title: T-cell responses against CD19+ pediatric acute lymphoblastic leukemia mediated by bispecific T-cell engager (BiTE) are regulated contrarily by PD-L1 and CD80/CD86 on leukemic blasts.
abstract: T-cell immunotherapies are promising options in relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). We investigated the effect of co-signaling molecules on T-cell attack against leukemia mediated by CD19/CD3-bispecific T-cell engager. Primary CD19+ ALL blasts (n≥10) and physiologic CD19+CD10+ bone marrow precursors were screened for 20 co-signaling molecules. PD-L1, PD-1, LAG-3, CD40, CD86, CD27, CD70 and HVEM revealed different stimulatory and inhibitory profiles of pediatric ALL compared to physiologic cells, with PD-L1 and CD86 as most prominent inhibitory and stimulatory markers. PD-L1 was increased in relapsed ALL patients (n=11) and in ALLs refractory to Blinatumomab (n=5). Exhaustion markers (PD-1, TIM-3) were significantly higher on patients' T cells compared to physiologic controls. T-cell proliferation and effector function was target-cell dependent and correlated to expression of co-signaling molecules. Blockade of inhibitory PD-1-PD-L and CTLA-4-CD80/86 pathways enhanced T-cell function whereas blockade of co-stimulatory CD28-CD80/86 interaction significantly reduced T-cell function. Combination of Blinatumomab and anti-PD-1 antibody was feasible and induced an anti-leukemic in vivo response in a 12-year-old patient with refractory ALL. In conclusion, ALL cells actively regulate T-cell function by expression of co-signaling molecules and modify efficacy of therapeutic T-cell attack against ALL. Inhibitory interactions of leukemia-induced checkpoint molecules can guide future T-cell therapies.
authors.affiliation: Department of General Pediatrics, Hematology and Oncology, Children's University Hospital Tübingen, Tübingen, Germany.|Memorial Sloan Kettering Cancer Center, Center for Cell Engineering, New York, NY, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Feucht
authors.affiliation: Department of General Pediatrics, Hematology and Oncology, Children's University Hospital Tübingen, Tübingen, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Kayser
authors.affiliation: Department of General Pediatrics, Hematology and Oncology, Children's University Hospital Tübingen, Tübingen, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Gorodezki
authors.affiliation: Memorial Sloan Kettering Cancer Center, Center for Cell Engineering, New York, NY, USA.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Hamieh
authors.affiliation: Department of General Pediatrics, Hematology and Oncology, Children's University Hospital Tübingen, Tübingen, Germany.|Dr. von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Döring
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Blaeschke
authors.affiliation: Department of General Pediatrics, Hematology and Oncology, Children's University Hospital Tübingen, Tübingen, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schlegel
authors.affiliation: Institute of Pathology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Bösmüller
authors.affiliation: Institute of Pathology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Leticia
authors.initials: L
authors.lastname: Quintanilla-Fend
authors.affiliation: Department of General Pediatrics, Hematology and Oncology, Children's University Hospital Tübingen, Tübingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Ebinger
authors.affiliation: Department of General Pediatrics, Hematology and Oncology, Children's University Hospital Tübingen, Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lang
authors.affiliation: Department of General Pediatrics, Hematology and Oncology, Children's University Hospital Tübingen, Tübingen, Germany.
authors.forename: Rupert
authors.initials: R
authors.lastname: Handgretinger
authors.affiliation: Department of General Pediatrics, Hematology and Oncology, Children's University Hospital Tübingen, Tübingen, Germany.|Dr. von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Feuchtinger
mesh_terms: D018033:Antibodies, Bispecific / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D018941:Antigens, CD19 / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D005260:Female; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D018033:Antibodies, Bispecific; D061067:Antibodies, Monoclonal, Humanized; D018941:Antigens, CD19; D014408:Biomarkers, Tumor; C510808:blinatumomab; C582435:pembrolizumab
keywords: CD80/86; PD-L1; T cells; blinatumomab; immune checkpoints; pediatric acute lymphoblastic leukemia