Dual Targeting Nanoparticle Stimulates the Immune System To Inhibit Tumor Growth

Abstract

We describe the development of a nanoparticle platform that overcomes the immunosuppressive tumor microenvironment. These nanoparticles are coated with two different antibodies that simultaneously block the inhibitory checkpoint PD-L1 signal and stimulate T cells via the 4-1BB co-stimulatory pathway. These "immunoswitch" particles significantly delay tumor growth and extend survival in multiple in vivo models of murine melanoma and colon cancer in comparison to the use of soluble antibodies or nanoparticles separately conjugated with the inhibitory and stimulating antibodies. Immunoswitch particles enhance effector-target cell conjugation and bypass the requirement for a priori knowledge of tumor antigens. The use of the immunoswitch nanoparticles resulted in an increased density, specificity, and in vivo functionality of tumor-infiltrating CD8+ T cells. Changes in the T cell receptor repertoire against a single tumor antigen indicate immunoswitch particles expand an effective set of T cell clones. Our data show the potential of a signal-switching approach to cancer immunotherapy that simultaneously targets two stages of the cancer immunity cycle resulting in robust antitumor activity.

Nanoparticle‐Based Nanomedicines to Promote Cancer Immunotherapy: Recent Advances and Future Directions

“…Small 2019, 15,1900262 FA-modified PEI 170 Anti-PD-L1 [144] Disulfide-cross-linked PEI 200-300 siPD-L1 [145] Alginate hydrogel Anti-PD-1 + celecoxib [146] Immune-tolerant elastin-like polypeptide 45 Anti-PD-1 [147] PLGA nanoparticles 180 Anti-CTLA-4 [148] Maleimide-terminated PEG-PLGA nanoparticles 160 Anti-PD-L1 + anti-OX-40 [149] Lipid-based Lipid calcium phosphate nanoparticles 45 pPD-L1 + pCXCL12 [150] Cationic lipid SAINT-18 siPD-L1 + siPD-L2 [151] Liposomal cerasome nanoparticles 90-150 Anti-PD-L1 + paclitaxel [152] Inorganic Iron oxide nanoparticles 80 Anti-PD-L1 + anti-4-lBB [153] Mesoporous silica nanoparticles 30 Anti-CTLA-4 [154] Fucoidan-based iron oxide nanoparticles 142 Anti-PD-L1 + anti-CD3/anti-CD28 [155] Cell-based Platelets 100-200 Anti-PD-L1 [156] siRNA with mitochondrion-targeting photosensitizer for photodynamic therapy (PDT) in one tumor pH-sensitive micellar nanocomplex, consisting of a PEG shielding layer, a PEI middle layer, and a poly(2-(diethylamino) ethyl methacrylate (PDEA) core (Figure 6). [159] The PEG layer helps prolong the circulation time and is shed in response to the weak acidity in the tumor microenvironment.…”

Ditelluride-Bridged PEG-PCL Copolymer as Folic Acid-Targeted and Redox-Responsive Nanoparticles for Enhanced Cancer Therapy

“…Accordingly, optimization of the carriers with active targeting moieties are of great interest in drug delivery field. The targeting ligands can recognize the overexpressed receptors on cancer cells, thus facilitate cell internalization via receptor-ligand mediated endocytosis (Lazarovits et al, 2015;Kosmides et al, 2017). For example, high-affinity folate receptor is a glycosylphosphatidylinositol-linked cell surface receptor and usually expressed at elevated levels on tumoral cells.…”

Nanoengineered Immune Niches for Reprogramming the Immunosuppressive Tumor Microenvironment and Enhancing Cancer Immunotherapy

“…The specific generation of PMPs in the tumor resection bed resulted in reduced off‐target effects and the effective binding of PD‐L1 to residual tumor cells. Kosmides et al coated anti‐PD‐L1 and anti‐4‐1BB mAbs on 80 nm iron–dextran NPs as an immunoswitch to stimulate T cells via costimulatory pathways and blocking inhibitory checkpoint signals simultaneously, as shown in Figure . By confining mAbs physically at the nanoscale, a synergistic effect was observed between two signaling pathways, even at low doses (10–100‐fold lower than the amount needed for treatment by systemic administration).…”

“…injections of immunoswitch NPs and the controls. Reproduced with permission . Copyright 2017, American Chemical Society.…”