Gética 2020

[ F I T C á n c e r - 6 ] 57 COMUNICACIONES PÓSTERES and Cell Engineering Laboratory. Aarhus University. Aarhus, Denmark. 4 Departamento de Inmunología, Oftalmología y ORL. Facultad de Medicina. Universidad Complutense de Madrid. Grupo de Inmunobiología Linfocitaria. Instituto de Investigación 12 de Octubre (i+12). Madrid, Spain. 5 Servei d’Immunologia. Hospital Clínic. Fundació de Rercerca Clínic. Barcelona, Spain. 6 Unidad de Inmu- nología Molecular. Hospital Universitario Puerta de Hierro Majadahonda. Majadahonda. Madrid, Spain. 7 Unidad de Inmunoterapia del Cáncer (UNICA). Servicio de Inmunología. Hospital Universitario 12 de Octubre. Madrid, Spain. 8 Grupo de Inmuno-Oncología e Inmunoterapia. Instituto de Investigación 12 de Octubre (i+12). Madrid, Spain. 9 Departamento de Inmunología, Oftalmología y ORL. Facultad de Medicina. Universidad Complutense de Madrid. Grupo de Inmunobiología Linfocitaria. Instituto de Investigación 12 de Octubre (i+12). Madrid, Spain. 10 Servei d’Immunologia. Hospital Clínic. Fundació de Rercerca Clínic. Barcelona, Spain. 11 Unidad de Inmunoterapia del Cáncer (UNICA). Servicio de Inmunología. Grupo de Inmuno-Oncología e Inmunoterapia. Instituto de Investiga- ción 12 de Octubre (i+12). Hospital Universitario 12 de Octubre. Madrid, Spain. Immunotherapy and Cell Engineering Laboratory. Aarhus University. Aarhus, Denmark Introduction and objectives: Impressive clinical results have been observed by redirecting T cell ef- fector functions towards CD19 + cancer cells using sol- uble bispecific antibodies (bsAbs) or chimeric antigen receptor (CAR) T cells in patients with hematological malignancies. However, these therapies still face sig- nificant challenges, such as toxicity, lack of response or, in the case of bsAbs, the need for continuous intrave- nous administration due to their short serum half-life. We propose an emergent approach, which combines aspects of antibody- and cell-based therapies, name- ly “STAb immunotherapy”, based on the endogenous secretion of T cell-redirecting bsAbs (STAb). Genetic modification of T cells to in vivo secrete an anti-CD19 x anti-CD3 bsAb, in BiTE format (CD19 BiTE), could over- come the limitations of the current strategies Methods: The ability of the CD19 BiTE, secreted by lentivirally transduced human primary T lymphocytes, to activate T cells against CD19 + tumor cells in vitro was determined by standard proliferation (flow cytometry) and cytotoxicity (luciferase activity) assays. Synapse topology studies were performed using confocal mi- croscopy. The ability of in vivo secreted bsAbs by STAb T cells to inhibit tumor growth was demonstrated in a murine xenograft model of leukemia. Results: We have previously shown that human primary T cells can be efficiently transduced to se- crete high levels of a novel CD19 BiTE, with cytotox- ic activity against CD19 + tumor cells in vitro . Here, we demonstrated the potency of the STAb T strate- gy over CAR T cells, due to the ability of the secret- ed BiTE to efficiently recruit the tumoricidal activi- ty of bystander non-transduced T cells. Moreover, we have observed that the immunological synapse mediated by the secreted BiTE is more physiolog- ical than the disorganized CAR-mediated synapse. Finally, we demonstrated the ability of STAb T cells to inhibit tumor growth in vivo (Figs. 1,2). Conclusions: The endogenous secretion of CD19 BiTEs, by STAb T cells, represents a promising alter- native to current CD19-targeted immunotherapies such as CAR T cells or the systemic administration of bsAbs, due to its ability to induce the formation of conventional synapses, and to redirect bystander T cells to tumors avoiding the use of continuous in- fusion systems. Figure 1. Figure 2.