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TLR Agonist Nano Immune Therapy Clears Peritoneal and Systemic Ovarian Cancer
Two doses of iMSN cleared or reduced ovarian and colorectal cancer and protected against future tumor engraftment. In contrast, subcutaneous (SC) and intravenous (IV) delivery of iMSN were without therapeutic effect in mice with peritoneal metastases, supporting the need for activation of regional immune cells. Remarkably, intraperitoneal delivery of iMSN cleared subcutaneously implanted ovarian cancer, supporting homing of antigen specific T cells to extraperitoneal tumor sites.
Regional immune mechanisms enhance efficacy of an autologous cellular cancer vaccine with intraperitoneal administration
Accumulating evidence of a central role for regional immunity in cancer control indicates that intraperitoneal immunotherapy may have treatment advantages. This study delineates immune mechanisms engaged by intraperitoneal delivery of a cell-based vaccine comprised of silicified ovarian cancer cells associated with enhanced survival.
Cancer vaccines from cryogenically silicified tumour cells functionalized with pathogen-associated molecular patterns
The production of personalized cancer vaccines made from autologous tumour cells could benefit from mechanisms that enhance immunogenicity. Here we show that cancer vaccines can be made via the cryogenic silicification of tumour cells, which preserves tumour antigens within nanoscopic layers of silica, followed by the decoration of the silicified surface with pathogen-associated molecular patterns. These pathogen-mimicking cells activate dendritic cells and enhance the internalization, processing and presentation of tumour antigens to T cells. In syngeneic mice with high-grade ovarian cancer, a cell-line-based silicified cancer vaccine supported the polarization of CD4+ T cells towards the T-helper-1 phenotype in the tumour microenvironment, and induced tumour-antigen-specific T-cell immunity, resulting in complete tumour eradication and in long-term animal survival. In the setting of established disease and a suppressive tumour microenvironment, the vaccine synergized with cisplatin. Silicified and surface-modified cells from tumour samples are amenable to dehydration and room-temperature storage without loss of efficacy and may be conducive to making individualized cancer vaccines across tumour types.
Direct transfer of mesoporous silica nanoparticles between macrophages and cancer cells
Macrophages line the walls of microvasculature, extending processes into the blood flow to capture foreign invaders, including nano-scale materials. Using mesoporous silica nanoparticles (MSNs) as a model nano-scale system, we show the interplay between macrophages and MSNs from initial uptake to intercellular trafficking to neighboring cells along microtubules. The nature of cytoplasmic bridges between cells and their role in the cell-to-cell transfer of nano-scale materials is examined, as is the ability of macrophages to function as carriers of nanomaterials to cancer cells. Both direct administration of nanoparticles and adoptive transfer of nanoparticle-loaded splenocytes in mice resulted in abundant localization of nanomaterials within macrophages 24 h post-injection, predominately in the liver. While heterotypic, trans-species nanomaterial transfer from murine macrophages to human HeLa cervical cancer cells or A549 lung cancer cells was robust, transfer to syngeneic 4T1 breast cancer cells was not detected in vitro or in vivo. Cellular connections and nanomaterial transfer in vivo were rich among immune cells, facilitating coordinated immune responses.
Monitoring Therapeutic Responses to Silicified Cancer Cell Immunotherapy Using PET/MRI in a Mouse Model of Disseminated Ovarian Cancer
Current imaging approaches used to monitor tumor progression can lack the ability to distinguish true progression from pseudoprogression. Simultaneous metabolic 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET) and magnetic resonance imaging (MRI) offers new opportunities to overcome this challenge by refining tumor identification and monitoring therapeutic responses to cancer immunotherapy. In the current work, spatial and quantitative analysis of tumor burden were performed using simultaneous [18F]FDG-PET/MRI to monitor therapeutic responses to a novel silicified cancer cell immunotherapy in a mouse model of disseminated serous epithelial ovarian cancer. Tumor progression was validated by bioluminescence imaging of luciferase expressing tumor cells, flow cytometric analysis of immune cells in the tumor microenvironment, and histopathology. While PET demonstrated the presence of metabolically active cancer cells through [18F]FDG uptake, MRI confirmed cancer-related accumulation of ascites and tissue anatomy. This approach provides complementary information on disease status without a confounding signal from treatment-induced inflammation. This work provides a possible roadmap to facilitate accurate monitoring of therapeutic responses to cancer immunotherapies.