# BCL11B activation as an approach for enhancing the efficacy of immunotherapy

> **NIH NIH R01** · CHILDREN'S HOSPITAL OF LOS ANGELES · 2022 · $461,674

## Abstract

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 engin...

## Key facts

- **NIH application ID:** 10349588
- **Project number:** 5R01AI152068-02
- **Recipient organization:** CHILDREN'S HOSPITAL OF LOS ANGELES
- **Principal Investigator:** Chintan Parekh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $461,674
- **Award type:** 5
- **Project period:** 2021-02-11 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10349588

## Citation

> US National Institutes of Health, RePORTER application 10349588, BCL11B activation as an approach for enhancing the efficacy of immunotherapy (5R01AI152068-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10349588. Licensed CC0.

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