Nanotechnology enabled quantitative imaging of dendritic cell anti-cancer vaccines

PROJECT SUMMARY Dendritic cells (DCs) are pivotal in mediating anti-tumor immunity, and an effective DC vaccine devoid of intolerable immune-related toxicity would be groundbreaking. Clinical trials underscore the therapeutic promise of next-generation DC vaccines and non-invasive imaging in patients suggests an important link between DC to lymph node (LN) migration and treatment success. However, established clinical and pre-clinical imaging technologies suffer limitations that preclude systematic studies that link DC vaccine therapy and migration to LN. This project will enhance understanding of DC migration and its impact on DC vaccine efficacy through an innovative nanotechnology-enabled imaging technology called magnetic particle imaging (MPI), where signal arises from the unique response of superparamagnetic iron oxide nanoparticles (SPIONs) to an alternating magnetic field. MPI overcomes the limitations of other imaging approaches by enabling non-invasive, tomographic, quantitative, unambiguous imaging with high sensitivity and negligible tissue background signal or attenuation, while using biocompatible tracers with long shelf life. Preliminary studies demonstrate that MPI enables longitudinal tracking of DC vaccines that capture the biological diversity of DC to LN migration and is predictive of treatment response, while suggesting that SPION-labeling enhances therapeutic outcome of DC vaccine by activating immune-related gene pathways. The proposed research combines SPIONs with enhanced MPI performance, optimized protocols for DC labeling coupled with comprehensive characterization of the effects of tracer uptake on DCs, and state-of-the-art MPI acquisition, analysis, and validation approaches to study DC migration and its correlation to treatment response in DC vaccine immunotherapy through three specific aims: Specific Aim 1: Obtain a robust quantitative understanding of DC to LN migration dynamics. Specific Aim 2: Investigate theranostic SPION-DC vaccine in models of early- and late-stage melanoma. Specific Aim 3: Investigate theranostic SPION-DC vaccine in a model of glioblastoma (GBM). These studies will leverage MPI to evaluate the influence of sex, administration site, DC dose, and use of pre- sensitizing and co-stimulating factors on DC to LN migration and will systematically investigate the use of MPI in predicting response to therapy in murine models of immunotherapy. Complementary studies will compare MPI measures of DC migration to flow cytometry and study the DC microenvironmental niche in the LN to gain mechanistic insights into the enhanced therapeutic response to SPION labeled DC vaccines. As a result, the proposed work will contribute new fundamental knowledge on the use of nanotechnology in monitoring cancer treatment response and will establish specific and sensitive tracking of DC migration using MPI as a powerful tool linking therapy and mechanism of action. The proposed research benefits from a synergistic collaboration between a nano-bioengineer specializing in MPI development, a clinician-scientist with translational expertise in cancer immunotherapy, and a leading developer of MPI instrumentation.