Abstract 3808: 225Ac-CD33 Radioimmunotherapy potently increases the sensitivity of resistant acute myeloid leukemia lines to the Bcl-2 inhibitor venetoclax by mediating a reduction in cellular Mcl-1 levels
Authors: Garg Ravendra , Geoghegan Eileen , Allen Kevin J. , Dawicki Wojciech , Dadachova Ekaterina , Ludwig Dale L. 
Published: August 2019

Abstract
Acute myeloid leukemia (AML) is a complex hematological disease often occurring in older patients. While a number of new targeted therapies have been recently approved, patient outcomes remain poor. In the US, about 19,520 new cases AML occur annually and approximately 10,670 will die from the disease. Venetoclax is a promising new targeted therapy that is under regulatory review in the US for use in combination with a hypomethylating agent (HMA) or with low-dose cytarabine (LDAC) for the treatment of newly diagnosed patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. Recently, several studies have demonstrated that increased expression of Mcl-1 is a mediator of resistance to venetoclax in AML and other hematologic malignancies. Indeed, significant up-regulation of Mcl-1 has been reported in patients with relapsed/refractory AML and venetoclax treatment itself has been shown to increase Mcl-1 levels tumor cell lines. 225Ac-lintuzumab is a clinical stage radioimmunotherapy targeting CD33 that has shown evidence of single agent activity in relapsed/refractory AML. 225Ac-lintuzumab enables delivery of the potent alpha emitting warhead 225-actinium (T1/2 = 10 days; high linear energy transfer = 6.83 MeV; and short path length = 40-100 μm or about 3-5 cell diameters) directly to tumor cells. This elicits DNA cluster breaks and double strand breaks to kill within a short radius, thereby limiting damage to normal tissue. In this study, we demonstrate that 225Ac-lintuzumab is capable of dramatically enhancing the potency of venetoclax when used in combination in both venetoclax sensitive and resistant AML cell lines. AML lines U937 and OCI-AML3 are Mcl-1 positive AML lines which are highly resistant to venetoclax (IC50 &gt; 1 μM). While treatment of these lines with single agent venetoclax at 500 nM was ineffective at suppressing tumor cell growth in either model, the combination of 40 nCi 225Ac-lintuzumab plus 500 nM venetoclax induced a statistically significant increase tumor cell killing in vitro. While 225Ac-lintuzumab can directly effect tumor cell killing by multiple mechanisms, we investigated the potential for 225Ac-lintuzumab-directed DNA damage to suppress Mcl-1 levels as a potential mechanism of enhancing the potency of venetoclax in these models. Cell lines were incubated with titrations of 225Ac-lintuzumab prior to analysis of Mcl-1 protein by ELISA. In both cell lines, treatment with 225Ac-lintuzumab lead to a significant depletion of Mcl-1 levels in cells. This supports a mechanistic basis of Mcl-1 suppression when 225Ac-lintuzumab is used in combination with venetoclax to increase the potency of resistant AML cells to the Bcl-2 inhibitor. Results of in vivo tumor xenograft studies will also be presented.
Citation Format: Ravendra Garg, Eileen Geoghegan, Kevin J. Allen, Wojciech Dawicki, Ekaterina Dadachova, Dale L. Ludwig. 225Ac-CD33 Radioimmunotherapy potently increases the sensitivity of resistant acute myeloid leukemia lines to the Bcl-2 inhibitor venetoclax by mediating a reduction in cellular Mcl-1 levels [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 3808.