Antibody Targeted Natural Killer Cell-Derived Extracellular Vesicles for the Treatment of Childhood Acute Lymphoblastic Leukemia and Neuroblastoma
Although about 80% of newly diagnosed children with acute lymphoblastic leukemia (ALL) are cured, less than 10% with recurrent/refractory ALL who do not respond completely to additional treatment are expected to survive. Only 45% of patients with high-risk neuroblastoma (NB) survive. We are developing a new treatment for malignancies of childhood. Natural killer (NK) cells are blood cells that can kill ALL and NB cells. Blood NK cells from normal individuals and children with NB or ALL can be grown and activated (aNK) in the laboratory to be potent killers of cancer cells. We discovered that such aNK cells release large quantities of small particles called extracellular vesicles (EVs or exosomes) that can kill NB and ALL cells in a test tube. Further, EVs, which can bind antibodies, are even better killers when targeted to ALL and NB cells by antibodies that recognize ALL and NB cells. Finally, human ALL and NB cells growing in mice can be killed by injecting the mice with EVs and targeting antibodies.
We hypothesize that combining antibodies and these EVs can be a potent new immunotherapy. Our aims are 1) to standardize characterization and large-scale production of aNK EVs; and 2) to optimize EV + antibody killing of ALL and NB cells in the test tube and in mice. This research will establish the potential of aNK EVs with antibodies and will lay the foundation for clinical trials in Therapeutic Advances in Childhood Leukemia/ Lymphoma (TACL) and New Approaches to Neuroblastoma Therapy (NANT) consortia.