SBIR-STTR Award

The goal of this Phase I project is to develop a method to objectively measure immune reconstitution following hematopoietic stem cell transplantation using direct sequencing of the T-cell repertoire. This method will be developed using data from patients treated with stem cells derived from umbilical cord blood. Umbilical cord blood (CB) has emerged as an effective source of stem cells and has several advantages over conventional stem cell sources. However, cord blood recipients are at significant risk of delayed hematopoietic recovery and immune reconstitution, and thus appear to have higher susceptibility to infections, particularly from viral pathogens. The high rate of infections is associated with an alarming level of morbidity and mortality. At present, there is no objective measurement available for clinicians to determine the extent of immune reconstitution in transplant patients, and there are risks and side-effects associated with treatments currently used to prevent infections. The ability to measure immune reconstitution will relieve clinicians and their patients of the burdens associated with excessive, or insufficient, prophylactic treatments. Herein, we propose to utilize our high-throughput TCR sequencing assay to quantify the T-cell repertoire over time in individuals who have undergone cord blood transplantation. We will establish the correlation between the T-cell repertoire and reconstitution of clinical immunity. The ability to simultaneously sequence millions of individual T-cell receptor genes in single individuals provides, for the first time, the potential to directly observe changes in the immune repertoire, and this could allow clinicians to make better informed decisions about patient care.

Public Health Relevance:
The goal of this Phase I project is to develop a method to objectively measure immune reconstitution following hematopoietic stem cell transplantation using direct sequencing of the T cell repertoire. This method will be developed using umbilical cord blood transplant data, but will be relevant and beneficial to the broader transplantation field.

Thesaurus Terms:
21+ Years Old;Adolescent;Adolescent Youth;Adult;Adult Human;Adverse Effects;Anti-Infective Agents;Anti-Infective Drugs;Anti-Infectives;Anti-Infective Preparation;Antiinfective Drugs;Antiinfectives;Antiinfective Agents;Assay;Bioassay;Biologic Assays;Biological Assay;Blood Neutrophil;Blood Polymorphonuclear Neutrophil;Blood Precursor Cell;Blood Sample;Blood Segmented Neutrophil;Blood Specimen;Cmv;Cell Transplantation;Cell Transplants;Childhood;Clinical;Cord Blood;Cord Blood Transplantation;Cytomegalovirus;Data;Disease;Disorder;Engraftment;Ensure;Ethnic Origin;Ethnicity;Ethnicity Aspects;Gvhd;Goals;Graft-Versus-Host Disease;Graft-Vs-Host Disease;Hcmv;Hsc Transplantation;Hematologic Cancer;Hematologic Malignancies;Hematologic Neoplasms;Hematological Malignancies;Hematological Neoplasms;Hematological Tumor;Hematopoietic;Hematopoietic Cancer;Hematopoietic Progenitor Cells;Hematopoietic Stem Cell Transplantation;Hematopoietic Stem Cells;Heterophil Granulocyte;History;Homologous Wasting Disease;Immune;Immune System;Immunity;Incidence;Individual;Infection;Infection Prevention;Laboratories;Mhc Receptor;Major Histocompatibility Complex Receptor;Malignant Hematologic Neoplasm;Marrow Neutrophil;Measurement;Measures;Methods;Minority;Morbidity;Morbidity - Disease Rate;Mortality;Mortality Vital Statistics;Neutrophilic Granulocyte;Neutrophilic Leukocyte;Opportunistic Infections;Outcome;Patient Care;Patient Care Delivery;Patients;Phase;Phase I Study;Polymorph;Polymorphonuclear Cell;Polymorphonuclear Leukocytes;Polymorphonuclear Neutrophils;Predisposition;Prevent Infection;Prevention Measures;Procedures;Progenitor Cell Transplantation;Progenitor Cells;Prophylactic Treatment;Prophylaxis;Receptors, Antigen, T-Cell;Recording Of Previous Events;Recovery;Regimen;Risk;Runt Disease;Salivary Gland Viruses;Source;Stem Cell Transplantation;Stem Cell Transplant;Stem Cells;Susceptibility;T-Cell Receptor;T-Cell Receptor Beta Locus;T-Cell Receptor Genes;T-Cell Receptor Beta Genes;T-Cell Receptor Beta-Chain Genes;T-Cells;T-Lymphocyte;Tcrb;Trb@ Gene Cluster;Tcr Genes;Tcr Beta Genes;Technology;Thymus-Dependent Lymphocytes;Time;Transplant Recipients;Transplantation;Treatment Side Effects;Ucb Transplantation;Umbilical Cord Blood;Umbilical Cord Blood Transplantation;Universities;Viral;Work;Adult Human (21+);Adulthood;Allergic/Immunologic Body System;Allergic/Immunologic Organ System;Communicable Disease Control Agent;Cytomegalovirus Group;Disease/Disorder;Fetal Cord Blood;Human Cytomegalovirus;Juvenile;Juvenile Human;Neutrophil;Pathogen;Pediatric;Peripheral Blood;Phase 1 Study;Prevent;Preventing;Reconstitute;Reconstitution;Side Effect;Therapy Adverse Effect;Thymus Derived Lymphocyte;Transplant;Transplant Patient;Treatment Adverse Effect

Many patients requiring stem cell transplantation for hematological malignancies are unable to find a suitable HLA-matched sibling or unrelated donor. Transplants using stem cells from umbilical cord blood provide an alternative for these patients, allowing transplantation to proceed with less stringent HLA-matching requirements. Unfortunately, in addition to the risk of relapsed disease, patients undergoing cord blood transplants have a high risk of death from infections due to slow reconstitution of their immune system. In this clinical observational study, we propose to use high-throughput DNA sequencing of T- Cell Receptor (TCR) and Immunoglobulin heavy chain (IgH) genes from peripheral blood to study the reconstitution of the adaptive immune system following cord blood transplant. We will use high-throughput sequencing to estimate the diversity of T- and B-cell receptors in each of approximately 240 patients at defined time-points following transplant, and demonstrate a correlation between our measure of adaptive immune receptor diversity and subsequent morbidity and mortality from infectious complications. Further development of this technique would lead to a Phase III application with a clinical intervention study in which this assay would provide a diagnostic method to identify patients at high risk for infectious complications soon after transplant. Clinical care would be administered for an increased-intensity regimen of antimicrobial prophylaxis to high-risk patients. We expect that early identification of high-risk patients, combined with more aggressive prophylaxis for these patients, will reduce the high treatment-related mortality present in cord blood transplants.

Public Health Relevance Statement:


Public Health Relevance:
The goal of this Phase II SBIR submission is to evaluate the ability of high-throughput T- and B- Cell Receptor sequencing to predict the risk of infectious complications in patients recovering from umbilical cord blood-derived stem cell transplants. Such transplants carry a high risk of patient mortality, but if successful this study will lead to improved management of infectious disease based on each patient's individual risk and improved overall patient survival.

NIH Spending Category:
Clinical Research; Hematology; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Nonembryonic - Human; Stem Cell Research - Umbilical Cord Blood/ Placenta; Stem Cell Research - Umbilical Cord Blood/ Placenta - Human; Transplantation

Project Terms:
Adult; Age; Allogenic; antimicrobial; B-Lymphocytes; base; Base Sequence; Binding (Molecular Function); Biological Assay; Bone Marrow Purging; Case Report Form; Cell Count; Cessation of life; Childhood; Clinical; clinical application; clinical care; cohort; Communicable Diseases; cost; Data; Diagnostic; Diagnostic Procedure; DNA Sequence; DNA Sequence Rearrangement; Early identification; Feedback; Funding; Goals; Guidelines; Heavy-Chain Immunoglobulins; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; high risk; IGH@ gene cluster; Immune; Immune system; Immunoglobulins; Immunologic Monitoring; Immunologic Receptors; improved; Individual; Infection; Intention; Intervention Studies; Lead; Measures; minimal risk; Monitor; Morbidity - disease rate; Mortality Vital Statistics; Observational Study; Opportunistic Infections; Outcome; Patients; Peripheral; peripheral blood; Phase; Predictive Value; Process; Prophylactic treatment; Protocols documentation; public health relevance; Receptors, Antigen, B-Cell; reconstitution; Recruitment Activity; Recurrent disease; Regimen; Resources; Risk; Sampling; Siblings; Small Business Innovation Research Grant; Stem cell transplant; Stem cells; Stratification; success; T-Cell Receptor; T-Lymphocyte; technique development; Techniques; Technology; Therapeutic; Time; Transplantation; Umbilical Cord Blood; Umbilical Cord Blood Transplantation