Kidney transplant recipients have suboptimal long-term outcomes on current therapy predominantly due to off- target effects of calcineurin inhibitor (CNI)-based protocols, and/or their failure to control the immune response to the graft. Improving patient outcomes will require novel therapeutic agents that inhibit components of the recipient?s immune response not controlled by CNI-based therapy. Interleukin (IL)-6 is a cytokine that promotes T cell proinflammatory phenotypes (i.e. Tfh, Th1, Th17 cells) while inhibiting regulatory T cells, as well as promoting antibody formation by inducing B cell differentiation into plasmablasts. The critical involvement of IL- 6 in these pathways makes it an attractive target for attempts to improve kidney transplant outcomes, especially in the context of CNI substitution strategies. Additionally, while CNI withdrawal/substitution can improve kidney function, randomized controlled trials of CNI withdrawal/substitution performed by our group and others, in clinically ?low risk? kidney transplant recipients have failed. Thus, current clinical risk stratification strategies and available immunosuppressive therapies are inadequate for guiding individualized immunosuppression. The co- PIs of this proposal have identified that the level of HLA-DR/DQ molecular mismatch (mMM): a) classifies kidney transplant recipients as high, intermediate or low risk for developing a primary alloimmune response (i.e. rejection), and b) identifies the low-risk category as those likely to tolerate CNI minimization/withdrawal. Based on these data the FDA accepted HLA-DR/DQ mMM into its Biomarker Qualification Program with the caveat that prospective multicenter validation is required. To this end, we propose a prospective observational, multicenter, HLA mMM validation study (Aim 1) that includes, in a subset of 300 immune quiescence patients, a randomized controlled trial substituting anti-IL-6 mAb (Clazakizumab [Claza]) for CNI (Aim 2), testing the impact of the intervention on 2 year outcomes. Mechanistic studies will delineate the pathways by which Claza impacts outcomes after CNI substitution. Within this framework, we will test the hypothesis that in the absence of pre-existing DSA, the HLA-DR/DQ mMM score is both a prognostic and predictive biomarker capable of guiding immunosuppressive therapy in kidney transplantation. In addition, our consortium has identified multiple non-invasive diagnostic biomarkers of subclinical/clinical rejection.
In Aim 3 we will: a) validate the utility of each biomarker alone and together as non-invasive diagnostic tests for detect rejection in a real-world kidney transplant cohort, and b) assess the utility of each biomarker to detect resolution of rejection in response to therapy as determined by a post-treatment biopsy. The goal of this R34 proposal is to complete the study protocol design, finish designing the mechanistic studies, finalize the statistical analysis plan, and establish the framework for trial operation and management in order to be in a position to submit an FDA trial IND application, a final application for IRB approval and a U01 application.
Currently clinicians cannot accurately identify ahead of time those kidney transplant recipients who need more or less anti-rejection medications; some patients do not get sufficient medication and have rejection, while others experience significant side effects that might be diminished if less medication was employed. Our goal is to identify specific treatment regimens tailored to the individual?s risk for rejection in order to optimize patient and transplant outcomes. This is a planning grant to develop a clinical trial that addresses this unmet need by evaluating a novel biomarker?s (HLA molecular mismatch) utility to prognosticate and predict risk for transplant rejection and at the same time evaluate a novel therapy (anti-IL-6 monoclonal antibody) that we hypothesize is as effective as current immunosuppressive therapies, but with a more favorable adverse event profile.
