U01AI170424

Assessment of Biomarker Guided CNI Substitution in Kidney Transplantation

Current standard of care for kidney transplant (KTX) recipients has only modestly improved long-term aggregate graft and/or patient survival, identifying a crucial unmet medical need. As the at-risk KTX population is heterogeneous, the currently employed and relatively homogeneous therapeutic approach to immunosuppression in KTX in the US and Canada is suboptimal, and results in a significant proportion of over-immunosuppressed recipients, many with tacrolimus-related toxicities.

In this U01 application, Co-PIs Heeger and Nickerson will build upon their past, productive collaborative efforts, their established multicenter trial consortium and infrastructure, as well as their expertise in biomarkers and mechanistic studies to address this unmet need. The overarching goal of the proposed work is to determine the utility of the HLA-DR/DQ molecular mismatch (MMM) score as a risk stratifying biomarker in KTX. While retrospective studies showed strong correlations between the HLA-DR/DQ MMM score and the risk of developing biopsy proven acute rejection (BPAR) and/or donor specific antibodies (DSA), no prospective studies have tested the HLA MMM score as a risk stratifying biomarker for immunological KTX injury. Nor have any studies attempted to test whether and how the HLA-DR/DQ MMM score performs as a predictor of outcome following a change in transplant immunosuppression.

Herein, we propose a multicenter observational study with a nested randomized controlled (RCT) trial to address these deficiencies. We will prospectively test the utility of the HLA-DR/DQ MMM score as a prognostic biomarker of primary alloimmunity [T cell mediated rejection (TCMR), DSA, and antibody mediated rejection (ABMR)] in KTX (Aim 1, observational study of 800 KTX). We will also test the hypothesis that the HLA-DR/DQ MMM score is a predictive biomarker that identifies KTX recipients who will tolerate substituting the calcineurin inhibitor with self-administered, subcutaneous abatacept (costimulatory blockade), without an unacceptable increased risk of BPAR, while reducing the morbidity of CNI off-target effects (300 KTX, nested RCT with a non-inferiority endpoint, Aim 2). Accompanying mechanistic studies (Aim 3) will provide novel immunological and molecular insights that will also aid in interpreting graft and recipient outcomes of the trial.

If successful, the work will provide crucial information capable of positively, and directly affecting clinical care. The results from the proposed work also have the potential to influence positively the design of future RCTs by providing an HLA-DR/DQ MMM score-based stratification or enrichment strategy for enrolling subjects into trials most likely to be informative for the proposed study agent-- thereby increasing likelihood of trial success in the shortest possible time.

Cedars-Sinai Medical Center

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Los Angeles, California 900481804 United States

Single Zip Code

Investigator Initiated Extended Clinical Trial (R01 Clinical Trial Required) (PAR-20-139)