Thursday, May 15, 2025 5/15/2025

Immunomodulatory effects of desmoglein 3 chimeric autoantibody receptor T cells (DSG3-CAART) in mucosal pemphigus vulgaris

Award Number: R01AR082675
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Immunomodulatory effects of desmoglein 3 chimeric autoantibody receptor T cells (DSG3-CAART) in mucosal pemphigus vulgaris - Project summary: Chimeric antigen receptor T (CART) cells have transformed the cancer therapy paradigm by genetically engineering a patient's own T cells to specifically kill cells expressing the targeted antigen, such as CD19 for B cell malignancies. CART cell proliferation and formation of memory CART cells result in complete B cell depletion and durable remission of otherwise refractory B cell cancers. We re-designed CART technology for autoimmune disease therapy by utilizing an autoantigen as the extracellular domain of a chimeric autoantibody receptor (CAAR), linked to cytoplasmic T cell receptor costimulatory and activation domains. CAARs direct T cell cytotoxicity against autoantigen-specific B cells by targeting their B cell receptor, a surface-bound autoantibody identical in specificity to the autoantibody the B cell will secrete once activated to mature into a plasmablast. We established proof-of-concept for CAAR safety and efficacy in experimental models of pemphigus vulgaris (PV), a potentially fatal blistering disease caused by autoantibodies to the epithelial adhesion protein desmoglein 3 (DSG3). If CAARs for autoimmunity prove to be as effective as CARs for B cell cancers, CAAR T cells could represent a one-time treatment leading to autoimmune disease cure. An open-label, dose-escalation, first-in-human phase 1 trial to determine the safety and tolerability of DSG3 CAAR T cell therapy (DSG3-CAART) in mucosal-dominant pemphigus vulgaris has been initiated. DSG3-CAART is the first precision cellular immunotherapy for autoimmune disease to enter clinical trials, which presents a unique opportunity to define the immunomodulatory effects of this novel therapeutic approach in humans. DSG3-CAART is designed to specifically eliminate DSG3-reactive memory B cells that replenish the autoantibody-producing plasmablasts in PV. Depletion of anti-DSG3 memory B cells could remove a key driver of DSG3-specific T cell activation, and DSG3-CAART persistence may induce changes in global T cell subset composition and/or cytokine milieu, resulting in dual mechanisms for disease remission through both the B and T cell compartments. The proposal will evaluate the hypothesis that DSG3-CAART will reset immune tolerance in PV by depleting DSG3-reactive B cells and normalizing pathologic T cell subsets, potentially leading to safe and lasting disease remission.


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 = $377,457 )
2025	2025	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	2/19/2025	NON-COMPETING CONTINUATION	$377,457
2025	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	2	2/28/2025	NON-COMPETING CONTINUATION	-$127
2025	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	3	2/28/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$127
2025	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	2/14/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $377,457

Issue Date FY: 2024 ( Subtotal = $410,698 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	5/29/2024	NON-COMPETING CONTINUATION	$29,601
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	3	9/20/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$41,689
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	2	9/19/2024	NON-COMPETING CONTINUATION	-$41,182
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	1/19/2024	NON-COMPETING CONTINUATION	$380,590
														Subtotal = $410,698

Issue Date FY: 2023 ( Subtotal = $429,000 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	3/15/2023	NEW	$429,000
														Subtotal = $429,000

Grand Total All Awards = $1,217,155

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Immunomodulatory effects of desmoglein 3 chimeric autoantibody receptor T cells (DSG3-CAART) in mucosal pemphigus vulgaris

Award Number: R01AR082675

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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