020)) will be used to compare and contrast the immunity of patients treated under these trials with those receiving standard of care therapy. This analysis will further build on the concept of recipient immunity as a determinant of outcome post alloSCT and identify new leads for future clinical trials. Potential scholarship funding may be available for outstanding candidates.
This research project is available to Honours students to join as part of their thesis.
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