# Locally Targeted Off-The-Shelf NK Cells For Ovarian Cance

> **NIH NIH P01** · UNIVERSITY OF MINNESOTA · 2021 · $294,004

## Abstract

In 2010 we treated our first patient with advanced ovarian cancer (OC) with intravenous (IV) allogeneic NK cells.
Since then, we have worked to improve the persistence and function of NK cells in this disease. Based on our
pre-clinical findings, we designed and completed a clinical trial testing the safety and efficacy of ex vivo expanded
(IL-15 + GSK3b inhibitor) adaptive NK cells administered intraperitoneally (IP) to treat OC. These allogeneic NK
cells persisted and had enhanced in vivo function for up to 21 days with promising clinical responses. These
initial results support improved NK cell persistence with IP versus IV delivery and NK cell-mediated antitumor
effects in advanced OC. The overarching hypothesis for Project 3 is that IP delivery of NK cells will be optimal
for clinical testing of NK cells gene modified to target OC through their Fc receptors. We will test an off-the-shelf
NK cell product that resists CD16 cleavage (hnCD16) in combination with IL-2 and an Fc-optimized mAb against
B7-H3, a target highly expressed on OC. We predict this NK product will overcome suppressive mechanisms
and mediate potent anti-tumor activity and that targeting these cells with specific killer immune engagers
containing IL-15 will enhance their specificity to kill OC. These studies are supported by strong pre-clinical data
showing high NK cell frequencies with markedly diminished CD16 expression in ascites from OC patients. The
induced pluripotent stem cell (iPSC)-derived NK (iNK) cell product (FT516) proposed for use in this project has
non-cleavable CD16 to sustain antibody-dependent cellular cytotoxicity (ADCC) when combined with an Fc
optimized anti-B7-H3 antibody. To further enhance the antitumor efficacy of FT516 NK cells, we will test our own
IL-15-containing Trispecific Killer Engagers: 1) a 1615B7H3 TriKE comprised of three functional domains: a) an
NK cell-engaging single domain Ab fragment against CD16, b) an OC-engaging Ab fragment against B7-H3, and
c) an IL-15 linker between them; 2) a 1615CD133 TriKE to target OC stem cells; and 3) a 1615CD133B7H3
TriKE for dual targeting of OC cells. Lastly, supported by strong pre-clinical data, we developed a CD64/CD16
chimeric receptor, as CD64 is the only high-affinity receptor that can stably bind monomeric IgG with >30-fold
higher affinity than CD16. This novel receptor has been genetically edited into iPSC-derived NK cells and will be
tested in vitro and in xenogeneic mouse models of OC. We have developed Specific Aims to 1) clinically test
whether IP delivery of FT516 iNK cells combined with enoblituzumab (anti B7-H3 antibody) will enhance efficacy
through ADCC in advanced OC; 2) pre-clinically test whether single- or dual-targeted TriKEs will enhance the
antitumor efficacy of FT516 NK cells; and 3) pre-clinically test whether multi-antibody targeting by iNK cells
expressing the chimeric CD64/16A receptor will enhance function. The themes developed in Project 3 will inform
the Program on wheth...

## Key facts

- **NIH application ID:** 10172128
- **Project number:** 2P01CA111412-16
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Melissa Ann Geller
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $294,004
- **Award type:** 2
- **Project period:** 2005-07-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10172128

## Citation

> US National Institutes of Health, RePORTER application 10172128, Locally Targeted Off-The-Shelf NK Cells For Ovarian Cance (2P01CA111412-16). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10172128. Licensed CC0.

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