title: A novel three-dimensional heterotypic spheroid model for the assessment of the activity of cancer immunotherapy agents.
abstract: The complexity of the tumor microenvironment is difficult to mimic in vitro, particularly regarding tumor-host interactions. To enable better assessment of cancer immunotherapy agents in vitro, we developed a three-dimensional (3D) heterotypic spheroid model composed of tumor cells, fibroblasts, and immune cells. Drug targeting, efficient stimulation of immune cell infiltration, and specific elimination of tumor or fibroblast spheroid areas were demonstrated following treatment with a novel immunocytokine (interleukin-2 variant; IgG-IL2v) and tumor- or fibroblast-targeted T cell bispecific antibody (TCB). Following treatment with IgG-IL2v, activation of T cells, NK cells, and NKT cells was demonstrated by increased expression of the activation marker CD69 and enhanced cytokine secretion. The combination of TCBs with IgG-IL2v molecules was more effective than monotherapy, as shown by enhanced effects on immune cell infiltration; activation; increased cytokine secretion; and faster, more efficient elimination of targeted cells. This study demonstrates that the 3D heterotypic spheroid model provides a novel and versatile tool for in vitro evaluation of cancer immunotherapy agents and allows for assessment of additional aspects of the activity of cancer immunotherapy agents, including analysis of immune cell infiltration and drug targeting.
authors.affiliation: Roche Pharmaceutical Research and Early Development, Oncology DTA, Roche Innovation Center Zurich, Wagistrasse 18, 8952, Schlieren, Switzerland.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Herter
authors.affiliation: Roche Pharmaceutical Research and Early Development, Oncology DTA, Roche Innovation Center Zurich, Wagistrasse 18, 8952, Schlieren, Switzerland.
authors.forename: Laura
authors.initials: L
authors.lastname: Morra
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Schmelzbergstrasse 12, 8091, Zurich, Switzerland.
authors.forename: Ramona
authors.initials: R
authors.lastname: Schlenker
authors.affiliation: Roche Pharmaceutical Research and Early Development, Oncology DTA, Roche Innovation Center Zurich, Wagistrasse 18, 8952, Schlieren, Switzerland.
authors.forename: Jitka
authors.initials: J
authors.lastname: Sulcova
authors.affiliation: Roche Pharmaceutical Research and Early Development, Oncology DTA, Roche Innovation Center Zurich, Wagistrasse 18, 8952, Schlieren, Switzerland.
authors.forename: Linda
authors.initials: L
authors.lastname: Fahrni
authors.affiliation: Roche Pharmaceutical Research and Early Development, Oncology DTA, Roche Innovation Center Zurich, Wagistrasse 18, 8952, Schlieren, Switzerland.
authors.forename: Inja
authors.initials: I
authors.lastname: Waldhauer
authors.affiliation: Roche Pharmaceutical Research and Early Development, Oncology DTA, Roche Innovation Center Zurich, Wagistrasse 18, 8952, Schlieren, Switzerland.|Institute for Biomedical Engineering, ETH Zurich, Wolfgang-Pauli-Strasse 10, 8093, Zurich, Switzerland.
authors.forename: Steffi
authors.initials: S
authors.lastname: Lehmann
authors.affiliation: Roche Pharmaceutical Research and Early Development, Oncology DTA, Roche Innovation Center Zurich, Wagistrasse 18, 8952, Schlieren, Switzerland.|Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058, Basel, Switzerland.
authors.forename: Timo
authors.initials: T
authors.lastname: Reisländer
authors.affiliation: InSphero AG, Wagistrasse 27, 8952, Schlieren, Switzerland.
authors.forename: Irina
authors.initials: I
authors.lastname: Agarkova
authors.affiliation: InSphero AG, Wagistrasse 27, 8952, Schlieren, Switzerland.
authors.forename: Jens M
authors.initials: JM
authors.lastname: Kelm
authors.affiliation: Roche Pharmaceutical Research and Early Development, Oncology DTA, Roche Innovation Center Zurich, Wagistrasse 18, 8952, Schlieren, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Klein
authors.affiliation: Roche Pharmaceutical Research and Early Development, Oncology DTA, Roche Innovation Center Zurich, Wagistrasse 18, 8952, Schlieren, Switzerland.
authors.forename: Pablo
authors.initials: P
authors.lastname: Umana
authors.affiliation: Roche Pharmaceutical Research and Early Development, Oncology DTA, Roche Innovation Center Zurich, Wagistrasse 18, 8952, Schlieren, Switzerland. marina.bacac@roche.com.
authors.forename: Marina
authors.initials: M
authors.lastname: Bacac
mesh_terms: D000818:Animals; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D018874:Spheroids, Cellular; D059016:Tumor Microenvironment / Q000276:immunology*
keywords: 3D model; Cancer immunotherapy; Heterotypic spheroid model; Interleukin-2 immunocytokine fusion; T cell bispecific antibodies; Tumor–stroma interaction