Manipulating Recipient Immunological Microenvironment to Improve Outcomes in Allogeneic Transplantation
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.
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