Development of a Nano-Enabled Platform for Combination Immunotherapy

Abstract Immunotherapies have shown promising therapeutic outcomes in cancer treatment. However, the diverse tumor responses in patients prompt the development of combinatorial immunotherapies that can overcome the immunological barriers in nonimmunogenic cancers. Here we develop a magnetic iron oxide nanoparticles (MNPs)-enabled platform that co-delivers local tumor hyperthermia, reactive oxygen species (ROS), and doxorubicin for targeted and multiplexed immunomodulation in the tumor. Compared with conventional thermal modalities, MNP-mediated magnetic hyperthermia (MHT) has the advantages of image-guided delivery and controllable, focal, and deep tissue heating. Targeted MHT are more effective in inducing heat shock response-mediated immune processes, including cell apoptosis, antigen presentation, and the recruitment and activation of immune cells. In this project, we combine local tumor hyperthermia with two stimuli of immunogenic cell death, ROS and doxorubicin. The central hypothesis is that the immunological effects of MNP-delivered hyperthermia, ROS, and doxorubicin can be coordinated to induce potent immunogenic cell death in a "cold" tumor. This hypothesis will be tested in a well-established mouse melanoma model, which recapitulates nonimmunogenic human tumors that only respond to combinatorial immune modulation. In Aim 1, we will design and synthesize MNPs with different sizes to optimize the heating efficiency, ROS generation, and doxorubicin loading. In Aim 2, we will optimize MNP-enable combination treatment for inducing immunogenic cell death in vitro. In Aim 3, we will perform pilot studies to examine the tumor-targeting efficiency of MNPs and evaluate the immunological responses induced by the combination treatment in vivo. The success of the project will provide an overview of the influence of the combination treatment on immunogenic cell death in the tumor and pave the way for the development of an effective and safe in situ cancer vaccination approach. After identifying an immune profile consistent with the anticancer immune response, we will submit an R21/R01 proposal to expand the study to 1) optimize the MNP-enable combination treatment for immunogenic cell death in in vivo settings, 2) investigate the combination treatment-mediated tumor responses, and 3) investigate the combination of the MNP-platform with the immune checkpoint blockade (CTLA-4) for inducing a sustained anticancer immunity.