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

  • Cancer Immunol Res. 2021 Sep;9(9):1071-1087. doi: 10.1158/2326-6066.CIR-20-1002.
Michelle K Becker-Hapak  1 ,  Niraj Shrestha  2 ,  Ethan McClain  1 ,  Michael J Dee  2 ,  Pallavi Chaturvedi  2 ,  Gilles M Leclerc  2 ,  Lynne I Marsala  1 ,  Mark Foster  1 ,  Timothy Schappe  1 ,  Jennifer Tran  1 ,  Sweta Desai  1 ,  Carly C Neal  1 ,  Patrick Pence  1 ,  Pamela Wong  1 ,  Julia A Wagner  1 ,  David A Russler-Germain  1 ,  Xiaoyun Zhu  2 ,  Catherine M Spanoudis  2 ,  Victor L Gallo  2 ,  Christian A Echeverri  2 ,  Laritza L Ramirez  2 ,  Lijing You  2 ,  Jack O Egan  2 ,  Peter R Rhode  2 ,  Jin-An Jiao  2 ,  Gabriela J Muniz  2 ,  Emily K Jeng  2 ,  Caitlin A Prendes  2 ,  Ryan P Sullivan  3 ,  Melissa M Berrien-Elliott  1 ,  Hing C Wong  2 ,  Todd A Fehniger  4
Affiliations
  • 1. Washington University School of Medicine, Division of Oncology, Saint Louis, Missouri.
  • 2. HCW Biologics Inc., Miramar, Florida.
  • 3. Wugen, Inc., Saint Louis, Missouri.
  • 4. Washington University School of Medicine, Division of Oncology, Saint Louis, Missouri. [email protected].
PMID: 34244297 DOI: 10.1158/2326-6066.CIR-20-1002
Abstract

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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