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Principal Investigator: JEFFERY J AULETTA
Organization: NATIONAL MARROW DONOR PROGRAM
Fiscal Year: 2024
Award: $1,072,951
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Severe combined immunodeficiency (SCID) is a group of genetic disorders that abrogate T cell development
and function. Allogeneic hematopoietic cell transplantation (HCT) is the standard treatment for the disease and
can be performed successfully in SCID patients without the high dose pre-HCT busulfan conditioning due to the
unique capacity for progenitors to engraft in the empty thymus and reconstitute T cell development. Without
conditioning, lineages other than T cells remain of host origin. The CSIDE protocol was funded with an earlier
grant to test the efficacy and safety of a regimen of low dose, individualized targeted busulfan compared to
moderate dose in SCID patients at risk of poor humoral outcome undergoing non-matched sibling donor HCT.
We hypothesize that patients randomized to receive low dose busulfan will achieve similar outcomes compared
to those receiving moderate dose (myeloablative) busulfan, achieving both T and B cell immune reconstitution.
Due to COVID and competition with gene therapy, accrual slowed, but with 50 centers open and a redesigned
approach, additional enrollment facilitated by this grant will ensure that the trial reaches meaningful conclusions.
In Aim 1, patients have been randomized to cumulative area-under-the-curve (cAUC) exposure of busulfan
of 30 mg*h/L versus 60 mg*h/L. IL2RG/JAK3 patients also receive rATG, while RAG1/2 patients receive rATG,
fludarabine, and thiotepa. Stem cell sources include unrelated and haploidentical related donor products that
have been TCRαβ+/CD19+ depleted with no post-HCT GVHD prophylaxis. The safety profile of the trial has
been excellent to date. The original primary endpoint was protective antibody response to tetanus by 2 years
post-HCT. Because of enrollment challenges, we redesigned the primary endpoint into an ordinal ranked win
comparison, which allows higher power even if we cannot fully enroll. The primary outcome will center around
the IL2RG/JAK3 cohort, which should achieve full accrual, randomizing 32 patients. The RAG1/2 cohort will
close once the IL2RG/JAK3 cohort closes, likely accruing up 18-20 patients which we will analyze descriptively.
In Aim 2, We hypothesize that donor HSC engraftment measured by the surrogate of myeloid donor
chimerism will be associated with superior quality of T cell reconstitution and improved adaptive immune
responses to vaccination. We hypothesize that T cell exhaustion and poor T cell receptor (TRB) diversity seen
in patients undergoing HCT in the absence of conditioning will be diminished or absent in CSIDE participants
due to improvements in thymic output associated with engraftment of donor-derived HSC. We hypothesize that
IL2RG/JAK3 patients receiving moderate dose busulfan and/or with high level donor chimerism will exhibit
multiple in vitro biomarkers of IL-21 response, as this cytokine signals via IL2RG/JAK3. We hypothesize that
vaccine response will correlate with normalization of IGH CDR3 diversity in RAG1/2 patients with mixed
chimerism due to strong selective advantage for antigen-specific B cells. We hypothesize that T cell tolerance
will occur by different mechanisms (central deletion versus peripheral regulation) according to donor type. Finally,
we hypothesize that analysis of pK samples for elements of our preparative approaches (rATG, thiotepa, and
fludarabine) will allow targeted treatment of infants undergoing HCT for SCID or other disorders moving forward.
Terms: <2 year old><2 years of age><ATGAM><Active Follow-up><Adoptive Transfer><Affect><Age><Allogenic><Anti-Thymocyte Globulin><Antibody Response><Antigens><Antithymocyte Globulin><Antithymoglobulin><Area Under Curve><B blood cells><B cell><B cells><B-Cell Development><B-Cells><B-Lymphocytes><B-cell><Biological Markers><Biology><Birth><Blood><Blood Precursor Cell><Blood Reticuloendothelial System><Bone Marrow Grafting><Bone Marrow Transplant><Bone Marrow Transplantation><Bussulfam><Busulfan><Busulfanum><CD132><CD19><CD19 gene><COVID-19><CV-19><Cell Compartmentation><Cell Compartmentations><Cell Therapy><Chemotherapy Protocol><Chemotherapy Regimen><Chemotherapy-Oncologic Procedure><Childhood><Chimerism><Clinical><Clinical Trials><Combination Chemotherapy Regimen><Coronavirus Infectious Disease 2019><Cytokine Signal Transduction><Cytokine Signaling><DNA Therapy><Data><Development><Disease><Disorder><Domestic Rabbit><Dose><Elements><Engraftment><Enrollment><Ensure><Exhibits><Funding><Future><Gene Transfer Clinical><Genetic><Genetic Diseases><Genetic Intervention><Genotype><Goals><Graft Rejection><Grant><HSC transplantation><Hematopoietic><Hematopoietic Progenitor Cells><Hematopoietic Stem Cell Transplant><Hematopoietic Stem Cell Transplantation><Hematopoietic stem cells><Host vs Graft Reaction><IGH><IGH@ gene cluster><IL21><IL2RG><IL2RG gene><IMD4><IgH locus><Immune><Immune Globulins><Immune Tolerance><Immune system><Immunes><Immunity><Immunoglobulin Heavy Chain Genes><Immunoglobulin Heavy Gene><Immunoglobulin Heavy Locus><Immunoglobulins><Immunologic Tolerance><In Vitro><Infant><Infection><JAK-3><JAK3><JAK3 gene><JAK3 protein><JAKL><Janus kinase 3><Joints><LJAK><Life><Lymphatic cell><Lymphocyte><Lymphocytic><MHC Receptor><Major Histocompatibility Complex Receptor><Marrow Transplantation><Mature T-Cell><Mature T-Lymphocyte><Measures><Myelogenous><Myeloid><Myeloid Cells><Neonatal Screening><Newborn Infant Screening><North America><Opportunistic Infections><Orphan Disease><Oryctolagus cuniculus><Outcome><Output><PK/PD><Participant><Parturition><Patients><Peripheral><Pharmacodynamics><Process><Progenitor Cell Engraftment><Progenitor Cells><Prophylactic treatment><Prophylaxis><Protocol><Protocols documentation><Quimioterapia><Rabbits><Rabbits Mammals><Rag1><Rag1 Mouse><Randomization trial><Randomized><Rare Diseases><Rare Disorder><Regimen><Regulation><Replacement Therapy><Risk><SCIDX><SCIDX1><Safety><Sampling><Science><Severe Combined Immunodeficiency><Severe Combined Immunodeficiency Syndrome><Severe Combined Immunologic Deficiency><Siblings><Source><Subgroup><Sulfabutin><Survival Rate><Suspension substance><Suspensions><T cell reconstitution><T-Cell Antigen Receptors><T-Cell Development><T-Cell Ontogeny><T-Cell Receptor><T-Cells><T-Lymphocyte><T-Lymphocyte Development><TSPA><Testing><Tetanus><Tetanus Vaccine><Therapy trial><Thio-Tepa><Thiofosfamide><Thiophosphamide><Thiophosphoramide><Thiotepa><Thymoglobulin><Thymus><Thymus Gland><Thymus Proper><Thymus Reticuloendothelial System><Toxic effect><Toxicities><Transplant Rejection><Transplantation><Transplantation Rejection><Triethylene thiophosphoramide><Triethylenethiophosphoramide><active followup><adaptive immune response><age 2 years><aged 2 years><aged two years><ages><arm><bio-markers><biologic marker><biomarker><blood cell progenitor><blood progenitor><blood stem cell><blood-forming stem cell><cancer chemotherapy><cell mediated therapies><cell-based therapeutic><cell-based therapy><cellular therapeutic><cellular therapy><clinical outcome assessment><clostridial tetanus><cohort><combined T and B cell inborn immunodeficiency><conditioning><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><curative intervention><curative therapeutic><curative therapy><curative treatments><design><designing><developmental><dosage><efficacy testing><enroll><exhaustion><fludarabine><follow up><follow-up><followed up><followup><gene repair therapy><gene therapy><gene-based therapy><genetic condition><genetic disorder><genetic therapy><genomic therapy><hematopoietic cell transplantation><hematopoietic cellular transplantation><hematopoietic progenitor><hematopoietic progenitor cell transplantation><hematopoietic stem progenitor cell><hemopoietic><hemopoietic progenitor><hemopoietic stem cell><high risk><host versus graft reaction><host vs. graft reaction><immune reconstitution><immune response to vaccination><immune response to vaccines><immune system tolerance><immune unresponsiveness><immunogen><immunoglobulin heavy chain locus><immunological paralysis><improved><interleukin-21><lymph cell><newborn screening><novel><orphan disorder><pediatric><pharmacokinetics and pharmacodynamics><primary end point><primary endpoint><primary outcome><progenitor><prospective><randomisation><randomization><randomized trial><randomly assigned><response><standard care><standard of care><standard treatment><stem cell engraftment><stem cells><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><thymus derived lymphocyte><transplant><transplant therapy><transplant treatment><transplantation therapy><transplantation treatment><trial design><two year old><two years of age><vaccine associated immune response><vaccine immune response><vaccine immunogenicity><vaccine induced immune response><vaccine response><vaccine responsiveness><vaccine-induced response>