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Becker-Hapak, Michelle K; Shrestha, Niraj; McClain, Ethan; Dee, Michael J; Chaturvedi, Pallavi; Leclerc, Gilles M; Marsala, Lynne I; Foster, Mark; Schappe, Timothy; Tran, Jennifer; Desai, Sweta; Neal, Carly C; Pence, Patrick; Wong, Pamela; Wagner, Julia A; Russler-Germain, David A; Zhu, Xiaoyun; Spanoudis, Catherine M; Gallo, Victor L; Echeverri, Christian A; Ramirez, Laritza L; You, Lijing; Egan, Jack O; Rhode, Peter R; Jiao, Jin-An; Muniz, Gabriela J; Jeng, Emily K; Prendes, Caitlin A; Sullivan, Ryan P; Berrien-Elliott, Melissa M; Wong, Hing C; Fehniger, Todd A
Cancer immunology research, 09/2021, Letnik: 9, Številka: 9Journal Article
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.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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