4-1BB immunotherapy: advances and hurdles

Exp Mol Med. 2024 Feb;56(1):32-39. doi: 10.1038/s12276-023-01136-4. Epub 2024 Jan 4.

Abstract

Since its initial description 35 years ago as an inducible molecule expressed in cytotoxic and helper T cells, 4-1BB has emerged as a crucial receptor in T-cell-mediated immune functions. Numerous studies have demonstrated the involvement of 4-1BB in infection and tumor immunity. However, the clinical development of 4-1BB agonist antibodies has been impeded by the occurrence of strong adverse events, notably hepatotoxicity, even though these antibodies have exhibited tremendous promise in in vivo tumor models. Efforts are currently underway to develop a new generation of agonist antibodies and recombinant proteins with modified effector functions that can harness the potent T-cell modulation properties of 4-1BB while mitigating adverse effects. In this review, we briefly examine the role of 4-1BB in T-cell biology, explore its clinical applications, and discuss future prospects in the field of 4-1BB agonist immunotherapy.

Trial registration: ClinicalTrials.gov NCT04903873 NCT04121676 NCT05614258 NCT05060263 NCT04144842 NCT3802955 CTR20201794 NCT03881488 NCT04130542.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies
  • Humans
  • Immunotherapy
  • Neoplasms* / drug therapy
  • Tumor Necrosis Factor Receptor Superfamily, Member 9* / metabolism

Substances

  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Antibodies

Associated data

  • ClinicalTrials.gov/NCT04903873
  • ClinicalTrials.gov/NCT04121676
  • ClinicalTrials.gov/NCT05614258
  • ClinicalTrials.gov/NCT05060263
  • ClinicalTrials.gov/NCT04144842
  • ClinicalTrials.gov/NCT3802955
  • ClinicalTrials.gov/CTR20201794
  • ClinicalTrials.gov/NCT03881488
  • ClinicalTrials.gov/NCT04130542
  • EudraCT/2019–003329-11
  • JapicCTI/CTI-205153