Tuesday, February 17, 2026 2/17/2026

Reprogramming T cell function with multiplexed genome engineering to develop next-generation immunotherapy

Award Number: K99CA282989
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 03/08/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2025

Group Awards By:

View Award Description

Reprogramming T cell function with multiplexed genome engineering to develop next-generation immunotherapy - Project Summary: Adoptive cellular immunotherapy utilizing T cells engineered with chimeric antigen receptor (CAR) has shown durable clinical responses in hematologic malignancies. However, relapse remains a challenge, urging for better CAR designs. CAR, analogous to the T cell receptor (TCR), is specifically engineered to redirect T cell specificity towards tumor antigens. Optimal regulation on TCR dynamics is crucial for proper TCR function. Altered dynamics of TCR leads to disfunction or even immune disorders. While the importance of control TCR dynamics has been well established, there is a notable lack of comprehensive studies focusing specifically on CAR dynamics, including endocytosis, recycling/degradation, and its impact on CAR-T function. My previous work demonstrated that modulating molecular dynamics of CAR greatly improves CAR-T function. By utilizing the endocytic feature of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) cytoplasmic tail (CCT), I reprogrammed CAR dynamics and substantially enhanced CAR-T efficacy in vivo. To control CAR dynamics more precisely and elucidate its impact on CAR-T function, further modulation on CCT fusion and investigation on cell-intrinsic regulators to control CAR dynamics are needed. In Aim 1 of this K99/R00 application, I propose to identify the optimal position and functional motif of CCT fusion. Completion of this aim will not only develop a novel CAR engineering approach but also provide a deeper understanding of how altering CAR dynamics contributes to improved CAR-T function. In Aim 2, I plan to uncover cell-intrinsic regulator of CAR dynamics using CRISPR-based gene perturbation. This aim will serve to fill the gap in our understanding of the improved anti-tumor efficacy of CAR-CCT but also uncover novel regulators on CTLA-4 dynamics. In Aim 3, I propose to develop self-regulated CAR with CCT fusion in response to antigen stimulation. This novel engineer approach will enable precise control over the timing and duration of CAR signaling, which is crucial for maintaining CAR- T efficacy with limited toxicity. All aims center on engineering CAR dynamics with CCT fusion to develop novel immunotherapies. The innovative insights and versatile engineering approach proposed in this study will also contribute significantly to addressing the existing knowledge gap in CAR engineering. This grant will facilitate my career development during both the postdoctoral training phase and transition phase as an independent faculty and group leader.


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 = $142,502 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	002	2	8/22/2025	NON-COMPETING CONTINUATION	$0
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	2	2/13/2025	NON-COMPETING CONTINUATION	$142,502
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	001	2	7/17/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $142,502

Issue Date FY: 2024 ( Subtotal = $142,502 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	1	3/8/2024	NEW	$142,502
														Subtotal = $142,502

Grand Total All Awards = $285,004

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Reprogramming T cell function with multiplexed genome engineering to develop next-generation immunotherapy

Award Number: K99CA282989

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 03/08/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer