U01AI163072

Advancing Transplantation Outcomes in Children - Project Summary/Abstract

Renal transplantation is widely recognized as the treatment of choice for children with end-stage renal disease (ESRD). The life expectancy benefit is significant, and a functioning renal transplant enables children to grow well, develop almost normally, and improve their school educational performance levels.

However, current data indicate that virtually all grafts in pediatric recipients will eventually fail due to chronic allograft dysfunction. Therefore, the goal of preserving long-term allograft function is the key area for future progress. Furthermore, registry data indicate that opportunistic infections are now the most common cause for hospitalization and death in the pediatric population. Little is known about pathogen-specific protective immunity in pediatric recipients who are exposed to multiple novel infectious agents throughout the post-transplant period in the absence of memory.

Our approach in this trial is based on the concept that successful preservation of long-term allograft function requires an immunosuppressive regimen that targets donor-specific alloantibody (DSA) production while preserving pathogen-specific immunity. We also propose that pediatric recipients require precision tools to monitor, identify, and prevent silent subclinical intragraft inflammation/rejection, which is common at early times in the post-transplant period.

Based on a recent pilot study using de novo belatacept therapy in combination with an mTOR inhibitor (MTORI) in pediatric recipients, we will test the hypothesis that early introduction of a belatacept/sirolimus maintenance immunosuppressive regimen is safe and efficacious in children to augment immunoregulation, prevent DSA production, and enhance long-term allograft function.

EBV seropositive primary renal transplant recipients, aged between 6 and 21 years, from eleven experienced pediatric clinical centers will be randomized to receive induction therapy with anti-thymocyte globulin and either belatacept therapy in combination with sirolimus or remain on standard immunosuppression therapy using tacrolimus and mycophenolate mofetil. The primary endpoint analysis includes de novo DSA development and assessment of allograft function after 36 months of follow-up.

Associated studies include surveillance monitoring using a novel automated point-of-care urine biomarker assay and in-depth mechanistic studies on the cellular basis for pathogen-specific immunity and evaluation of functional antibody responses to vaccines. Extensive mechanistic studies will also be performed to assess the impact of belatacept/MTORI on cellular and humoral alloimmunity and the further development of urinary biomarkers to differentiate subclinical rejection from infection.

There are significant unmet clinical needs in pediatric recipients who have unique pathogen-specific and alloimmune responses following transplantation. Overall, the relevance of this proposal is that it builds upon previous trials to test if a novel agent (belatacept) targets allograft dysfunction. In-depth mechanistic monitoring will allow for the prediction of patient course, and our findings will be applicable to recipients of other solid organ transplants.

Children's Hospital Corporation

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]

Massachusetts United States

State-Wide

Clinical Trials in Organ Transplantation in Children and Adults (CTOT-CA) (U01 Clinical Trial Optional) (RFA-AI-20-029)

Amendment Since initial award the total obligations have increased 259% from $2,341,354 to $8,408,838.