PT  - JOURNAL ARTICLE
AU  - Marta Trüb
AU  - Franziska Uhlenbrock
AU  - Christina Claus
AU  - Petra Herzig
AU  - Martin Thelen
AU  - Vaios Karanikas
AU  - Marina Bacac
AU  - Maria Amann
AU  - Rosemarie Albrecht
AU  - Claudia Ferrara-Koller
AU  - Daniela Thommen
AU  - Sacha Rothschield
AU  - Spasenija Savic Prince
AU  - Kirsten D Mertz
AU  - Gieri Cathomas
AU  - Robert Rosenberg
AU  - Viola Heinzelmann-Schwarz
AU  - Mark Wiese
AU  - Didier Lardinois
AU  - Pablo Umana
AU  - Christian Klein
AU  - Heinz Laubli
AU  - Abhishek S Kashyap
AU  - Alfred Zippelius
TI  - Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer
AID  - 10.1136/jitc-2019-000238
DP  - 2020 Jul 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - e000238
VI  - 8
IP  - 2
4099  - http://jitc.bmj.com/content/8/2/e000238.short
4100  - http://jitc.bmj.com/content/8/2/e000238.full
SO  - J Immunother Cancer2020 Jul 01; 8
AB  - Background The costimulatory receptor 4-1BB (CD137, TNFRSF9) plays an important role in sustaining effective T cell immune responses and is investigated as target for cancer therapy. Systemic 4-1BB directed therapies elicit toxicity or low efficacy, which significantly hampered advancement of 4-1BB-based immunotherapy. Therefore, targeted delivery of 4-1BB agonist to the tumor side is needed for eliciting antitumor efficacy while avoiding systemic toxicity.Methods We analyzed the immunostimulatory properties of a fibroblast activation protein (FAP)-targeted 4-1BB agonist (FAP-4-1BBL) by assessing tumor-infiltrating lymphocytes’ (TIL) activity from patients with non-small cell lung cancer and epithelial ovarian cancer.Results Combination treatment with FAP-4-1BBL and T cell receptor stimulation by either anti-CD3 or T cell bispecific antibodies significantly enhanced TIL activation and effector functions, including T cell proliferation, secretion of proinflammatory cytokines and cytotoxicity. Notably, costimulation with FAP-4-1BBL led to de novo secretion of interleukin (IL)−13. This was associated with cytokine-mediated tumor cell apoptosis, which was partially dependent on IL-13 alpha 1/2 receptors and STAT6 phosphorylation.Conclusions Our study provides mechanistic insights into T cell stimulation induced by FAP-4-1BBL in primary human tumors and supports the investigation of FAP-4-1BBL compound in early clinical trials.