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Engineering synthetic cellular crosstalk for transplantation tolerance

Award Number: DP2AI164319
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Engineering synthetic cellular crosstalk for transplantation tolerance - Organ transplantation remains the definitive treatment option for patients with end-stage organ failure. Maintenance of functional allografts requires organ recipients to stay on immune- suppressive drugs. However, most allografts have a limited lifespan because of the chronic rejection initiated by the host alloimmune responses. The majority of immunosuppressive treatments are targeted to the effector immune cells, such as T cells, leaving the root of alloimmune responses—alloantigen presentation—untouched and leading to an immune equilibrium which eventually is shifted toward graft rejection. Regulatory T cells (Tregs) with user- defined specificity could be harnessed to induce immune suppression at desired tissues. They also preserve the ability to tolerize antigen-presenting cells (APCs) through contact-dependent cellular crosstalk. Our vision is to develop a robust allospecific immune regulatory strategy that restricts alloimmune T cell responses at both the effector site (allograft) and the alloantigen presentation site(graft draining lymphoid tissue) to shift the immune equilibrium to long-term suppression in the allograft while keeping the remainder of the host immune system fully operational. By leveraging the ability of chimeric antigen receptor (CAR) to recognize any desired target and a lymph node targeting molecular vaccine to specifically deliver the target to lymph node APCs, we will engineer an orthogonal synthetic vaccine to bridge crosstalk between CAR Tregs and APCs via the CAR-directed interaction with its cognate bio-inert ligand synthetically displayed on APCs. This synthetic vaccine-mediated crosstalk will have two outcomes: 1) APC- to-CAR Treg signaling promotes CAR Treg expansion and migration to the allograft for targeted suppression with enhanced regulatory functions. 2) CAR Treg-to-APC signaling tolerizes APC to restrict alloreactive T cell priming and to promote the generation of induced regulatory T cells (iTregs), which enforces a self-sustaining immunosuppression cycle via “infectious tolerance”. We will evaluate the synthetic crosstalk in murine allotransplantation models. If successful, this platform technology could be implemented across a broad landscape for precision control of pathological conditions, including autoimmune diseases, graft-versus-host disease, and transplant rejection.


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 = $527,222 )
2025	2025	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	4	1/17/2025	NON-COMPETING CONTINUATION	$527,222
														Subtotal = $527,222

Issue Date FY: 2024 ( Subtotal = $527,222 )
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	3	5/22/2024	NON-COMPETING CONTINUATION	$52,722
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	3	1/25/2024	NON-COMPETING CONTINUATION	$474,500
														Subtotal = $527,222

Issue Date FY: 2023 ( Subtotal = $527,222 )
2023	2023	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	2	1/13/2023	NON-COMPETING CONTINUATION	$527,222
														Subtotal = $527,222

Issue Date FY: 2022 ( Subtotal = $528,000 )
2022	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	1/28/2022	NEW	$528,000
														Subtotal = $528,000

Grand Total All Awards = $2,109,666

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Engineering synthetic cellular crosstalk for transplantation tolerance

Award Number: DP2AI164319

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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