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Sequential Exposure to IL21 and IL15 During Human Natural Killer Cell Expansion Optimizes Yield and Function
Caimei Zhang1, Siddhant Kadu1, Yansen Xiao1
1Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania.
Cancer Immunology Research
|August 30, 2023
Summary
This study compares membrane-bound IL15 (mbIL15) and mbIL21 feeder cells for natural killer (NK) cell expansion. Sequential mbIL21 followed by mbIL15 expansion yields highly functional NK cells with potent anti-tumor activity.
Area of Science:
- Immunology
- Cell Biology
- Cancer Therapy
Background:
- Natural killer (NK) cells are crucial for immune surveillance and cancer therapy.
- Current NK cell expansion methods utilize engineered K562 feeder cells, often expressing membrane-bound IL15 (mbIL15) and/or mbIL21.
Purpose of the Study:
- To comprehensively compare the impact of mbIL15 versus mbIL21 feeder cells on NK cell expansion, including phenotype, polyfunctionality, cytotoxicity, metabolism, and in vivo efficacy.
- To investigate the effects of sequential feeder cell stimulation on NK cell attributes.
Main Methods:
- NK cells were expanded using irradiated K562 feeder cells engineered to express mbIL15 and/or mbIL21.
- Comprehensive analysis of NK cell phenotype, polyfunctionality, cytotoxicity, cellular metabolism, and gene expression.
- Evaluation of NK cell activity in xenograft tumor models.
- Assessment of sequential expansion strategies using mbIL21 followed by mbIL15 feeder cells.
Main Results:
- mbIL15 feeder cells promoted superior NK cell functionality across most measured parameters, while mbIL21 feeder cells yielded a higher quantity of NK cells.
- Combined mbIL15/mbIL21 stimulation resulted in NK cell attributes primarily resembling those induced by mbIL21.
- Sequential stimulation with mbIL21 followed by mbIL15 yielded substantial numbers of highly functional NK cells.
- NK cells expanded sequentially with mbIL21 then mbIL15 showed comparable in vivo anti-tumor activity to those expanded with mbIL15 alone in two of three models.
Conclusions:
- Distinct phenotypic and functional profiles arise from mbIL15 versus mbIL21 feeder cell stimulation.
- A trade-off exists between NK cell yield and function, with sequential expansion offering a potential optimization.
- Sequential expansion using mbIL21 followed by mbIL15 feeder cells represents a promising strategy for generating therapeutically effective NK cells.
