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Novel Approaches to Inducing Lung Allograft Tolerance in NHPs

Award Number: U19AI174967
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/23/2023
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Novel Approaches to Inducing Lung Allograft Tolerance in NHPs - PROJECT SUMMARY/ABSTRACT Over 40% of lung allograft recipients succumb within five years of being transplanted, making it clear that there is an urgent unmet need to address the inadequacies of chronic immunosuppression (IS) in these patients. Achieving a robust state of tolerance in lung recipients would reduce or eliminate the major lung-specific and drug-related factors that contribute to this dismal statistic. Tolerance of kidney allografts has been achieved in nonhuman primates (NHPs) and humans by using a combination of nonmyeloablative conditioning and donor bone marrow transplantation that results in transient mixed hematopoietic chimerism. However, identical protocols have failed to induce tolerance in recipients of lung allografts. Despite the resistance of lung allografts to tolerance induction, we have now shown for the first time, that achieving a state of durable (for the life of the organ) mixed chimerism in NHP recipients results in long-term, IS-free survival of lung allografts. This remarkable result was achieved by modifying the mixed chimerism conditioning to augment host regulatory mechanisms. While a significant advance, this modified mixed chimerism protocol was only successful in recipients of MHC haplo-matched lung allografts and was associated with significant toxicity in the form of posttransplant lymphoproliferative disease (PTLD), cytomegalovirus (CMV) infection, and radiation-induced myelosuppression. Our goal now is to render this breakthrough clinically applicable by generating a safer and more effective protocol that is capable of inducing long-term tolerance of unrelated, fully MHC mismatched lung allografts using FDA-approved or soon-to-be-approved drugs. This Program’s unifying hypothesis is that inducing durable chimerism and long-term tolerance in recipients of stringent lung allografts will require next-generation mixed chimerism protocols that augment systemic and intra-graft adaptive and innate regulatory mechanisms. In Project 1, we will test this hypothesis using intra-organ delivery of αIL-6R-specific and mTORi-specific nanotherapies to reduce IS-related complications, block trained immunity, and promote intra-graft regulation. Bcl-2 inhibition will be used to promote durable mixed chimerism while diminishing the toxicities related to total body irradiation (TBI)-driven myelosuppression. These studies will be complemented by Project 2, which will test our unifying hypothesis using novel strategies for antibody-based conditioning, regulatory T cells (Treg)-supportive immunomodulation, and gene- modified Tregs, all poised for immediate clinical translation. State-of-the-art mechanistic assays coordinated by Core A (The Molecular Immunology Core, ‘MIC’) will enable rapid cross-fertilization of insights gained in each project. We anticipate that together, these highly interactive projects will generate one or more safe and effective durable mixed chimerism tolerance protocols ready for clinical trials by the end of the funding period. If successful, these studies could impact the entire field of transplantation and provide insights that could also be field-changing for bone marrow transplantation and autoimmune disease.


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: 2025 ( Subtotal = $4,164,788 )
2025	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	3	8/25/2025	SUPPLEMENT FOR EXPANSION	$865,000
2025	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Allergy and Infectious Diseases Research	003	3	9/8/2025	NON-COMPETING CONTINUATION	$0
2025	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Allergy and Infectious Diseases Research	002	3	9/4/2025	NON-COMPETING CONTINUATION	$0
2025	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	3	2/13/2025	NON-COMPETING CONTINUATION	$3,299,788
														Subtotal = $4,164,788

Issue Date FY: 2024 ( Subtotal = $3,801,842 )
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Allergy and Infectious Diseases Research	002	2	7/30/2024	SUPPLEMENT FOR EXPANSION	$400,000
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	2	4/19/2024	NON-COMPETING CONTINUATION	$340,179
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	2/14/2024	NON-COMPETING CONTINUATION	$3,061,663
														Subtotal = $3,801,842

Issue Date FY: 2023 ( Subtotal = $3,485,857 )
2023	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	3/23/2023	NEW	$3,485,857
														Subtotal = $3,485,857

Grand Total All Awards = $11,452,487

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Novel Approaches to Inducing Lung Allograft Tolerance in NHPs

Award Number: U19AI174967

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 03/23/2023

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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