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Related Experiment Video

Updated: Jul 26, 2025

Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
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Engineered soluble, trimerized 4-1BBL variants as potent immunomodulatory agents.

Claire Battin1,2, Annika De Sousa Linhares1,2, Judith Leitner3

  • 1Themis Bioscience GmbH, Vienna, Austria; a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Cancer Immunology, Immunotherapy : CII
|June 13, 2023
PubMed
Summary

A novel engineered soluble 4-1BB ligand (s4-1BBL-TriXVIII) effectively stimulates anti-tumor T cell responses. Oncolytic measles viruses encoding s4-1BBL-TriXVIII demonstrated significant tumor reduction in preclinical models.

Keywords:
4-1BBCostimulationCostimulation agonistImmunotherapyT cell activationTNFR-superfamily

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Area of Science:

  • Immunology
  • Oncology
  • Virology

Background:

  • Targeting co-stimulatory receptors like 4-1BB (CD137/TNFSF9) enhances anti-tumor lymphocyte function.
  • Agonistic antibodies targeting 4-1BB show therapeutic promise in clinical trials.
  • The 4-1BB ligand (4-1BBL) plays a crucial role in T cell activation and effector functions.

Purpose of the Study:

  • To evaluate engineered soluble 4-1BBL formats for their ability to induce 4-1BB co-stimulation.
  • To assess the therapeutic potential of s4-1BBL-TriXVIII as an immunomodulatory payload in oncolytic viruses.
  • To investigate the efficacy of oncolytic measles virus encoding s4-1BBL-TriXVIII in a humanized mouse model.

Main Methods:

  • Utilized a T cell reporter system to assess 4-1BBL variants.
  • Engineered a soluble 4-1BBL ectodomain with a collagen-derived trimerization domain (s4-1BBL-TriXVIII).
  • Constructed oncolytic measles viruses encoding s4-1BBL-TriXVIII and evaluated their anti-tumor activity in a CD34+ humanized mouse model.

Main Results:

  • s4-1BBL-TriXVIII demonstrated potent induction of 4-1BB co-stimulation and T cell proliferation, comparable to the agonistic antibody urelumab.
  • Oncolytic measles viruses encoding s4-1BBL-TriXVIII significantly reduced tumor burden.
  • Measles viruses without s4-1BBL-TriXVIII showed no significant anti-tumor effect.

Conclusions:

  • Engineered soluble 4-1BBL, specifically s4-1BBL-TriXVIII, is a potent stimulator of 4-1BB co-stimulation and T cell responses.
  • s4-1BBL-TriXVIII serves as an effective immunomodulatory payload for therapeutic viral vectors, particularly oncolytic viruses.
  • Targeted delivery of 4-1BBL, such as via oncolytic viruses, may offer a promising strategy for tumor therapy, warranting further investigation into potential systemic toxicities like liver toxicity.