A Fusion Protein Complex that Combines IL-12, IL-15, and IL-18 Signaling to Induce Memory-Like NK Cells for Cancer Immunotherapy.

Autor:	Becker-Hapak MK; Washington University School of Medicine, Division of Oncology, Saint Louis, Missouri., Shrestha N; HCW Biologics Inc., Miramar, Florida., McClain E; Washington University School of Medicine, Division of Oncology, Saint Louis, Missouri., Dee MJ; HCW Biologics Inc., Miramar, Florida., Chaturvedi P; HCW Biologics Inc., Miramar, Florida., Leclerc GM; HCW Biologics Inc., Miramar, Florida., Marsala LI; Washington University School of Medicine, Division of Oncology, Saint Louis, Missouri., Foster M; Washington University School of Medicine, Division of Oncology, Saint Louis, Missouri., Schappe T; Washington University School of Medicine, Division of Oncology, Saint Louis, Missouri., Tran J; Washington University School of Medicine, Division of Oncology, Saint Louis, Missouri., Desai S; Washington University School of Medicine, Division of Oncology, Saint Louis, Missouri., Neal CC; Washington University School of Medicine, Division of Oncology, Saint Louis, Missouri., Pence P; Washington University School of Medicine, Division of Oncology, Saint Louis, Missouri., Wong P; Washington University School of Medicine, Division of Oncology, Saint Louis, Missouri., Wagner JA; Washington University School of Medicine, Division of Oncology, Saint Louis, Missouri., Russler-Germain DA; Washington University School of Medicine, Division of Oncology, Saint Louis, Missouri., Zhu X; HCW Biologics Inc., Miramar, Florida., Spanoudis CM; HCW Biologics Inc., Miramar, Florida., Gallo VL; HCW Biologics Inc., Miramar, Florida., Echeverri CA; HCW Biologics Inc., Miramar, Florida., Ramirez LL; HCW Biologics Inc., Miramar, Florida., You L; HCW Biologics Inc., Miramar, Florida., Egan JO; HCW Biologics Inc., Miramar, Florida., Rhode PR; HCW Biologics Inc., Miramar, Florida., Jiao JA; HCW Biologics Inc., Miramar, Florida., Muniz GJ; HCW Biologics Inc., Miramar, Florida., Jeng EK; HCW Biologics Inc., Miramar, Florida., Prendes CA; HCW Biologics Inc., Miramar, Florida., Sullivan RP; Wugen, Inc., Saint Louis, Missouri., Berrien-Elliott MM; Washington University School of Medicine, Division of Oncology, Saint Louis, Missouri., Wong HC; HCW Biologics Inc., Miramar, Florida., Fehniger TA; Washington University School of Medicine, Division of Oncology, Saint Louis, Missouri. tfehnige@wustl.edu.
Jazyk:	angličtina
Zdroj:	Cancer immunology research [Cancer Immunol Res] 2021 Sep; Vol. 9 (9), pp. 1071-1087. Date of Electronic Publication: 2021 Jul 09.
DOI:	10.1158/2326-6066.CIR-20-1002
Abstrakt:	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. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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