Tuesday, July 1, 2025 7/1/2025

BCL11B activation as an approach for enhancing the efficacy of immunotherapy

Award Number: R01AI152068
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: 02/11/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

Group Awards By:

View Award Description

BCL11B activation as an approach for enhancing the efficacy of immunotherapy - Our goal is to investigate overexpression of the T-lineage transcription factor (TF) BCL11B as a novel strategy to enhance: 1) T-cell reconstitution after allogeneic hematopoietic stem cell transplantation (HSCT), and 2) the efficacy of anticancer chimeric antigen receptor (CAR) T-cells. HSCT is a curative therapy for many leukemias by itself or as a post-CAR consolidation therapy. However, the generation of T-cells from donor hematopoietic stem and progenitor cells (HSPC) takes many months making life threatening infections and leukemia relapse major challenges in HSCT. While CAR T-cells induce high remission rates in CD19+ leukemias, poor T-cell function and persistence and T-cell exhaustion due to inhibition by the tumor microenvironment remain major obstacles to the curative efficacy of CAR T-cells in leukemia and solid tumors. Species related differences in the regulation of T-cell differentiation by TF and the poor understanding of mechanisms in human T-cell differentiation have been hurdles to the development of approaches to enhance T-cell differentiation and function. The tumor suppressor TF Bcl11b is required for the repression of alternative (non-T) lineage potentials but does not play a role in the induction of T-lineage gene expression during the initial stages of T-cell differentiation of murine HSPC. In contrast, we showed that BCL11B is critical for both the induction of the T- lineage program and repression of alternative lineage programs during the initial stages of human T-cell differentiation. We now have novel preliminary in vitro data that lentiviral BCL11B overexpression: 1) expedites T-cell differentiation from human HSPC including the generation of mature T-cells, and 2) enhances the function, promotes differentiation into cells with a central memory phenotype, and delays exhaustion of human T-cells. Integrated analysis of functional, Chip-Seq, and single cell RNA-Seq data revealed NOTCH3 and IRF8 as species specific candidate targets of BCL11B in humans. Of note, BCL11B overexpression studies have not been possible in murine HSPC due to toxicity. Based on these data, we hypothesize that transplantation of HSPC engineered to overexpress BCL11B will enhance post-HSCT T-cell reconstitution. BCL11B overexpression will increase the efficacy of CAR T-cells by enhancing their function and persistence and ameliorating exhaustion. We will test the hypothesis through the following aims: 1.1) Determine the epigenetic effects of BCL11B on T- cell genes and the role of BCL11B mediated regulation of NOTCH3 (1.2) and IRF8 (1.3) in human T-cell differentiation. 1.4) Define the efficacy of BCL11B overexpressing human HSPC for the enhancement of post- HSCT T-cell reconstitution in humanized mouse models, and 2) Define the effects of BCL11B overexpression on anti-cancer efficacy, persistence, and exhaustion of human CAR T-cells in leukemia and neuroblastoma models. These studies could reveal new functions of BCL11B and lead to BCL11B engineered cell therapies that improve outcomes in leukemia and solid tumors. This proposal is innovative because it builds on our work defining species specific effects of BCL11B in humans to address key barriers in HSCT and CAR T-cell therapy.


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 = $505,946 )
2025	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Allergy and Infectious Diseases Research	003	6	2/13/2025	NON-COMPETING CONTINUATION	$490,646
2025	2024	CHILDREN'S HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Allergy and Infectious Diseases Research	004	4	3/24/2025	NON-COMPETING CONTINUATION	-$44,944
2025	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Allergy and Infectious Diseases Research	005	5	3/24/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$44,944
2025	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Allergy and Infectious Diseases Research	002	5	12/5/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2025	2024	CHILDREN'S HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	4	11/22/2024	NON-COMPETING CONTINUATION	-$305,100
2025	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	5	11/25/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$320,400
														Subtotal = $505,946

Issue Date FY: 2024 ( Subtotal = $474,453 )
2024	2024	CHILDREN'S HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	4	1/17/2024	NON-COMPETING CONTINUATION	$427,008
2024	2024	CHILDREN'S HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	4	5/28/2024	NON-COMPETING CONTINUATION	$47,445
														Subtotal = $474,453

Issue Date FY: 2023 ( Subtotal = $499,162 )
2023	2023	CHILDRENS HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	3	1/19/2023	NON-COMPETING CONTINUATION	$499,162
														Subtotal = $499,162

Issue Date FY: 2022 ( Subtotal = $461,674 )
2022	2022	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	3/1/2022	NON-COMPETING CONTINUATION	$461,674
														Subtotal = $461,674

Issue Date FY: 2021 ( Subtotal = $435,925 )
2021	2021	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	2/11/2021	NEW	$435,925
														Subtotal = $435,925

Grand Total All Awards = $2,377,160

Top

All Categories

About

Search

Reports

Data Submission

Award Information

BCL11B activation as an approach for enhancing the efficacy of immunotherapy

Award Number: R01AI152068

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: 02/11/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer