Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with most patients relapsing even after initial therapies. Despite recent advances in treatment, the development of efficacious novel treatments remains an unmet need.
CD47 is a myeloid checkpoint upregulated by tumor cells to evade the host immune response, and its blockade enhances anti-tumor immunity (Weiskopf, 2017). Recently, pre-clinical and clinical studies that explored the use of CD47 targeting agents in combination with azacitidine, a hypomethylating chemotherapeutic, demonstrated robust anti-cancer activity (Feng, ASH 2018 and Sallman, ASH 2019). ALX148 is an engineered fusion protein comprised of a high affinity CD47 blocker linked to an inactive human immunoglobulin Fc region. In preclinical studies, ALX148 bridges innate and adaptive immunity by promoting macrophage phagocytosis, dendritic cell activation and a shift of tumor-associated macrophages towards an inflammatory phenotype, leading to increased anti-tumor activity when combined with various anti-cancer therapeutics (Kauder, 2018). ALX148 has previously been shown to be well tolerated in patients with both solid tumor and hematological malignancies with encouraging anti-tumor responses reported in combination with anti-cancer therapeutics (EHA 2020, #EP1247 and ASCO 2020, #3056). Recently, the combination of azacitidine with venetoclax, a BCL2 inhibitor, has shown increased efficacy compared to azacitidine alone in patients with AML (EHA 2020, #LB2601). We observed in vitro treatment with azacitidine or venetoclax increased the cell surface expression of both CD47 and calreticulin, a pro-phagocytic marker, in multiple AML cell lines. We thereby hypothesize that combining ALX148 with either azacitidine or venetoclax would enhance the therapeutic efficacy against AML and report our preclinical findings here.
In vitro treatment with ALX148 led to enhanced phagocytic engulfment by human monocyte-derived macrophages across multiple AML cell lines treated with azacitidine or venetoclax, including those harboring TP53 and FLT3 mutations, compared to either treatment alone. Our in vitro findings correlated with enhanced in vivo antileukemic activity in several murine AML xenograft models. Mice were inoculated via tail vein or implanted subcutaneously with AML cells, and when tumors reached exponential growth, mice were randomized to receive the following: vehicle control, azacitidine, venetoclax, ALX148 alone or ALX148 in combination. Cohorts receiving ALX148 combination therapies demonstrated significantly greater inhibition of tumor progression with evidence of tumor eradication, leading to markedly enhanced survival over any single agent therapy.
Together, these in vitro and in vivo results provide rationale that ALX148 combinations may benefit AML and MDS patients. Clinical trials with ALX148 in patients with MDS (NCT04417517) and AML are currently planned.
Disclosures
Chen: ALX Oncology: Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months; Tallac Therapeutics: Current Employment, Current equity holder in private company. Harrabi:ALX Oncology Inc: Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months; Tallac Therapeutics: Current Employment, Current equity holder in private company. Fong:ALX Oncology Inc: Current Employment, Current equity holder in publicly-traded company. Ruffner:ALX Oncology Inc: Current Employment, Current equity holder in publicly-traded company. Forgie:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company; Pfizer Inc.: Ended employment in the past 24 months. Sim:ALX Oncology Inc: Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months; Tallac Therapeutics: Current Employment, Current equity holder in private company. Randolph:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Wan:Tallac Therapeutics: Current Employment, Current equity holder in private company; ALX Oncology Inc: Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months. Pons:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Kuo:ALX Oncology Inc: Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months; Tallac Therapeutics: Current Employment, Current equity holder in private company.
Selection and Characterization of YKL-40-Targeting Monoclonal Antibodies from Human Synthetic Fab Phage Display Libraries