# Off-the-shelf iPSC-Derived Natural Killer Cell Immunotherapies for AML

> **NIH NIH P01** · UNIVERSITY OF MINNESOTA · 2024 · $378,249

## Abstract

Acute myeloid leukemia (AML) is a clinically heterogeneous disease characterized by the expansion and
accumulation of immature myeloid cells in the bone marrow and peripheral blood. Advances in the AML genetics
have led to a better understanding of disease progression, paving the way for the development of novel targeted
therapies. Still, the mainstay of AML treatment is chemotherapy, which has remained mostly unchanged for
several decades, and fewer than one-third of adult AML patients experience a durable remission. Reduced-
intensity hematopoietic stem cell transplantation (HSCT) for AML is potentially curative, but relapse rates exceed
50%. We have shown that allogeneic natural killer (NK) cell infusions after high-dose lymphodepletion (LD) can
induce remission in 30-40% of patients with relapsed/refractory AML. However, this approach is limited by the
toxicity of high-dose LD, NK cell numbers within haploidentical blood products, inadequate donor NK cell
persistence, lack of NK cell antigen specificity, allogeneic rejection and challenges of exporting adoptive NK cell
therapy beyond specialty centers. To overcome these barriers, we have developed a scalable GMP-compliant
platform for the differentiation of induced pluripotent stem cells (iPSCs) into highly potent NK cells (termed iNK).
With our system, we can generate stable gene-edited lines for tailored approaches to NK cell immunotherapy.
In the past year, we have safely treated patients with up to 6 cryopreserved doses of off-the-shelf iNK cell
products. In this project we will test the central hypothesis that triple gene-modified iNK cells (FT538) represent
a novel and effective immunotherapy for the treatment of AML. FT538 is a cell product with three functional
modifications: a high affinity, non-cleavable CD16 Fc receptor to augment antibody-dependent cellular
cytotoxicity; a membrane-bound IL-15/IL-15 receptor fusion molecule (IL-15RF) that acts intrinsically to enhance
NK cell activity; and knockout of CD38 to mitigate NK cell fratricide in the presence of the anti-CD38 monoclonal
antibody, daratumumab. The central hypothesis will be tested in three independent aims. In Aim 1, we will test
the hypothesis that FT538 iNK cells will exhibit sustained persistence and function after adoptive transfer for
targeting of CD38+ AML cells when combined with daratumumab in an FDA-approved and enrolling phase I
clinical trial. Because CD38 is highly expressed on AML, immune suppressor cells, and activated CD8+ T cells,
our clinical trial will test whether daratumumab dosing before FT538 iNK cell treatment enhances the persistence
of iNK through selective immunodepletion. In Aim 2, we will test the hypothesis that iNK cell specificity, potency,
and persistence can be enhanced by optimizing IL-15 signaling in the context of CD38 knockout and that a novel
anti-CD5-ADC will provide effective and safer LD to enhance persistence. In Aim 3, we will test the hypothesis
that dual antigen-specific target...

## Key facts

- **NIH application ID:** 10837847
- **Project number:** 5P01CA065493-27
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Jeffrey S. Miller
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $378,249
- **Award type:** 5
- **Project period:** 1997-09-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10837847

## Citation

> US National Institutes of Health, RePORTER application 10837847, Off-the-shelf iPSC-Derived Natural Killer Cell Immunotherapies for AML (5P01CA065493-27). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10837847. Licensed CC0.

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