Nanocomplex‐Mediated In Vivo Programming to Chimeric Antigen Receptor‐M1 Macrophages for Cancer Therapy

Abstract

Chimeric antigen receptor‐T (CAR‐T) cell immunotherapy has shown impressive clinical outcomes for hematologic malignancies. However, its broader applications are challenged due to its complex ex vivo cell‐manufacturing procedures and low therapeutic efficacy against solid tumors. The limited therapeutic effects are partially due to limited CAR‐T cell infiltration to solid tumors and inactivation of CAR‐T cells by the immunosuppressive tumor microenvironment. Here, a facile approach is presented to in vivo program macrophages, which can intrinsically penetrate solid tumors, into CAR‐M1 macrophages displaying enhanced cancer‐directed phagocytosis and anti‐tumor activity. In vivo injected nanocomplexes of macrophage‐targeting nanocarriers and CAR‐interferon‐γ‐encoding plasmid DNA induce CAR‐M1 macrophages that are capable of CAR‐mediated cancer phagocytosis, anti‐tumor immunomodulation, and inhibition of solid tumor growth. Together, this study describes an off‐the‐shelf CAR‐macrophage therapy that is effective for solid tumors and avoids the complex and costly processes of ex vivo CAR‐cell manufacturing.

Nanotechnology-enabled immunoengineering approaches to advance therapeutic applications

“…In multiple cancer models, CAR-Ms displayed direct anti-tumor effects in vitro and in vivo; additionally, these altered macrophages were engaged in antigen cross-presentation and activating T cells in vivo, which is crucial for fostering active anti-tumor immunity. The switch towards a pro-inflammatory (M1) state upon antigen recognition and involvement in antigen presentation were similarly found in CAR-Ms generated from iPSCs via GSEA analysis [ 114 , 115 ]. The TAMs could be redirected to a CAR-expressing M1 state using a nonviral, piggyBac vector encoding an anti-ALK CAR and the IFNγ gene.…”

In vivo fate and intracellular trafficking of vaccine delivery systems

“…Polyethyleneimine takes on various structures, including linear and branched; it can have secondary or tertiary amine groups, and has a positive charge that enables it to efficiently bind negatively charged nucleic acids. Polyethyleneimine nanocomplexes show excellent gene transfection efficiency and have exhibited great promise as versatile gene delivery vehicles for delivering nucleic acids, including plasmids, siRNA, and mRNA [29] , [30] . However, their clinical application has been somewhat challenged by cytotoxicity and low function.…”

Myeloid Immune Cells CARrying a New Weapon Against Cancer

“…More recently, Kang and collaborators ( Kang et al, 2021 ) have described an in vivo approach for CAR-Mac reprograming using mannose-conjugated polyethylenimine (MPEI) nanocomplex as a gene delivery of plasmids for anti-ALK (anaplastic lymphoma kinase) CAR and IFN-gamma. Based on the fact that TAMs with anti-inflammatory properties may overexpress the mannose receptor (CD206), authors took advantage of this system to target macrophages in situ.…”