Harnessing macrophage-drug conjugates for allogeneic cell-based therapy of solid tumors via the TRAIN mechanism
Bartłomiej Taciak, Maciej Białasek, Małgorzata Kubiak, Ilona Marszałek, Małgorzata Górczak, Olha Osadchuk, Daria Kurpiel, Damian Strzemecki, Karolina Barwik, Marcin Skorzynski, J Nowakowska, Waldemar Lipiński, Łukasz Kiraga, Jan Brancewicz, Robert Klopfleisch, Łukasz Krzemiński, Emilia Górka, Anna Smolarska, Irena Padzińska-Pruszyńska, Małgorzata Siemińska, Jakub Guzek, Jan Kutner, M. Kisiala, Krzysztof Woźniak, Giacomo Parisi, Roberta Piacentini, Luca Cassetta, Lesley M. Forrester, Lubomir Bodnar, Tobias Weiß, Alberto Boffi, Paulina Kucharzewska, Tomasz P. Rygiel, Magdalena Król
Abstract
Treatment of solid tumors remains challenging and therapeutic strategies require continuous development. Tumor-infiltrating macrophages play a pivotal role in tumor dynamics. Here, we present a Macrophage-Drug Conjugate (MDC) platform technology that enables loading macrophages with ferritin-drug complexes. We first show that macrophages actively take up human heavy chain ferritin (HFt) in vitro via macrophage scavenger receptor 1 (MSR1). We further manifest that drug-loaded macrophages transfer ferritin to adjacent cancer cells through a process termed 'TRAnsfer of Iron-binding protein' (TRAIN). The TRAIN process requires direct cell-to-cell contact and an immune synapse-like structure. At last, MDCs with various anti-cancer drugs are formulated with their safety and anti-tumor efficacy validated in multiple syngeneic mice and orthotopic human tumor models via different routes of administration. Importantly, MDCs can be prepared in advance and used as thawed products, supporting their clinical applicability. This MDC approach thus represents a promising advancement in the therapeutic landscape for solid tumors.