# Project 4: Off-the-shelf engineered cord blood-derived natural killer cells for the treatment acute lymphoblastic  leukemia

> **NIH NIH P50** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $272,372

## Abstract

Summary:
The past several years have seen tremendous advances in the engineering of immune effector cells as
therapy for cancer. However, chimeric antigen receptor (CAR)-modified T-cells have a number of limitations.
The generation of an autologous product for each individual patient is logistically cumbersome and restrictive
for widespread clinical use. The manufacturing of CAR T-cells often takes several weeks, making it impractical
for patients with rapidly advancing disease. Furthermore, it is not always possible to generate clinically relevant
doses of CAR T-cells from heavily pre-treated, often lymphopenic patients. A previously collected allogeneic
product could overcome these limitations; however, allogeneic T-cells (even if HLA-matched) carry a
significant risk of graft-versus-host disease (GVHD) mediated through their native αβ T-cell receptor prohibiting
their use as a clinical product without further manipulation to eliminate the T cell receptor. Natural killer (NK)
cells provide an extremely attractive alternative to T-cells for CAR engineering. NK cells do not cause GVHD
and thus open opportunities to produce an off-the-shelf product for immediate clinical use. Moreover, as
engineered NK cells should also retain their full array of native receptors, they have the potential to exert
cytotoxicity through mechanisms other than that dictated by the specificity of the CAR, which in principle could
reduce the risk of relapse mediated by loss of CAR-targeted antigen, as reported for CAR-T cell therapy.
Autologous NK cells can be reproducibly generated in vitro, but have extremely limited activity against
autologous tumor which cannot be overcome by CAR engineering. Cord blood (CB) is a readily available
source of allogeneic NK cells with clear advantages. CB is available as an off-the-shelf frozen product, an
advantage that has been bolstered by methods to generate large numbers of highly functional NK cells from
frozen CB units ex vivo. The generation of CAR-transduced NK cells from frozen CB units stored in large
global CB bank inventories holds promise for widespread scalability that cannot be replicated with individual
adult donors who require screening and leukapheresis.
In Aim 1 we will perform the first-inhuman clinical trial to test the safety and efficacy of CB-NK cells engineered
to express a CAR against CD19 (a B cell-specific antigen), to ectopically produce IL-15 to support their in vivo
proliferation and persistence, and to express a suicide gene, based on IC9, that will address safety concerns
related to the potential risk of direct toxicity; In Aim 2 we will apply highly innovative correlative studies to
describe the therapeutic potential of the clinical trial; Aim 3 in preclinical murine studies, we will protect the
transduced NK cells from the TGF-β/SMAD signaling axis using a novel retroviral construct that, in addition to
CAR.CD19 and IL-15, includes the gene for the dominant-negative version of human TGFβ receptor II (...

## Key facts

- **NIH application ID:** 10247506
- **Project number:** 5P50CA100632-19
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Katy Rezvani
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $272,372
- **Award type:** 5
- **Project period:** 2003-08-05 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247506

## Citation

> US National Institutes of Health, RePORTER application 10247506, Project 4: Off-the-shelf engineered cord blood-derived natural killer cells for the treatment acute lymphoblastic  leukemia (5P50CA100632-19). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10247506. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*