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Nanoparticle anchoring targets immune agonists to tumors enabling anti-cancer immunity without systemic toxicity
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Journal Article
Nanoparticle anchoring targets immune agonists to tumors enabling anti-cancer immunity without systemic toxicity
2018
Overview
Immunostimulatory agents such as agonistic anti-CD137 and interleukin (IL)−2 generate effective anti-tumor immunity but also elicit serious toxicities, hampering their clinical application. Here we show that combination therapy with anti-CD137 and an IL-2-Fc fusion achieves significant initial anti-tumor activity, but also lethal immunotoxicity deriving from stimulation of circulating leukocytes. To overcome this toxicity, we demonstrate that anchoring IL-2 and anti-CD137 on the surface of liposomes allows these immune agonists to rapidly accumulate in tumors while lowering systemic exposure. In multiple tumor models, immunoliposome delivery achieves anti-tumor activity equivalent to free IL-2/anti-CD137 but with the complete absence of systemic toxicity. Immunoliposomes stimulated tumor infiltration by cytotoxic lymphocytes, cytokine production, and granzyme expression, demonstrating equivalent immunostimulatory effects to the free drugs in the local tumor microenvironment. Thus, surface-anchored particle delivery may provide a general approach to exploit the potent stimulatory activity of immune agonists without debilitating systemic toxicities.
Immunostimulatory agents used in cancer treatment often elicit serious toxicities, limiting their clinical application. Here, the authors show that the use of liposomes to intravenously deliver surface-anchored IL-2 and anti-CD137 proteins enables anti-cancer immunity and reduces the toxic side effects.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ Agonists
/ Animals
/ Antineoplastic Agents - pharmacology
/ Cancer
/ Humanities and Social Sciences
/ Immunity
/ Interleukin-2 - pharmacology
/ Killer Cells, Natural - drug effects
/ Killer Cells, Natural - immunology
/ Lymphocytes, Tumor-Infiltrating - drug effects
/ Lymphocytes, Tumor-Infiltrating - immunology
/ Mice
/ Science
/ T-Lymphocytes, Cytotoxic - drug effects
/ T-Lymphocytes, Cytotoxic - immunology
/ Toxicity
/ Tumor Microenvironment - drug effects
/ Tumor Microenvironment - immunology
/ Tumor Necrosis Factor Receptor Superfamily, Member 9 - agonists
/ Tumors
