Manipulating Recipient Immunological Microenvironment to Improve Outcomes in Allogeneic Transplantation

Research Opportunity
PhD students, Masters by Research
Number of Master Places Available
1
Department / Centre
Medicine and Radiology
Location
Royal Melbourne Hospital
Primary Supervisor Email Number Webpage
Prof David Ritchie david.ritchie@mh.org.au 8559 7266 Personal web page
Co-supervisor Email Number Webpage
Dr Rachel Koldej rachel.koldej@mh.org.au 8559 7264 Personal web page
Dr Joanne Davis joanne.davis@mh.org.au

Summary Allogeneic stem cell transplant (alloSCT) cures blood cancers by establishing a new immune system from the donor. Currently, AlloSCT has significant side effects including graft versus host disease (GVHD) and toxicity from strong chemotherapy. We will use new types of drugs to more safely modify recipient’s immunity prior to transplantation and examine how modifications in immunity allows for successful engraftment, freedom from toxicity (including GVHD) and improve anti-cancer responses.

Project Details

Allogeneic stem cell transplantation (alloSCT) represents the single most common, widely available and potent immunotherapy for the treatment and cure of blood cancers, yet outcome in patients is vastly divergent ranging from complication-free cures through to catastrophic acute and chronic complications. These include graft versus host disease (GVHD), relapse and opportunistic infections, which limit quality of life, place significant psychological and financial burdens on patients and their carers and are fatal in 20% of cases.
Current standard pharmacological GVHD prophylaxis approaches or modifications of pre-transplant conditioning fail to avoid GHVD in two thirds of patients and attempts to intensify T cell depletion/suppression results in unacceptable excess rates of relapse and/or opportunistic infection. Given the “replacement-of-old-with-new” focus of transplant research to date, little attention has been paid to the contribution of residual recipient immunity as a contributor to post-transplant immunity. Variation in post-conditioning residual immunity (and its sculpting of subsequent engrafting donor immunity) is the likely driver of the ongoing disappointing outcomes from conventional reduced intensity conditioning (RIC) regimens in which an excess of relapse and poorer overall survival is observed despite a lowering of transplant related mortality.
In this study, we will utilise mouse models of alloSCT to examine the manipulation of recipient immunity to improve donor cell engraftment and alloSCT outcomes. The incorporation of venetoclax or ruxolitinib into pre-alloSCT conditioning will be investigated as a mechanism to enable the use of RIC while simultaneously allowing full donor cell engraftment, maintaining the anti-cancer effect and preventing GVHD. This project will further validate our hypothesis that recipient immunity pre alloSCT has a significant impact on post alloSCT outcomes. Ultimately, our project will maintain the potent immunotherapeutic potential of alloSCT while reducing its often debilitating and sometimes fatal side effects.



Faculty Research Themes

Cancer, Infection and Immunology

School Research Themes

Cancer in Medicine



Research Opportunities

PhD students, Masters by Research
Students who are interested in joining this project will need to consider their elegibility as well as other requirements before contacting the supervisor of this research

Graduate Research application

Honours application

Key Contact

For further information about this research, please contact a supervisor.

Department / Centre

Medicine and Radiology

Research Group / Unit / Centre

ACRF Translational Research Laboratory

Research Node

Royal Melbourne Hospital

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