Trüb et al. showed that FAP-4-1BBL (a non-FcγR binding IgG1 heterodimer comprising TNF superfamily 4-1BB ligand and a Fab specific for the fibroblast activation protein [FAP]), enhanced activation, proliferation, cytokine secretion and tumor killing by human peripheral blood 4-1BBlo T cells stimulated in the presence of FAP+ fibroblasts with anti-CD3 or bispecific antibodies specific for tumor antigen and CD3. FAP-4-1BBL revitalized PD-1hi TIGIThi TIM-3hi CD160hi BTLAhi Lag-3hi 4-1BBlo T cells from primary tumor digests to upregulate Bcl2 and secrete IFNγ, IL-2, TNFα and IL-13. IL-13 upregulated the apoptotic marker active caspase 3 in IL-13R+ tumor cells.
Contributed by Paula Hochman
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.
Author Info: (1) Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland. (2) Laboratory of Cancer Immunology, Department of Biomedicine, University
Author Info: (1) Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland. (2) Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland. (3) Roche Innovation Center Zurich, Schlieren, Switzerland. (4) Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland. (5) Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany. (6) Roche Innovation Center Zurich, Schlieren, Switzerland. (7) Roche Innovation Center Zurich, Schlieren, Switzerland. (8) Roche Innovation Center Zurich, Schlieren, Switzerland. (9) Roche Innovation Center Zurich, Schlieren, Switzerland. (10) Roche Innovation Center Zurich, Schlieren, Switzerland. (11) Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (12) Medical Oncology, University Hospital Basel, Basel, Switzerland. (13) Institute of Pathology, University Hospital Basel, Basel, Switzerland. (14) Institute of Pathology, Cantonal Hospital Basel-Landschaft, Liestal, Switzerland. (15) Institute of Pathology, Cantonal Hospital Basel-Landschaft, Liestal, Switzerland. (16) Department of Surgery, Cantonal Hospital Basel-Landschaft, Liestal, Switzerland. (17) Department of Gynecology and Obstetrics, University Hospital Basel, Basel, Switzerland. (18) Division of Thoracic Surgery, University Hospital Basel, Basel, Switzerland. (19) Division of Thoracic Surgery, University Hospital Basel, Basel, Switzerland. (20) Roche Innovation Center Zurich, Schlieren, Switzerland. (21) Roche Innovation Center Zurich, Schlieren, Switzerland. (22) Medical Oncology, University Hospital Basel, Basel, Switzerland. (23) Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland. (24) Medical Oncology, University Hospital Basel, Basel, Switzerland alfred.zippelius@usb.ch.
