A new Natural Killer cell therapy to target relapse Acute Lymphoblastic Leukemia

Abstract

Abstract Acute Lymphoblastic Leukemia (ALL) is the most common childhood cancer. Drug resistance and relapse are two major problems in ALL. Pre-B ALL cells express B-cell activating factor receptor (BAFF-R) on their surface, which is not present on normal pre-B cells. This makes it an attractive therapeutic target for ALL. We used a BAFF-R antibody optimized for antibody dependent cell cytotoxicity (ADCC) to enhance NK cell mediated killing of drug resistant and relapsed ALL cells, which are difficult to treat by conventional chemotherapy. We found that anti-BAFF-R antibody enhanced NK cell mediated killing of drug resistant ALL cells in vitro. Early treatment with anti-BAFF-R antibody and NK cells significantly reduced disease burden in xenograft ALL models and increased overall mice survival. However, in advanced disease, the efficacy of NK cells to mediate ADCC is reduced. ALL cells are known to produce TGF beta, a cytokine that causes NK cell dysfunction. We found that ALL cells produce TGF-β and co-culturing ALL cells with NK cells lead to a decrease in CD16 expression on NK cells, which is reversible by addition of EW-7197, a potent TGF-beta receptor I inhibitor. We found that EW-7197 treatment improved anti-BAFF-R antibody mediated ADCC of drug resistant ALL cells, in vivo, even if treatment is started late. Our data validate this novel BAFF-R antibody as a very promising tool for pre-B ALL therapy.