title: Expression of inhibitory receptors on intratumoral T cells modulates the activity of a T cell-bispecific antibody targeting folate receptor.
abstract: T-cell bispecific antibodies (TCBs) are a novel therapeutic tool designed to selectively recruit T-cells to tumor cells and simultaneously activate them. However, it is currently unknown whether the dysfunctional state of T-cells, embedded into the tumor microenvironment, imprints on the therapeutic activity of TCBs. We performed a comprehensive analysis of activation and effector functions of tumor-infiltrating T-cells (TILs) in different tumor types, upon stimulation by a TCB targeting folate receptor 1 and CD3 (FolR1-TCB). We observed a considerable heterogeneity in T-cell activation, cytokine production and tumor cell killing upon exposure to FolR1-TCB among different FolR1-expressing tumors. Of note, tumors presenting with a high frequency of PD-1hiTILs displayed significantly impaired tumor cell killing and T-cell function. Further characterization of additional T-cell inhibitory receptors revealed that PD-1hiTILs defined a T-cell subset with particularly high levels of multiple inhibitory receptors compared with PD-1intand PD-1negT-cells. PD-1 blockade could restore cytokine secretion but not cytotoxicity of TILs in a subset of patients with scarce PD-1hiexpressing cells; in contrast, patients with abundance of PD-1hiexpressing T-cells did not benefit from PD-1 blockade. Our data highlight that FolR1-TCB is a promising novel immunotherapeutic treatment option which is capable of activating intratumoral T-cells in different carcinomas. However, its therapeutic efficacy may be substantially hampered by a pre-existing dysfunctional state of T-cells, reflected by abundance of intratumoral PD-1hiT-cells. These findings present a rationale for combinatorial approaches of TCBs with other therapeutic strategies targeting T-cell dysfunction.
authors.affiliation: Laboratory of Cancer Immunology, Department of Biomedicine , Basel, Switzerland.
authors.forename: Jens
authors.initials: J
authors.lastname: Schreiner
authors.affiliation: Laboratory of Cancer Immunology, Department of Biomedicine, Basel, Switzerland; Department of Medical Oncology, University Hospital Basel, Basel, Switzerland.
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Thommen
authors.affiliation: Laboratory of Cancer Immunology, Department of Biomedicine , Basel, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Herzig
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Zurich , Schlieren, Switzerland.
authors.forename: Marina
authors.initials: M
authors.lastname: Bacac
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Zurich , Schlieren, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Klein
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Penzberg, Roche Innovation Center Penzberg , Penzberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Roller
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Penzberg, Roche Innovation Center Penzberg , Penzberg, Germany.
authors.forename: Anton
authors.initials: A
authors.lastname: Belousov
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Zurich , Schlieren, Switzerland.
authors.forename: Victor
authors.initials: V
authors.lastname: Levitsky
authors.affiliation: Institute of Pathology, University Hospital Basel , Basel, Switzerland.
authors.forename: Spasenija
authors.initials: S
authors.lastname: Savic
authors.affiliation: Department of Surgery, University Hospital Basel , Basel, Switzerland.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Moersig
authors.affiliation: Laboratory of Cancer Immunology, Department of Biomedicine , Basel, Switzerland.
authors.forename: Franziska
authors.initials: F
authors.lastname: Uhlenbrock
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Basel , Basel, Switzerland.
authors.forename: Viola A
authors.initials: VA
authors.lastname: Heinzelmann-Schwarz
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Zurich , Schlieren, Switzerland.
authors.forename: Pablo
authors.initials: P
authors.lastname: Umana
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Zurich , Schlieren, Switzerland.
authors.forename: Pavel
authors.initials: P
authors.lastname: Pisa
authors.affiliation: Klinik I für Innere Medizin, Klinikum der Universitäat zu Köln, Germany
authors.forename: M
authors.initials: M
authors.lastname: von Bergwelt-Baildon
authors.affiliation: Department of Surgery, University Hospital Basel , Basel, Switzerland.
authors.forename: Didier
authors.initials: D
authors.lastname: Lardinois
authors.affiliation: Laboratory of Cancer Immunology, Department of Biomedicine , Basel, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Müller
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Zurich , Schlieren, Switzerland.
authors.forename: Vaios
authors.initials: V
authors.lastname: Karanikas
authors.affiliation: Laboratory of Cancer Immunology, Department of Biomedicine, Basel, Switzerland; Department of Medical Oncology, University Hospital Basel, Basel, Switzerland.
authors.forename: Alfred
authors.initials: A
authors.lastname: Zippelius
keywords: Cancer; T-cell bispecific antibodies; T-cell exhaustion; immune checkpoints; tumor-infiltrating T-cells