Local hyperthermia and nanoparticle targeting for cancer immunotherapy

Local hyperthermia treatment for cancer has been used clinically in combination with and to enhance the efficacy of traditional treatments such as chemotherapy and radiation. In association with recent understanding of the importance of stimulating anti-tumor immune responses in cancer therapy, there is growing interest in the ability of local hyperthermia to improve tumor immunity and associated therapeutic effects. Using excisable mouse dermal tumor models and a local hyperthermia system consisting of intratumoral injection of iron oxide nanoparticles (IONPs) followed by an alternating magnetic field (AMF) application, we show that heating tumors at 43°C for 30 minutes retarded the growth of unheated contralateral tumors and secondary tumors given 7 days post treatment on the primary tumor side and contralateral side. This treatment activated dendritic cells (DCs) and subsequently CD8 + T cells in the draining lymph node (dLN), and depleting CD8 + T cells completely abrogated the treatment efficacy. These results demonstrate the promising potential of local hyperthermia for inducing CD8 + T cell responses that reduce the risk of recurrence and metastasis.;Even when tumors are disseminated and therefore nanoparticles cannot be directly injected, nanoparticles still need to be concentrated within tumors to localize the effect of hyperthermia. Many types of cancer whose tumors are disseminated in the peritoneal cavity, such as ovarian cancer, develop ascites containing large amount of immunosuppressive phagocytes. Since those cells are constantly recruited into the tumor, they can potentially be ideal drug delivery vehicles. Using a mouse model of disseminated ovarian cancer, we show that IP administered IONPs were taken up predominantly by CD45 + CD11b+ cells in the peritoneum and accumulated in the tumor but not in major organs. Peritoneal cell transfer studies revealed that those cells are indeed able to carry IP administerd IONPs into the tumor. The amount of IONPs in the tumor was enough to induce cell death in the tumor upon application of an AMF without causing systemic toxicity. These results verify peritoneal phagocytes as promising tumor delivery vehicles for nanoparticles. This strategy may further enhance anti-tumor immunity through heat-induced cell stress/death in the tumor and destruction of immunosuppressive phagocytes.