Engineering of T lymphocytes for the recognition of Acute Lymphoblastic Leukemia.

Abstract

Acute lymphoblastic leukemia (ALL) is the most common cancer in children, representing 31% of all tumors. The conventional treatment of pediatric ALL is based on chemotherapeutic protocols that have shown good results with cure rates close to 80-90%. Despite this, 10-20% of children fail to respond to first-line therapy as well as have disease recurrence. The immunotherapy with genetically modified T cells has shown promising results in the treatment of relapses. However, there are some limiting aspects to incorporate it into the regular therapeutic approach, such as: (i) the large number of vectors to be produced for each patient; (ii) the large number of cells to be transduced, despite the expansion in vivo and (iii) the high cost of vector production/purification and transduction of lymphocytes. Therefore, we propose the development of a more effective engineered lymphocyte to increase the efficiency of activation, effector function, and lifetime in vivo. In our strategy, autologous lymphocytes will be genetically modified ex vivo to induce the expression of a chimeric antigen receptor capable of recognizing a target protein expressed on the membrane of ALL cells and simultaneously activate antitumor mechanisms of cytolytic lymphocytes. The reprogrammed cells will be studied in tests of effector function in vitro and in ALL models in immunodeficient animals.