Generation of CD19 CAR variants with NK cell specific motifs to determine the best choice for treating relapsed or refractory leukemias and lymphomas

L Herrera(1,2) A Etxebarria(1,2) S Santos(1,2) M A Vesga(1,2) J Anguita(3,4) T Carrascosa(5) M Juan(6) C Eguizabal(1,2)

1:Research Unit, Basque Center for Blood Transfusion and Human Tissues, Osakidetza, Galdakao, Spain.; 2:Cell Therapy, Stem Cells and Tissues Group, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.; 3:Macrophage and Tick Vaccine Laboratory, CIC bioGUNE, Derio, Vizcaya; 4:Ikerbasque, Basque Foundation for Science, Bilbao, Vizcaya; 5:Servicio de Hematología, Hospital Galdakao-Usansolo, Galdakao; 6:Servei d´Immunologia. Hospital Clínic de Barcelona. Hospital Sant Joan de Déu. Institut d’Investigacions Biomèdiques August Pi i Sunyer Hospital. Universitat de Barcelona, Barcelona

B-cell hematologic cancers such as leukemia and lymphoma are common forms of pediatric and adult cancers worldwide. Acute Lymphoblastic Leukemia (ALL) is the most common cancer among children with a prevalence of 20-25% of all cases. The survival rate for these patients at 5 years is 79.2%, but it is still an incurable disease in many patients. Chimeric Antigen Receptor (CAR) T cells therapy has arisen as a new alternative to conventional therapies in order to treat advanced refractory cancers. However, this therapy has some undesirable side effects such as cytokine release syndrome (CRS) and neurotoxicity. Also, despite the good results in clinic, some patients are refractory or relapsed after CART cell treatment. Moreover, another potential problem with this treatment could be the need of using allogenic T cells when is not possible to perform an apheresis to the patient, as allogenic T cells carry a risk of graft versus-host disease (GVHD).   NK cells could be a good alternative for CAR based therapy, as they do not cause this kind of side effects, and exhibit a potent graft versus leukemia (GVL) effect without causing GVHD. In this study, we adapted CD19 CAR to NK cells signaling motifs, obtaining different variants of the CAR ARI-0001. These variants were tested in adult peripheral blood and cord blood NK cells in order to determine the best choice to perform a clinical trial phase I to evaluate the safety and viability of allogenic CD19 CARNK cells for treating patients with previous autologous CART treatment.