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Updated: Jun 12, 2025

Measurement of Natural Killer Cell-Mediated Cytotoxicity and Migration in the Context of Hepatic Tumor Cells
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Measurement of Natural Killer Cell-Mediated Cytotoxicity and Migration in the Context of Hepatic Tumor Cells

Published on: February 22, 2020

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Characterization and comparative analysis of multifunctional natural killer cell engagers during antitumor responses

Hang Lin1, Ryan Case2, Kathy Y Wei2

  • 1Amgen Research, South San Francisco, CA 94080, USA; Amgen R&D Postdoctoral Fellows Program, South San Francisco, CA 94080, USA.

Cell Reports. Medicine
|May 3, 2025
PubMed

Insights

Natural killer cell engagers (NKCEs) offer a promising alternative to T cell engagers (TCEs) by reducing cytokine release syndrome. Optimized NKCEs show potential as effective cancer immunotherapies.

Area of Science:

  • Immunology
  • Oncology
  • Biotechnology

Background:

  • T cell engagers (TCEs) are effective cancer therapies but cause cytokine release syndrome (CRS).
  • Natural killer (NK) cells produce fewer cytokines than T cells, making NK cell engagers (NKCEs) a potential alternative.
  • The mechanisms behind NK cells' lower cytokine production and NKCE efficacy compared to TCEs are not fully understood.

Purpose of the Study:

  • To investigate why NK cells secrete less tumor necrosis factor (TNF) compared to T cells.
  • To develop and optimize NK cell engagers (NKCEs) for enhanced anti-cancer activity.
  • To compare the therapeutic efficacy of NKCEs, interleukin-2 (IL-2), and TCEs in preclinical cancer models.

Main Methods:

  • Comparative analysis of TNF trafficking and processing in T cells versus NK cells.
  • Systematic development and benchmarking of NKCEs, including optimization for multiple activating receptors and IL-2 incorporation.
  • In vivo studies using animal tumor models to evaluate NKCE, IL-2, and TCE therapies.

Main Results:

  • NK cells exhibit reduced TNF trafficking and processing compared to T cells.
  • Optimized NKCEs demonstrated increased potency and durability by engaging multiple activating receptors and incorporating IL-2.
  • Comparative studies revealed shared and unique therapeutic benefits among NKCE, IL-2, and TCE treatments in animal models.

Conclusions:

  • NK cells' inherent mechanisms contribute to lower cytokine secretion, supporting their use in NKCEs.
  • Multifunctional NKCEs can be rationally designed for improved efficacy and reduced toxicity.
  • NKCEs represent a viable alternative to TCEs, offering a new avenue for cancer immunotherapy development.
Keywords:
CRSIL-2NK cell engagersNKCEsT cell engagerTCEsTNFcytokine release syndrome

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