# Off-the-shelf engineered NK cells for the treatment of AML

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $366,000

## Abstract

Summary:
Allogeneic hematopoietic transplantation (HSCT) is an effective treatment for AML. Relapse of the
malignancy remains the major cause of treatment failure and improved strategies to eradicate leukemia
are required. Natural killer (NK) cells are a unique class of lymphocytes, with cytotoxic, and
immunoregulatory function which can mediate potent antileukemia effects against myeloid leukemias
while simultaneously preventing GVHD in preclinical models. Relatively few NK cells are present in
peripheral blood or bone marrow transplant cell products and the NK cells recovering early post
transplant have functional defects impairing cytotoxicity. We have developed robust clinical procedures
for the ex vivo expansion and activation of cord blood (CB)-derived NK cells. The long-tem objective of
this research is to develop novel cell based therapies to harness the antileukemic potential of NK cells
against AML, and to further enhance their effector function by both redefining their specificity and/or
enhancing their potency Aim 1 tests the hypothesis that the addition of optimally selected, ex vivo
expanded and activated CB-derived NK cells will improve the outcomes of patients with AML after cord
blood transplantation (CBT). We have found that patients with AML whose HLA type is homozygous for
group C2 have a significantly higher risk of relapse following CBT compared to those who are
homozygous or heterozygous for HLA group C1. Mechanistically, we have shown that the increased risk
of disease progression in the C2/C2 risk group is related to delayed emergence of immunocompetent
C2-specific KIR2DL1/S1+ NK cells post-CBT. This suggests that such patients would benefit from the
post-CBT infusion of activated mature CB-NK cells that express KIR2DL1/S1. Extensive biologic
correlates will examine the phenotype, function and homing of adoptively infused CB-NK cells, and their
impact on immune reconstitution post-transplant. Aim 2 capitalizes on the finding that the baseline
cytotoxicity of NK cells can be augmented by expression of a chimeric antigen receptor (CAR) against
the target cells. CD123, the α chain of the interleukin-3 receptor, is an attractive target for cellular
immune therapy in AML, but cytotoxicity against normal hematopoietic cells would preclude safe delivery
in the absence of HSCT. We will test the hypothesis that NK cells transduced with a CAR to CD123, and
coexpressing CD28 and IL15 to mediate long term persistence, and inducible caspase 9 (IC9) to
manage potential toxicity will provide enhanced activity against AML. Aim 3 examines if blocking the
TGF-beta pathway by retrovirally transducing NK cells with a dominant negative TGF-beta type II
receptor can render NK cells resistant to the immunosuppressive AML microenvironment. Optimal
strategies formulated in aims 2 and 3 will be translated into human clinical trials, based on the optimal
platform protocol determined in aim 1.

## Key facts

- **NIH application ID:** 9829038
- **Project number:** 5R01CA211044-04
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Katy Rezvani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $366,000
- **Award type:** 5
- **Project period:** 2016-12-20 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9829038

## Citation

> US National Institutes of Health, RePORTER application 9829038, Off-the-shelf engineered NK cells for the treatment of AML (5R01CA211044-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9829038. Licensed CC0.

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