Research ArticleCancer

Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy

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Science Translational Medicine  12 Jun 2019:
Vol. 11, Issue 496, eaav5989
DOI: 10.1126/scitranslmed.aav5989

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For the love of 4-1BB

Antibodies activating the 4-1BB costimulatory molecule did not succeed as cancer immunotherapy due to adverse events in patients. Claus et al. have now taken a protein engineering approach to make a next-generation 4-1BB agonist. They generated constructs with a trimeric 4-1BBL portion that engages 4-1BB on T cells without harmful Fc receptor cross-linking. The constructs also include tumor antigen–targeting portions and can be used in conjunction with other immunotherapies. These proteins successfully stimulated T cells in explanted samples from patients with cancer and improved survival in multiple mouse models. This approach reveals a potentially better way to stimulate 4-1BB for cancer immunotherapy.

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