In order to reduce the high mortality of pancreatic (PC) and metastatic breast cancer (BC), we developed a chemo-immunotherapy approach that utilizes liposomal or silicasome carriers to simultaneously trigger immunogenic cell death (ICD) and interfere in a regional immune escape pathway. ICD was induced by doxorubicin or oxaliplatin delivery, in addition to co-delivery of a prodrug interfering in a metabolic checkpoint pathway. Intravenous injection of the encapsulated drug combinations dramatically improved the pharmacokinetics and intratumor drug concentrations of the API in orthotopic 4T1 (breast cancer) and KPC (pancreas cancer) tumor models in syngeneic mice. The induction of ICD resulted in tumor cell uptake and antigen presentation by dendritic cells, inducing the appearance of TILs. The activation of cytotoxic T-cells induced robust tumor cell killing at the primary as well as metastatic tumor sites. This effect was synergistically enhanced by interference in the metabolic checkpoint pathway, with disappearance of Tregs and an increase in CD8+/FOXP3+ T-cell ratios. Not only did the doxorubicin-delivering liposome provide a synergistic anti-tumor response that is superior to a DOX-only liposome, but also demonstrated that the carrier could be effectively combined with PD-1 blocking antibodies to eradicate lung metastases. In addition to triggering the ICD pathway by drug-delivering nanocarriers, it was also possible to use physicochemical stimuli (e.g., redox-active nanomaterials) to trigger anti-tumor immunity by activating the pathways (ER stress, autophagy and nuclear disintegration) that underpin the ICD effect. All considered, the use of a nano-enabled platform allows switching of immunological “cold” to “hot” tumor microenvironments, with response boosting by co-administered immune metabolic adjuvants or checkpoint blocking antibodies.

Harvesting immunogenic cell death-inducing nanocarriers and catalytically active redox-active nanomaterials for nano-enabled breast and pancreas cancer immunotherapy

2019 Spring National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.