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

被引:50
作者
Becker-Hapak, Michelle K. [1 ]
Shrestha, Niraj [2 ]
McClain, Ethan [1 ]
Dee, Michael J. [2 ]
Chaturvedi, Pallavi [2 ]
Leclerc, Gilles M. [2 ]
Marsala, Lynne I. [1 ]
Foster, Mark [1 ]
Schappe, Timothy [1 ]
Tran, Jennifer [1 ]
Desai, Sweta [1 ]
Neal, Carly C. [1 ]
Pence, Patrick [1 ]
Wong, Pamela [1 ]
Wagner, Julia A. [1 ]
Russler-Germain, David A. [1 ]
Zhu, Xiaoyun [2 ]
Spanoudis, Catherine M. [2 ]
Gallo, Victor L. [2 ]
Echeverri, Christian A. [2 ]
Ramirez, Laritza L. [2 ]
You, Lijing [2 ]
Egan, Jack O. [2 ]
Rhode, Peter R. [2 ]
Jiao, Jin-an [2 ]
Muniz, Gabriela J. [2 ]
Jeng, Emily K. [2 ]
Prendes, Caitlin A. [2 ]
Sullivan, Ryan P. [3 ]
Berrien-Elliott, Melissa M. [1 ]
Wong, Hing C. [2 ]
Fehniger, Todd A. [1 ]
机构
[1] Washington Univ, Sch Med, Div Oncol, St Louis, MO USA
[2] HCW Biol Inc, Miramar, FL USA
[3] Wugen Inc, St Louis, MO USA
关键词
NATURAL-KILLER-CELLS; GENE-EXPRESSION; TISSUE FACTOR; CYTOKINE; RECEPTOR; SUPERAGONIST; METHYLATION; ACTIVATION; EFFICACY; PACKAGE;
D O I
10.1158/2326-6066.CIR-20-1002
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Natural killer (NK) cells arc 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, rh I L-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 IFNy 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 multisigna I 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.
引用
收藏
页码:1071 / 1087
页数:17
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