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Updated: May 14, 2026
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
Development of CAR NK Cell Lines Selectively Targeting Cancer Cells Expressing Membrane Hsp70
Khouloud Hachani1, Mina Yazdi2, Charlotte Carcopino3
1Department of Otolaryngology Head and Neck Surgery TUM School of Medicine and Health Technical University of Munich Munich Germany.
Abstract:
An effective chimeric antigen receptor (CAR)-based immunotherapy depends on both a suitable immune cell platform and a tumor-specific antigen to overcome barriers in solid tumors. Natural killer (NK) cell lines are promising platforms for CAR constructs due to their inherent tumor-killing ability, safety profile, and feasibility for standardized, off-the-shelf therapeutic use. Herein, four human NK cell lines (YT, KHYG1, NKL, and NK92) were retrovirally transduced with an anti-Hsp70 CAR targeting membrane-bound heat shock protein 70 (mHsp70), a tumor-specific antigen with broad expression on many solid tumors, but not normal cells. Computational modeling suggested a strong binding between the CAR and the extracellular domain of mHsp70. Although all NK cell lines exhibited successful CAR integration and surface expression, only NKL and NK92 cells maintained stable CAR expression and long-term viability. The anti-Hsp70 CAR NKL and NK92 cells demonstrated enhanced expression of activation markers and secretion of cytotoxic effector molecules, and robust target-specific killing of mHsp70-positive cancer cells, while sparing mHsp70-negative targets. Our findings validate the therapeutic potential of anti-Hsp70 CAR NK cells and the suitability of NKL and NK92 cells for advancing off-the-shelf CAR NK cell therapies, thereby offering a promising strategy for targeting a broad range of solid tumors expressing mHsp70.
Insights
Chimeric antigen receptor (CAR) natural killer (NK) cells targeting membrane-bound heat shock protein 70 (mHsp70) show promise for solid tumor immunotherapy. NKL and NK92 cell lines demonstrated effective and specific cancer cell killing, supporting off-the-shelf therapeutic potential.
Area of Science:
- Immunotherapy
- Cellular therapy
- Oncology
Background:
- Chimeric antigen receptor (CAR)-based immunotherapy requires suitable immune cell platforms and tumor-specific antigens for solid tumor treatment.
- Natural killer (NK) cells are promising CAR platforms due to their inherent cytotoxicity, safety, and potential for standardized, off-the-shelf application.
Purpose of the Study:
- To develop and evaluate anti-Hsp70 CAR NK cell lines for targeting solid tumors expressing membrane-bound heat shock protein 70 (mHsp70).
Main Methods:
- Four human NK cell lines (YT, KHYG1, NKL, NK92) were retrovirally transduced with an anti-Hsp70 CAR.
- Computational modeling assessed CAR-mHsp70 binding.
- CAR integration, surface expression, cell viability, activation markers, effector molecule secretion, and target-specific cytotoxicity were evaluated.
Main Results:
- All NK cell lines showed CAR integration and surface expression, but only NKL and NK92 maintained stable expression and viability.
- Anti-Hsp70 CAR NKL and NK92 cells exhibited enhanced activation markers and cytotoxic molecule secretion.
- These CAR NK cells demonstrated robust, specific killing of mHsp70-positive cancer cells while sparing mHsp70-negative cells.
Conclusions:
- NKL and NK92 cells are suitable platforms for developing off-the-shelf CAR NK cell therapies targeting mHsp70-expressing solid tumors.
- Anti-Hsp70 CAR NK cells represent a promising therapeutic strategy for a broad spectrum of solid cancers.
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