Clinical translation of TLR agonist-modified silicified cancer cell therapy supported by humanized mouse models

Humanized patient-derived xenograft (huPDX) mouse models are crucial for evaluating the clinical translation of new immune therapeutics. Silicification of cancer cells renders the cells non-viable with enhanced stability and silica surface functionalization, enabling adsorption of pathogen-associated molecular patterns to attract and activate myeloid cells. While strong therapeutic efficacy has been demonstrated in syngeneic mouse models of ovarian cancer, promising results do not always translate to effective treatments for patients. To support clinical translation, therapeutic responses to silicified ovarian cancer cells were studied in huPDXs. Three humanized mouse models using different immunocompromised strains were used to evaluate recent advances in the field, including the addition of the <i>HHD</i> transgene and a <i>c-</i> <i>K</i> <i>it</i> mutation to improve T cell activation and overall engraftment, respectively. In the final model, NBSGW-HLA-A2/HHD, intraperitoneal administration of silicified cancer cells reduced the tumor burden (<i>p</i> = 0.0006) in the presence of elevated T cells (<i>p</i> = 0.0001), indicating the activation of a robust anti-tumor immune response. Improvements in outcomes, including stable humanization and demonstration of effective immune therapy with Toll-like receptor (TLR)-agonist-modified silicified cancer cells, highlight improvements in humanized mouse models and support the translation of silicified cancer cell technology for women with ovarian cancer.