A Fusion Protein Complex that Combines IL-12, IL-15, and IL-18 Signaling to Induce Memory-Like NK Cells for Cancer Immunotherapy
©2021 American Association for Cancer Research..
Natural killer (NK) cells are a promising cellular therapy for cancer, with challenges in the field including persistence, functional activity, and tumor recognition. Briefly, priming blood NK cells with recombinant human (rh)IL-12, rhIL-15, and rhIL-18 (12/15/18) results in memory-like NK cell differentiation and enhanced responses against cancer. However, the lack of available, scalable Good Manufacturing Process (GMP)-grade reagents required to advance this approach beyond early-phase clinical trials is limiting. To address this challenge, we developed a novel platform centered upon an inert tissue factor scaffold for production of heteromeric fusion protein complexes (HFPC). The first use of this platform combined IL-12, IL-15, and IL-18 receptor engagement (HCW9201), and the second adds CD16 engagement (HCW9207). This unique HFPC expression platform was scalable with equivalent protein quality characteristics in small- and GMP-scale production. HCW9201 and HCW9207 stimulated activation and proliferation signals in NK cells, but HCW9207 had decreased IL-18 receptor signaling. RNA sequencing and multidimensional mass cytometry revealed parallels between HCW9201 and 12/15/18. HCW9201 stimulation improved NK cell metabolic fitness and resulted in the DNA methylation remodeling characteristic of memory-like differentiation. HCW9201 and 12/15/18 primed similar increases in short-term and memory-like NK cell cytotoxicity and IFNγ production against leukemia targets, as well as equivalent control of leukemia in NSG mice. Thus, HFPCs represent a protein engineering approach that solves many problems associated with multisignal receptor engagement on immune cells, and HCW9201-primed NK cells can be advanced as an ideal approach for clinical GMP-grade memory-like NK cell production for cancer therapy.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
Cancer immunology research - 9(2021), 9 vom: 15. Sept., Seite 1071-1087 |
| Sprache: |
Englisch |
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| Links: |
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| Themen: |
187348-17-0 |
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| Anmerkungen: |
Date Completed 07.03.2022 Date Revised 07.11.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1158/2326-6066.CIR-20-1002 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM327901683 |
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| 100 | 1 | |a Becker-Hapak, Michelle K |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A Fusion Protein Complex that Combines IL-12, IL-15, and IL-18 Signaling to Induce Memory-Like NK Cells for Cancer Immunotherapy |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 07.03.2022 | ||
| 500 | |a Date Revised 07.11.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2021 American Association for Cancer Research. | ||
| 520 | |a Natural killer (NK) cells are a promising cellular therapy for cancer, with challenges in the field including persistence, functional activity, and tumor recognition. Briefly, priming blood NK cells with recombinant human (rh)IL-12, rhIL-15, and rhIL-18 (12/15/18) results in memory-like NK cell differentiation and enhanced responses against cancer. However, the lack of available, scalable Good Manufacturing Process (GMP)-grade reagents required to advance this approach beyond early-phase clinical trials is limiting. To address this challenge, we developed a novel platform centered upon an inert tissue factor scaffold for production of heteromeric fusion protein complexes (HFPC). The first use of this platform combined IL-12, IL-15, and IL-18 receptor engagement (HCW9201), and the second adds CD16 engagement (HCW9207). This unique HFPC expression platform was scalable with equivalent protein quality characteristics in small- and GMP-scale production. HCW9201 and HCW9207 stimulated activation and proliferation signals in NK cells, but HCW9207 had decreased IL-18 receptor signaling. RNA sequencing and multidimensional mass cytometry revealed parallels between HCW9201 and 12/15/18. HCW9201 stimulation improved NK cell metabolic fitness and resulted in the DNA methylation remodeling characteristic of memory-like differentiation. HCW9201 and 12/15/18 primed similar increases in short-term and memory-like NK cell cytotoxicity and IFNγ production against leukemia targets, as well as equivalent control of leukemia in NSG mice. Thus, HFPCs represent a protein engineering approach that solves many problems associated with multisignal receptor engagement on immune cells, and HCW9201-primed NK cells can be advanced as an ideal approach for clinical GMP-grade memory-like NK cell production for cancer therapy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 7 | |a Interleukin-15 |2 NLM | |
| 650 | 7 | |a Interleukin-18 |2 NLM | |
| 650 | 7 | |a Receptors, Natural Killer Cell |2 NLM | |
| 650 | 7 | |a Recombinant Fusion Proteins |2 NLM | |
| 650 | 7 | |a Interleukin-12 |2 NLM | |
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| 700 | 1 | |a Shrestha, Niraj |e verfasserin |4 aut | |
| 700 | 1 | |a McClain, Ethan |e verfasserin |4 aut | |
| 700 | 1 | |a Dee, Michael J |e verfasserin |4 aut | |
| 700 | 1 | |a Chaturvedi, Pallavi |e verfasserin |4 aut | |
| 700 | 1 | |a Leclerc, Gilles M |e verfasserin |4 aut | |
| 700 | 1 | |a Marsala, Lynne I |e verfasserin |4 aut | |
| 700 | 1 | |a Foster, Mark |e verfasserin |4 aut | |
| 700 | 1 | |a Schappe, Timothy |e verfasserin |4 aut | |
| 700 | 1 | |a Tran, Jennifer |e verfasserin |4 aut | |
| 700 | 1 | |a Desai, Sweta |e verfasserin |4 aut | |
| 700 | 1 | |a Neal, Carly C |e verfasserin |4 aut | |
| 700 | 1 | |a Pence, Patrick |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Pamela |e verfasserin |4 aut | |
| 700 | 1 | |a Wagner, Julia A |e verfasserin |4 aut | |
| 700 | 1 | |a Russler-Germain, David A |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Xiaoyun |e verfasserin |4 aut | |
| 700 | 1 | |a Spanoudis, Catherine M |e verfasserin |4 aut | |
| 700 | 1 | |a Gallo, Victor L |e verfasserin |4 aut | |
| 700 | 1 | |a Echeverri, Christian A |e verfasserin |4 aut | |
| 700 | 1 | |a Ramirez, Laritza L |e verfasserin |4 aut | |
| 700 | 1 | |a You, Lijing |e verfasserin |4 aut | |
| 700 | 1 | |a Egan, Jack O |e verfasserin |4 aut | |
| 700 | 1 | |a Rhode, Peter R |e verfasserin |4 aut | |
| 700 | 1 | |a Jiao, Jin-An |e verfasserin |4 aut | |
| 700 | 1 | |a Muniz, Gabriela J |e verfasserin |4 aut | |
| 700 | 1 | |a Jeng, Emily K |e verfasserin |4 aut | |
| 700 | 1 | |a Prendes, Caitlin A |e verfasserin |4 aut | |
| 700 | 1 | |a Sullivan, Ryan P |e verfasserin |4 aut | |
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| 700 | 1 | |a Wong, Hing C |e verfasserin |4 aut | |
| 700 | 1 | |a Fehniger, Todd A |e verfasserin |4 aut | |
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