Abstract
Abstract Direct clearance of immune-suppressive Tumor Associated Macrophages (TAM) is a less-explored cancer therapeutic approach. We developed a novel folate-ligand guided zinc-peptide complex 010DS-Zn for selective induction of parthanatos in folate receptor overexpressing targets that include many solid and blood cancer types, in addition to M2-like macrophages. Consistent with known parthanatos mechanism, its in vitro mode-of-action (MOA) tested against 4T1 murine breast cancer cell was characterized by specific and rapid PARP-dependent AIF translocation into nucleus that executed massive DNA fragmentation. This in vitro/ex vivo cytotoxicity was found highly consistent against the 90 blood and solid patient-derived cancer types tested. Further in vivo MOA studies against aPD-1 responder and non-responder syngenic cancer models showed 010DS-Zn to be effective against both, albeit at increased dosage in the MDSC enriched tumors. In the aPD-1 responder cancer model CT26, 010DS-Zn demonstrated robust T-cell immune response initiation, which was enhanced upon co-treatment with aPD-1 mAb. Regardless of the tumor-response in vivo, 010DS-Zn treatment produced robust TAM-reduction activity in dose-dependent manners. Collectively, 010DS-Zn presents new cancer immunotherapeutic potentials for enabling previously inaccessible 2-combination therapies for targeting 3 layers of immune-evasion: Tregs, TAM, and MDSC. Furthermore, its ability to directly clear M2-like macrophages presents opportunities-worth-investigation for treating the M2-like macrophage-driven severe SARS-CoV-2 autoimmune syndromes or its post-recovery heart-damages. Citation Format: Jinhyuk Fred Chung. Anti-tumor effects from simultaneous cancer and TAM targeting by 010DS-Zn [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1696.
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