Feeder Cells at the Interface of Natural Killer Cell Activation, Expansion and Gene Editing.

Mark Gurney,Soumyadipta Kundu,Michael O’Dwyer,Shubham Pandey

doi:10.3389/fimmu.2022.802906

Mark Gurney, Soumyadipta Kundu + Show 2 more

Open Access

https://doi.org/10.3389/fimmu.2022.802906

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Abstract

Genome engineered natural killer (NK) cell therapies are emerging as a promising cancer immunotherapy platform with potential advantages and remaining uncertainties. Feeder cells induce activation and proliferation of NK cells via cell surface receptor-ligand interactions, supported by cytokines. Feeder cell expanded NK cell products have supported several NK cell adoptive transfer clinical trials over the past decade. Genome engineered NK cell therapies, including CAR-NK cells, seek to combine innate and alloreactive NK cell anti-tumor activity with antigen specific targeting or additional modifications aimed at improving NK cell persistence, homing or effector function. The profound activating and expansion stimulus provided by feeder cells is integral to current applications of clinical-scale genome engineering approaches in donor-derived, primary NK cells. Herein we explore the complex interactions that exist between feeder cells and both viral and emerging non-viral genome editing technologies in NK cell engineering. We focus on two established clinical-grade feeder systems; Epstein-Barr virus transformed lymphoblastoid cell lines and genetically engineered K562.mbIL21.4-1BBL feeder cells.

Highlights

Natural killer (NK) cell-based adoptive cell transfer (ACT) is a promising experimental approach to cancer immunotherapy
Genome editing, supported by novel technologies and adaptation of existing techniques to NK cells appears fundamental to achieving this potential
Current protocols for clinical-scale genome editing of primary, donor-derived NK cells rely upon feeder cell stimulation

Summary

Department

Apoptosis Research Centre, National University of Ireland Galway, Galway, Ireland, 2 ONK Therapeutics, Galway, Ireland. Genome engineered natural killer (NK) cell therapies are emerging as a promising cancer immunotherapy platform with potential advantages and remaining uncertainties. Feeder cells induce activation and proliferation of NK cells via cell surface receptor-ligand interactions, supported by cytokines. Feeder cell expanded NK cell products have supported several NK cell adoptive transfer clinical trials over the past decade. Genome engineered NK cell therapies, including CAR-NK cells, seek to combine innate and alloreactive NK cell anti-tumor activity with antigen specific targeting or additional modifications aimed at improving NK cell persistence, homing or effector function. The profound activating and expansion stimulus provided by feeder cells is integral to current applications of clinical-scale genome engineering approaches in donor-derived, primary NK cells. We explore the complex interactions that exist between feeder cells and both viral and emerging non-viral genome editing technologies in NK cell engineering. We focus on two established clinical-grade feeder systems; Epstein-Barr virus transformed lymphoblastoid cell lines and genetically engineered K562.mbIL21.4-1BBL feeder cells

INTRODUCTION

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