A Fusion protein complex that combines il-12, il-15, and il-18 signaling to induce memory-like nk cells for cancer immunotherapy

Michelle K. Becker-Hapak, Niraj Shrestha, Ethan McClain, Michael J. Dee, Pallavi Chaturvedi, Gilles M. Leclerc, Lynne I. Marsala, Mark Foster, Timothy Schappe, Jennifer Tran, Sweta Desai, Carly C. Neal, Patrick Pence, Pamela Wong, Julia A. Wagner, David A. Russler-Germain, Xiaoyun Zhu, Catherine M. Spanoudis, Victor L. Gallo, Christian A. EcheverriLaritza L. Ramirez, Lijing You, Jack O. Egan, Peter R. Rhode, Jin An Jiao, Gabriela J. Muniz, Emily K. Jeng, Caitlin A. Prendes, Ryan P. Sullivan, Melissa M. Berrien-Elliott, Hing C. Wong, Todd A. Fehniger

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


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- A nd 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 IFNg 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.

Original languageEnglish
Pages (from-to)1071-1087
Number of pages17
JournalCancer immunology research
Issue number9
StatePublished - Sep 2021


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