PM21-particle stimulation augmented with cytokines enhances NK cell expansion and confers memory-like characteristics with enhanced survival
NK cell therapeutics have gained significant attention as a potential cancer treatment. Towards therapeutic use, NK cells need to be activated and expanded to attain high potency and large quantities for an effective dosage. This is typically done by ex vivo stimulation with cytokines to enhance fun...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2024-04-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1383281/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850087444621295616 |
|---|---|
| author | Jeremiah L. Oyer Tayler J. Croom-Perez Md Faqrul Hasan Javier A. Rivera-Huertas Sarah B. Gitto Joanna M. Mucha Xiang Zhu Deborah A. Altomare Robert Y. Igarashi Alicja J. Copik |
| author_facet | Jeremiah L. Oyer Tayler J. Croom-Perez Md Faqrul Hasan Javier A. Rivera-Huertas Sarah B. Gitto Joanna M. Mucha Xiang Zhu Deborah A. Altomare Robert Y. Igarashi Alicja J. Copik |
| author_sort | Jeremiah L. Oyer |
| collection | DOAJ |
| description | NK cell therapeutics have gained significant attention as a potential cancer treatment. Towards therapeutic use, NK cells need to be activated and expanded to attain high potency and large quantities for an effective dosage. This is typically done by ex vivo stimulation with cytokines to enhance functionality or expansion for 10-14 days to increase both their activity and quantity. Attaining a robust methodology to produce large doses of potent NK cells for an off-the-shelf product is highly desirable. Notably, past reports have shown that stimulating NK cells with IL-12, IL-15, and IL-18 endows them with memory-like properties, better anti-tumor activity, and persistence. While this approach produces NK cells with clinically favorable characteristics supported by encouraging early results for the treatment of hematological malignancies, its limited scalability, variability in initial doses, and the necessity for patient-specific production hinder its broader application. In this study, stimulation of NK cells with PM21-particles derived from K562-41BBL-mbIL21 cells was combined with memory-like induction using cytokines IL-12, IL-15, and IL-18 to produce NK cells with enhanced anti-tumor function. The use of cytokines combined with PM21-particles (cytokine and particle, CAP) significantly enhanced NK cell expansion, achieving a remarkable 8,200-fold in 14 days. Mechanistically, this significant improvement over expansion with PM21-particles alone was due to the upregulation of receptors for key stimulating ligands (4-1BBL and IL-2), resulting in a synergy that drives substantial NK cell growth, showcasing the potential for more effective therapeutic applications. The therapeutic potential of CAP-NK cells was demonstrated by the enhanced metabolic fitness, persistence, and anti-tumor function both in vitro and in vivo. Finally, CAP-NK cells were amenable to current technologies used in developing therapeutic NK cell products, including CRISPR/Cas9-based techniques to generate a triple-gene knockout or a gene knock-in. Taken together, these data demonstrate that the addition of cytokines enhanced the already effective method of ex vivo generation of therapeutic NK cells with PM21-particles, yielding a superior NK cell product for manufacturing efficiency and potential therapeutic applications. |
| format | Article |
| id | doaj-art-a1322c48c6044a24a3fa333918436d9b |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2024-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-a1322c48c6044a24a3fa333918436d9b2025-08-20T02:43:13ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-04-011510.3389/fimmu.2024.13832811383281PM21-particle stimulation augmented with cytokines enhances NK cell expansion and confers memory-like characteristics with enhanced survivalJeremiah L. OyerTayler J. Croom-PerezMd Faqrul HasanJavier A. Rivera-HuertasSarah B. GittoJoanna M. MuchaXiang ZhuDeborah A. AltomareRobert Y. IgarashiAlicja J. CopikNK cell therapeutics have gained significant attention as a potential cancer treatment. Towards therapeutic use, NK cells need to be activated and expanded to attain high potency and large quantities for an effective dosage. This is typically done by ex vivo stimulation with cytokines to enhance functionality or expansion for 10-14 days to increase both their activity and quantity. Attaining a robust methodology to produce large doses of potent NK cells for an off-the-shelf product is highly desirable. Notably, past reports have shown that stimulating NK cells with IL-12, IL-15, and IL-18 endows them with memory-like properties, better anti-tumor activity, and persistence. While this approach produces NK cells with clinically favorable characteristics supported by encouraging early results for the treatment of hematological malignancies, its limited scalability, variability in initial doses, and the necessity for patient-specific production hinder its broader application. In this study, stimulation of NK cells with PM21-particles derived from K562-41BBL-mbIL21 cells was combined with memory-like induction using cytokines IL-12, IL-15, and IL-18 to produce NK cells with enhanced anti-tumor function. The use of cytokines combined with PM21-particles (cytokine and particle, CAP) significantly enhanced NK cell expansion, achieving a remarkable 8,200-fold in 14 days. Mechanistically, this significant improvement over expansion with PM21-particles alone was due to the upregulation of receptors for key stimulating ligands (4-1BBL and IL-2), resulting in a synergy that drives substantial NK cell growth, showcasing the potential for more effective therapeutic applications. The therapeutic potential of CAP-NK cells was demonstrated by the enhanced metabolic fitness, persistence, and anti-tumor function both in vitro and in vivo. Finally, CAP-NK cells were amenable to current technologies used in developing therapeutic NK cell products, including CRISPR/Cas9-based techniques to generate a triple-gene knockout or a gene knock-in. Taken together, these data demonstrate that the addition of cytokines enhanced the already effective method of ex vivo generation of therapeutic NK cells with PM21-particles, yielding a superior NK cell product for manufacturing efficiency and potential therapeutic applications.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1383281/fullnatural killer cellNK cell therapymemory-like NK cellsimmunotherapyadoptive cell therapy |
| spellingShingle | Jeremiah L. Oyer Tayler J. Croom-Perez Md Faqrul Hasan Javier A. Rivera-Huertas Sarah B. Gitto Joanna M. Mucha Xiang Zhu Deborah A. Altomare Robert Y. Igarashi Alicja J. Copik PM21-particle stimulation augmented with cytokines enhances NK cell expansion and confers memory-like characteristics with enhanced survival Frontiers in Immunology natural killer cell NK cell therapy memory-like NK cells immunotherapy adoptive cell therapy |
| title | PM21-particle stimulation augmented with cytokines enhances NK cell expansion and confers memory-like characteristics with enhanced survival |
| title_full | PM21-particle stimulation augmented with cytokines enhances NK cell expansion and confers memory-like characteristics with enhanced survival |
| title_fullStr | PM21-particle stimulation augmented with cytokines enhances NK cell expansion and confers memory-like characteristics with enhanced survival |
| title_full_unstemmed | PM21-particle stimulation augmented with cytokines enhances NK cell expansion and confers memory-like characteristics with enhanced survival |
| title_short | PM21-particle stimulation augmented with cytokines enhances NK cell expansion and confers memory-like characteristics with enhanced survival |
| title_sort | pm21 particle stimulation augmented with cytokines enhances nk cell expansion and confers memory like characteristics with enhanced survival |
| topic | natural killer cell NK cell therapy memory-like NK cells immunotherapy adoptive cell therapy |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1383281/full |
| work_keys_str_mv | AT jeremiahloyer pm21particlestimulationaugmentedwithcytokinesenhancesnkcellexpansionandconfersmemorylikecharacteristicswithenhancedsurvival AT taylerjcroomperez pm21particlestimulationaugmentedwithcytokinesenhancesnkcellexpansionandconfersmemorylikecharacteristicswithenhancedsurvival AT mdfaqrulhasan pm21particlestimulationaugmentedwithcytokinesenhancesnkcellexpansionandconfersmemorylikecharacteristicswithenhancedsurvival AT javierariverahuertas pm21particlestimulationaugmentedwithcytokinesenhancesnkcellexpansionandconfersmemorylikecharacteristicswithenhancedsurvival AT sarahbgitto pm21particlestimulationaugmentedwithcytokinesenhancesnkcellexpansionandconfersmemorylikecharacteristicswithenhancedsurvival AT joannammucha pm21particlestimulationaugmentedwithcytokinesenhancesnkcellexpansionandconfersmemorylikecharacteristicswithenhancedsurvival AT xiangzhu pm21particlestimulationaugmentedwithcytokinesenhancesnkcellexpansionandconfersmemorylikecharacteristicswithenhancedsurvival AT deborahaaltomare pm21particlestimulationaugmentedwithcytokinesenhancesnkcellexpansionandconfersmemorylikecharacteristicswithenhancedsurvival AT robertyigarashi pm21particlestimulationaugmentedwithcytokinesenhancesnkcellexpansionandconfersmemorylikecharacteristicswithenhancedsurvival AT alicjajcopik pm21particlestimulationaugmentedwithcytokinesenhancesnkcellexpansionandconfersmemorylikecharacteristicswithenhancedsurvival |