# NIH grant: Improving NK cell engineering to target AML (1R21CA299372-01A1) — retained record

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[original source ↗](https://reporter.nih.gov/project-details/1R21CA299372-01A1)

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NIH grant 1R21CA299372-01A1: Improving NK cell engineering to target AML
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Challice  Bonifant. Award: $218089.
Start: 2026-08-01T00:00:00.
PROJECT SUMMARY
The overarching long-term goal of the proposed work is to develop and study engineered natural killer (NK) cell
therapy as a treatment for acute myeloid leukemia (AML). The project aims to test chimeric cytokine receptor
(CCR)-NK cells targeted to AML-associated surface antigens in cellular and animal models of disease, with
parallel study of reversal of AML-mediated NK cell inhibition. A barrier to efficacy of adoptively transferred NK
cell therapies has been in the rapid loss of anti-tumor activity and relatively poor NK cell expansion post-infusion.
Direct AML-mediated NK cell suppression via engagement of the Polio Virus Receptor (PVR)-like inhibitory
receptors PVRIG and TIGIT also contributes to suboptimal NK cell anti-tumor activity. We test potential
engineering solutions to these challenges in our proposal. Specifically, we hypothesize that CCR-NK cells
will retain an activated phenotype with expansion and maintenance of powerful cytotoxicity against AML
in vitro and in vivo, with NK cell anti-tumor functionality enhanced by PVR-like receptor blockade or
elimination. In Aim 1 we will test dual IL15Rb, IL21R, and gc expression, with these cytokine receptors
engineered to express extracellular domains that bind AML-associated targets. Engagement of the target cell is
expected to promote CCR heterodimerization, leading to full NK cell activation. We have developed a spectrum
of AML binding moieties targeting CD123 (IL3Ra), CLEC12A (CLL-1), and B7-H3 and will express these in the
context of our CCRs. The function and phenotype of engineered CCR-NK cells will be evaluated in cellular and
xenograft models, including those established from primary patient AML cells. We have carefully considered the
direct AML-mediated inhibition of NK cell function via PVR-like receptor ligation and thus include study of PVR
like receptor blockade and genetic deletion to compare these strategies in AML models in Aim 2. At the
conclusion of this R21 we expect to have gained understanding of the value of heterodimeric CCR expression,
including ranking of AML-associated antigen targets in this context. We will also learn whether removal of PVR
like receptor inhibitory signaling allows full NK cell activation in the AML microenvironment. We will have acquired
and disseminated valuable data describing allogeneic cell therapy agents, and ultimately plan to synthesize Aims
1 and 2 data to inform the best choice of engineered NK cell product. This work is of great translational relevance
for a challenging to cure cancer that affects a distribution of patients including very young children and the elderly.
```



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