Abstract
Multiple small molecule immune modulators have been identified as synergistic with immune checkpoint blockade (ICB) in their effects on T lymphocytes, but are limited in their successful application to combination cancer immunotherapy due to their short in vivo retention and lack of affinity for T cells. We engineered an antibody-nanoparticle conjugate (ANC) platform consisting of 30 nm polymer nanoparticles that, due to their size and formulation, efficiently distribute after administration to lymph nodes, tissues highly enriched in lymphocytes that contribute to tumor control mediated by ICB. Displaying monoclonal antibodies against surface-expressed T cell markers, NP delivery in vivo to circulating and lymph node-resident lymphocytes was substantially enhanced, as was delivery of small molecules formulated into the NP by passive encapsulation. Using ICB monoclonal antibodies as both targeting moiety and signal-blocking therapeutic, ANCs improved the local and systemic anti-tumor effects of small molecule TGFβ receptor 1 inhibitor and an adenosine 2A antagonist when administered either locoregionally or systemically into the circulation in two syngeneic, aggressive tumor models, slowing tumor growth and prolonging animal survival. As these benefits were lost in the absence of ANC targeting, co-formulation strategies enabling the targeted co-delivery of multiple immunotherapeutics to T lymphocytes have high potential to improve ICB cancer immunotherapy by concurrent inhibition of non-redundant suppressive pathways.