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Precise targeting of T1D specific T cells using CAR and peptide-MHC chimeric antigen ligands

Award Number: R01DK132576
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Precise targeting of T1D specific T cells using CAR and peptide-MHC chimeric antigen ligands - Project Summary Type 1 diabetes (T1D) is an incurable autoimmune disease manifested through the immune destruction of islet beta cells. This proposal describes a unique CAR T cell approach to eliminate islet-autoreactive T cells, thus eliminating the source of the autoimmunity and providing a highly specific treatment for T1D. We will leverage our recently developed split CAR system with a chimeric antigen ligand (CAL) adaptor consisting of a pMHC multimer fused to a recruitment molecule. The addition of CAL will bind to the autoreactive TCR and recruit the universal CAR T cells to kill autoreactive T1D specific T cells. The proposed experiments will test the hypoth- eses that (1) our modular CAR/CAL systems are uniquely suited for specifically targeting multiple auto- reactive TCRs, and (2) that we can identify novel epitopes against T1D specific TCRs to be paired with the CAR/CAL system. Importantly, preliminary data support these hypotheses, and well-characterized clinical specimens from T1D patients and rigorous experimental designs are established in this proposal with essential cross-disciplinary collaborations and expertise that encompass synthetic biology, large-scale epitope discovery, T1D immunology, and humanized T1D animal modeling. The specific aims of this five-year proposal are as follows: Aim 1 establish and optimize the CAL system against antigen-specific human TCRs, Aim 2 characterize the autoreactivity of TCRs from T1D patients/donors and identify peptide-MHC against these TCRs, and Aim 3 evaluate the performance of the CAL system in humanized T1D animal models. Outcomes from this work will establish the clinical potential of the CAR/CAL system as a safe, effective, and potentially curative T1D treatment.


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 = $764,333 )
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/29/2025	NON-COMPETING CONTINUATION	$764,333
														Subtotal = $764,333

Issue Date FY: 2024 ( Subtotal = $769,703 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/10/2024	NON-COMPETING CONTINUATION	$769,703
														Subtotal = $769,703

Issue Date FY: 2023 ( Subtotal = $674,605 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/11/2023	NON-COMPETING CONTINUATION	$674,605
														Subtotal = $674,605

Issue Date FY: 2022 ( Subtotal = $728,516 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/13/2022	NEW	$728,516
														Subtotal = $728,516

Grand Total All Awards = $2,937,157

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Precise targeting of T1D specific T cells using CAR and peptide-MHC chimeric antigen ligands

Award Number: R01DK132576

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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