Abstract
Abstract Purpose: Drug resistance and relapse are two major problems in Acute Lymphoblastic Leukemia (ALL) as these patients do not respond to chemotherapy. We observed BAFF-R expression on drug resistant and relapse B-ALL patient cells. We wanted to explore the in vivo therapeutic efficacy of a BAFF-R antibody, optimized for antibody dependent cellular cytotoxicity (ADCC), against drug resistant ALL cells. Experimental design: ADCC assay was performed using primary human natural killer (NK) cells isolated from normal donors or ALL patients. NK cell mediated cytotoxicity was measured using Calcein-AM assay. Immunocompromised NSG mice were used for in vivo xenograft model of ALL. Results: 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, 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. Conclusion: Combination treatment using BAFF-R antibody, NK cells and EW-7197 is a potential strategy to treat advanced drug resistant ALL patients with BAFF-R expressing blasts. Citation Format: Yorleny M. Vicioso, Rose Beck, Herman Gram, Abhishek Asthana, keman Zhang, Derek Wong, John Letterio, Reshmi Parameswaran. A novel combination therapy for treating advanced drug resistant acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3186.
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