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Principal Investigator: David M. Briscoe
Organization: BOSTON CHILDREN'S HOSPITAL
Fiscal Year: 2024
Award: $1,002,068
Funding agency: National Institute of Allergy and Infectious Diseases
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, and as such, 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 Tmemory. 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 yrs, 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. 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 vaccine. 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.
Terms: <0-11 years old><2-arm trial><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><ATGAM><Active Follow-up><Acute><Address><Adopted><Adult><Adult Human><Alloantibodies><Allografting><Anti-Rejection Therapy><Anti-Thymocyte Globulin><Antibody Response><Antithymocyte Globulin><Antithymoglobulin><Area><Assay><Binding><Bioassay><Biological Assay><Biological Markers><Biopsy><Burkitt Herpesvirus><Burkitt Lymphoma Virus><COVID-19 virus><COVID19 virus><Caring><Cell Body><Cell Communication><Cell Interaction><Cell-to-Cell Interaction><Cells><Cessation of life><Child><Child Youth><Childhood><Children (0-21)><Chronic><Clinical><Clinical Trials><CoV-2><CoV2><Collaborations><Creatinine><Data><Data Bases><Databases><Death><Development><Diagnostic><Donor person><Dysfunction><EB virus><EBV><ESRD><Education><Educational aspects><End stage renal failure><End-Stage Kidney Disease><End-Stage Renal Disease><Enrollment><Epstein Barr Virus><Evaluation><Exposure to><Failure><Functional disorder><Future><Genes><Genomics><Genotype><Goals><Graft Survival><Grafting Procedure><HHV-4><HHV4><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Hospital Admission><Hospitalization><Human Herpesvirus 4><Immune><Immune response><Immunes><Immunity><Immunobiology><Immunological response><Immunomodulation><Immunophysiology><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunosuppressive Therapy><Inducer Cells><Inducer T-Lymphocytes><Induction Therapy><Infection><Infectious Agent><Infectious Mononucleosis Virus><Inflammation><Investigators><Isoantibodies><Kidney Grafting><Kidney Transplantation><Kidney Transplants><Knowledge><Laboratories><Life><Life Expectancy><Living Donors><Maintenance><Maintenance Therapy><Mediating><Memory B Cell><Memory B-Lymphocyte><Molecular Interaction><Monitor><Morbidity><Morbidity - disease rate><NEOADJ><Neoadjuvant><Neoadjuvant Therapy><Neoadjuvant Treatment><Opportunistic Infections><Organ Transplantation><Organ Transplants><Outcome><Patients><Pattern><Performance><Physiopathology><Pilot Projects><Population><Process><Production><Proteins><Randomized><Rapamune><Rapamycin><Regimen><Renal Grafting><Renal Transplantation><Renal Transplants><Renal function><Research Personnel><Researchers><Risk><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Schools><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Signal Pathway><Sirolimus><Solid><Survival Rate><T-Cells><T-Lymphocyte><Tacrolimus><Testing><Therapeutic Agents><Therapeutic immunosuppression><Thymoglobulin><Transplant Recipients><Transplant immunology><Transplantation><Transplantation Immunology><Urine><Vaccines><Viral Diseases><Virus><Virus Diseases><Wuhan coronavirus><active followup><adulthood><age associated><age correlated><age dependent><age linked><age related><age specific><aged><allograft rejection><alloimmunity><arm><artificial immunosuppression><bio-markers><biologic marker><biomarker><child patients><clinical center><clinical significance><clinically significant><coronavirus disease 2019 virus><coronavirus disease-19 virus><data base><data registry><determine efficacy><developmental><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><enroll><evaluate efficacy><examine efficacy><experience><follow up><follow-up><followed up><followup><genome scale><genome-wide><genomewide><graft function><hCoV19><host response><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunosuppression therapy><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><induction therapies><infectious organism><innovate><innovation><innovative><insight><intervention arm><isoimmunity><kidney function><kidney tx><kids><mTOR Inhibitor><mortality><mycophenolate mofetil><mycophenolic acid morpholinoethyl ester><nCoV2><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><novel virus><open label><open label study><organ allograft><organ graft><organ xenograft><pathogen><pathophysiology><pediatric><pediatric patients><pilot study><point of care><post-transplant><post-transplantation><posttransplant><posttransplantation><prediction algorithm><preservation><prevent><preventing><primary end point><primary endpoint><randomisation><randomization><randomly assigned><response><seropositive><standard of care><thymus derived lymphocyte><tool><transcriptomics><transplant><transplant centers><transplant donor><transplant patient><treatment arm><treatment choice><two-arm trial><urinary><vaccine antibodies><vaccine induced antibodies><vaccine-induced antibodies><viral infection><virtual><virus infection><virus-induced disease><youngster>