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

// Judith Feucht 1, 2 , Simone Kayser 1 , David Gorodezki 1 , Mohamad Hamieh 2 , Michaela Doring 1, 3 , Franziska Blaeschke 3 , Patrick Schlegel 1 , Hans Bosmuller 4 , Leticia Quintanilla-Fend 4 , Martin Ebinger 1 , Peter Lang 1 , Rupert Handgretinger 1 , Tobias Feuchtinger 1, 3 1 Department of General Pediatrics, Hematology and Oncology, Children’s University Hospital Tubingen, Tubingen, Germany 2 Memorial Sloan Kettering Cancer Center, Center for Cell Engineering, New York, NY, USA 3 Dr. von Hauner Children’s Hospital, Ludwig Maximilians University Munich, Munich, Germany 4 Institute of Pathology, University Hospital Tubingen, Tubingen, Germany Correspondence to: Tobias Feuchtinger, email: tobias.feuchtinger@med.uni-muenchen.de Keywords: pediatric acute lymphoblastic leukemia, T cells, immune checkpoints, PD-L1, CD80/86, blinatumomab Received: April 18, 2016     Accepted: September 02, 2016     Published: September 30, 2016 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.