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Randomized study of low versus moderate dose busulfan in transplant for severe combined immunodeficiency

Award Number: U01AI126612
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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, which is typically fatal by age 2 years if not treated. HCT can be performed successfully in SCID patients without the high dose pre-HCT busulfan conditioning typically used, due to the lack of functional T cells. Despite restoration of T cell function, humoral immunity remains poor in many patients post-HCT. This project seeks 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 will target patients without active infection, leveraging the widespread implementation of universal newborn screening in the United States. We hypothesize that in our proposed multi-institutional randomized phase II trial patients receiving low dose busulfan will achieve similar outcomes compared to those receiving moderate dose (myeloablative) busulfan, achieving both T and B cell immune reconstitution. In Aim 1, we will examine immunological and safety outcomes in trial participants. Patients who lack matched sibling donors, confirmed to have the appropriate genotype, and who do not have active infection will be recruited over 4 1/2 years. Within each of 2 genotype cohorts (IL2RG/JAK3, RAG1/RAG2), 32 patients will be randomized to cumulative area-under-the-curve exposure of busulfan of 30 mg*h/L versus 60 mg*h/L (32 patients per cohort, 64 patients total). IL2RG/JAK3 patients will also receive rATG and RAG1/RAG2 patients will receive rATG, fludarabine, and thiotepa. Stem cell sources include unrelated and haploidentical related donor products that will be TCRaß+/CD19+ depleted with no post-HCT GVHD prophylaxis. The primary endpoint is protective antibody response to tetanus, a gold standard of normal humoral immune function in children, by 2 years post-HCT. Secondary endpoints include reconstitution of T cell number, thymic output, cell type specific chimerism, response to live viral vaccines at 3 years, survival, and incidence of HCT related complications. In Aim 2, we will examine the correction of T and B cell abnormalities in depth. The central question is whether mixed/split chimerism (donor-derived T cells with mixed chimerism in the B and myeloid compartments) will nevertheless be associated with normal immune phenotype, function, repertoire and tolerance in one or more genotypic cohorts. We hypothesize that generation of memory B cells, antibody- secreting cells and correction of pre-existing abnormalities of the B cell receptor repertoire post-HCT will be evident in all genotype cohorts and that the degree and quality of correction in the setting of mixed chimerism will vary according to the biology of each genetic abnormality. We hypothesize that T cell exhaustion seen in patients undergoing HCT in the absence of conditioning will be diminished or absent in trial participants due to improvements in thymic output associated with engraftment of donor-derived HSC. We hypothesize that T cell tolerance will occur by different mechanisms (central deletion versus peripheral regulation) according to donor type (haploidentical versus well matched unrelated donor) yet will be induced successfully in patients with mixed chimerism.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $989,251 )
2023	2023	CHILDRENS HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	7	7/26/2023	NON-COMPETING CONTINUATION	$989,251
2023	2022	CHILDRENS HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	6	6/8/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $989,251

Issue Date FY: 2022 ( Subtotal = $995,166 )
2022	2022	CHILDRENS HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Allergy and Infectious Diseases Research	003	6	8/12/2022	NON-COMPETING CONTINUATION	$995,166
2022	2021	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	5	2/8/2022	NON-COMPETING CONTINUATION	$0
2022	2021	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Allergy and Infectious Diseases Research	002	5	2/28/2022	NON-COMPETING CONTINUATION	$0
2022	2020	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	4	2/28/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $995,166

Issue Date FY: 2021 ( Subtotal = $544,688 )
2021	2021	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Allergy and Infectious Diseases Research	002	5	9/3/2021	SUPPLEMENT FOR EXPANSION	$18,548
2021	2021	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	5	8/24/2021	NON-COMPETING CONTINUATION	$526,140
2021	2020	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	4	3/19/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $544,688

Issue Date FY: 2020 ( Subtotal = $1,484,493 )
2020	2020	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	4	8/7/2020	NON-COMPETING CONTINUATION	$1,465,945
2020	2020	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	4	8/11/2020	SUPPLEMENT FOR EXPANSION	$18,548
														Subtotal = $1,484,493

Issue Date FY: 2019 ( Subtotal = $1,542,032 )
2019	2019	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	3	7/29/2019	NON-COMPETING CONTINUATION	$1,542,032
														Subtotal = $1,542,032

Issue Date FY: 2018 ( Subtotal = $1,496,446 )
2018	2018	THE CHILDRENS HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	2	8/3/2018	NON-COMPETING CONTINUATION	$1,496,446
2018	2017	THE CHILDRENS HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	8/2/2018	NEW	$0
														Subtotal = $1,496,446

Issue Date FY: 2017 ( Subtotal = $1,417,336 )
2017	2017	THE CHILDRENS HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	8/23/2017	NEW	$1,417,336
														Subtotal = $1,417,336

Grand Total All Awards = $8,469,412

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Randomized study of low versus moderate dose busulfan in transplant for severe combined immunodeficiency

Award Number: U01AI126612

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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