# Genome Engineered Natural Killer Cell Immunotherapy against Human Osteosarcoma

> **NIH NIH F30** · UNIVERSITY OF MINNESOTA · 2024 · $46,683

## Abstract

Abstract
Over the last decade Chimeric Antigen Receptor based T cell therapy (CAR-T) has developed into an effective
immunotherapy for some cancers. However, CAR-T cell therapies have several shortcomings and clinical
success has primarily been limited to hematological cancers. Challenges of CAR-T cell therapy include tumor
immune evasion through loss of target antigen expression by tumor cells and inhibition of CAR-T cell function
by tumor expressed inhibitory molecules. Natural killer (NK) cells present an alternative to T cells that could be
more effective due to their ability to perform both antigen dependent and independent killing. NK cells have
demonstrated antigen specific killing when engineered to express T cell CARs and NK cells also mediate the
direct killing of transformed cells with reduced or absent MHC expression. In fact, NK cells carry out antibody
dependent cell mediated cytotoxicity (ACDD) of cells that bind antibodies via the NK cell CD16A receptor. Due
to the multiple modalities for cancer cell killing, there is an increased interest in NK cells for cancer
immunotherapy. As NK cells are not associated with graft versus host disease, neurotoxicity, long-term
autoimmunity, nor cytokine release syndrome, they are more suited for use in allogeneic settings than T cells
and have significant clinical potential for use as off-the-shelf products. However, previous publications and
clinical trials have demonstrated that the use of unmanipulated NK cells to treat cancer is minimally effective,
likely due to limited engraftment, little in vivo expansion, and suppression by the tumor microenvironment. NK
cells activated and expanded with feeder cells expressing membrane bound interleukin-21 (mbIL-21) have
shown promising results clinically with high-risk myeloid malignancies and preclinically in several solid tumor
models. Therefore, we hypothesize that activated/expanded NK cells that have be genetically edited can be
used to successfully treat osteosarcoma, a disease for which patient outcome has not improved in over thirty
years. Our proposed objectives are to evaluate the baseline response of rested- and activated-NK cells against
various osteosarcoma cell lines, knockout negative regulators of NK cell function (specifically, c-CBL, IL-1R8,
and SMAD3), and implement a specific CAR that optimally activates NK cell antigen-specific killing. Genetically
engineered NK cells will be evaluated for enhanced therapeutic efficacy and safety in osteosarcoma models.
Our preliminary data strongly supports the hypothesis that NK cell-based cancer immunotherapy can be fully
realized using activated, genome engineered NK cells.

## Key facts

- **NIH application ID:** 10887434
- **Project number:** 5F30OD030021-04
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Gabrielle Matilde Robbins
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $46,683
- **Award type:** 5
- **Project period:** 2021-08-16 → 2025-05-11

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10887434

## Citation

> US National Institutes of Health, RePORTER application 10887434, Genome Engineered Natural Killer Cell Immunotherapy against Human Osteosarcoma (5F30OD030021-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10887434. Licensed CC0.

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