Co-delivery of immunomodulators in biodegradable nanoparticles improves therapeutic efficacy of cancer vaccines

To improve the efficacy of cancer vaccines we aimed to modulate the suppressive tumor microenvironment. In this study, the potential of intratumoral immune modulation with poly (I:C), Resiquimod (R848) and CCL20 (MIP3 alpha) was explored. Biodegradable polymeric nanoparticles were used as delivery vehicles for slow and sustained release of these drugs in the tumor area and were combined with specific immunotherapy based on therapeutic peptide vaccination in two aggressive murine carcinoma and lymphoma tumor models. Whereas nanoparticle delivery of poly (I:C) or R848 improved therapeutic efficacy, the combination with MIP3 alpha remarkably potentiated the cancer vaccine antitumor effects. The long-term survival increased to 75-100% and the progression free survival nearly doubled on mice with established large carcinoma tumors. The potent adjuvant effects were associated with lymphoid and myeloid population alterations in the tumor and tumor draining lymph node. In addition to a significant influx of macrophages into the tumor, the phenotype of the suppressor tumor-associated macrophages shifted towards an acute inflammatory phenotype in the tumor draining lymph node. Overall, these data show that therapeutic cancer vaccines can be potentiated by the combined nanoparticle mediated co-delivery of poly (I:C), R848 and MIP3 alpha, which indicates that a more favorable milieu for cancer fighting immune cells is created for T cells induced by therapeutic cancer vaccines.