Nanoparticle anchoring targets immune agonists to tumors enabling anti-cancer immunity without systemic toxicity
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.