Enhanced efficacy of a TLR3 agonist delivered by cowpea chlorotic mottle virus nanoparticles

Intratumoral immunotherapies are those that are administered directly into a tumor to remodel the local tumor microenvironment and stimulate systemic anti-tumor immunity. Small molecule Toll-like receptor (TLR) agonists are undergoing development as intratumoral immunotherapies, and here we considered the TLR3 agonist poly(I:C). Because small molecule therapeutics often suffer rapid washout effects and ineffective immune cell uptake, we encapsulated poly(I:C) into nanoparticles derived from cowpea chlorotic mottle virus (CCMV). The particles (but not the separate components) stimulated the activity of macrophages in vitro and were able to reduce tumor growth and prolong survival in mouse models of colon cancer and melanoma. We also combined CCMV-poly(I:C) with oxaliplatin and found the combination therapy to be even more potent, strongly inhibiting tumor growth and increasing survival. The analysis of immune markers revealed that CCMV-poly(I:C) VLPs with oxaliplatin promoted the infiltration and activation of CD4⁺ and CD8⁺ cells and the production of IL-4 and IFN-γ, indicating a synergistic immunogenic effect. The combined treatment also enhanced the rate of apoptosis and immunogenic cell death (ICD). Our data support the development of combination therapies involving immunomodulatory plant virus nanoparticles and antineoplastic drugs to attack tumors directly and via the activation of innate and adaptive immune responses.