ArticleCancer immunology research2021
A Fusion Protein Complex that Combines IL-12, IL-15, and IL-18 Signaling to Induce Memory-Like NK Cells for Cancer Immunotherapy.
Article in Cancer immunology research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 72 citations in OpenAlex.
- Anisodus tanguticus in Cancer Research: A Review of Traditional Use, Phytochemistry, Extraction Methods, and Preclinical Antitumor Evidence.Medical science monitor : international medical journal of experimental and clinical research · 2026Review
- Cytokine-induced expandable memory NK cells with significant metabolic, epigenetic remodeling, and persistence properties.Cell death discovery · 2026Article
- The long noncoding RNA lnc13 restrains inflammatory responses to maintain oral tolerance to gluten.Nature immunology · 2026Article
- A novel mRNA-based multi-cytokine strategy to reprogram the peritoneal tumor microenvironment in ovarian cancer.Journal of nanobiotechnology · 2026Article
- Enhancing cancer killing and natural killer cell persistence by targeting NOXA, a predictor of poor patient survival.Molecular therapy. Oncology · 2026Article
- Characteristics of NK cells activation following IL-12, IL-15, IL-18 cytokines stimulation for preclinical purposes.Scientific reports · 2026Article
- Optimal genetic feeder cell-expanded and engineered NK cell products are composed of CD56Cancer immunology, immunotherapy : CII · 2026Article
- The metabolic environment within solid tumors drives a complex crosstalk between macrophages and NK cells.Frontiers in immunology · 2026Review
- Phase 1 study evaluating the safety, preliminary efficacy, and pharmacodynamics of recombinant interleukin-15 in combination with nivolumab and ipilimumab in patients with refractory cancers.Journal for immunotherapy of cancer · 2025Article
- Paclitaxel and Cephalomannine Synergistically Induce PANoptosis in Triple-Negative Breast Cancer Through Oxygen-Regulated Cell Death Pathways.Antioxidants (Basel, Switzerland) · 2025Article
- Review
- Memory-like Natural Killer Cell and CD19 Antibody-Based Immunotherapy in Combination with Tyrosine Kinase Inhibition Has Antitumor Effects against Ph(-like) Acute Lymphoblastic Leukemia.Cancer immunology research · 2025Article
- Cytokines in Focus: IL-2 and IL-15 in NK Adoptive Cell Cancer Immunotherapy.Immune network · 2025Review
- From innate-like to innate: the next wave of off-the-shelf CAR immunotherapies.Frontiers in immunology · 2025Review
- The power and the promise of CAR-mediated cell immunotherapy for clinical application in pancreatic cancer.Journal of advanced research · 2025Review
- Memory-like NK cell differentiation, inhibitory NKG2A blockade, and improved recognition via antibody or CAR engineering combine to enhance NK cell attack against multiple myeloma.Journal of immunology (Baltimore, Md. : 1950) · 2025Article
- Mendelian Randomization Analysis Supports a Causal Relationship Between Circulating Inflammatory Proteins and Basal Cell Carcinoma.Clinical, cosmetic and investigational dermatology · 2025Article
- Natural killer cell memory: challenges and opportunities for cancer immunotherapy.Cancer biology & therapy · 2024Review
- DNMT1 inhibition improves the activity of memory-like natural killer cells by enhancing the level of autophagy.Molecular biology reports · 2024Article
- Nanoenabled IL-15 Superagonist via Conditionally Stabilized Protein-Protein Interactions Eradicates Solid Tumors by Precise Immunomodulation.Journal of the American Chemical Society · 2024Article
Corrections and comments
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Authors and funding
32 authors at 3 institutions in 2 countries.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.