Browsing by Subject "Cancer Vaccine"

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    Assessing Anti-B7-H3 Antibody and gp70 Cancer Vaccine Therapy for TNBC
    (2022-04-18) Sheu, Lauren
    Immunotherapy has emerged as a promising approach for addressing TNBC, an aggressive breast cancer subtype for which few targeted therapies exist. TNBC immunotherapy, however, is dominated by PD-1 immune checkpoint blockade (ICB), which only benefits a small minority of patients. To improve upon these initial efforts, we sought to target B7-H3 with TNBC immunotherapy, as this marker is expressed in a vast majority of TNBCs. In searching for an immunotherapy strategy, we decided to develop and assess a B7-H3-targeting antibody with cancer vaccine combination, as this regimen has recently shown resounding therapeutic benefits for another breast cancer type in the clinic (NCT00524277). To this end, we adapted NCT00524277’s treatment components for murine studies, creating M-m276, a B7-H3-targeting antibody, and a gp70-targeting cancer vaccine; both B7-H3 and gp70 are human/mouse TNBC-specific biomarkers. M-m276 and gp70 vaccine were administered in a B7-H3+ murine in vivo model of TNBC (i.e., Balb/C mice with lung-seeded 4T1). Significant survival extension was observed in mice treated with the combination therapy, relative to the monotherapies alone. Given these results, we next sought to better understand the mechanism of this combination therapy. Upon finding that M-m276 mediates antibody-dependent cellular phagocytosis (ADCP), we hypothesized that M-m276 augments the efficacy of cancer vaccines by increasing tumor antigen presentation to cytotoxic T lymphocytes (CTLs) through either cross-presentation or trogocytosis, two ADCP-linked processes. Although M-m276 was found to have no impact on cross-presentation, we found that M-m276 significantly increases the trogocytosis of tumor membrane by antigen-presenting cells (APCs) in vitro, enabling these APCs to present greater amounts of tumor antigen to CTLs. Altogether, our results support B7-H3-targeting antibody with cancer vaccine as a TNBC treatment strategy and propose a potential mechanism for how these therapy components interact.
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    Genetically Stable Poliovirus Vectors Activate Dendritic Cells and Prime Antitumor CD8 T Cell Immunity
    (2019) Mosaheb, Mohammad Mubeen

    Viruses naturally engage innate immunity, induce antigen presentation, and mediate CD8 T cell priming against foreign antigens. Polioviruses can provide a context optimal for generating antigen-specific CD8 T cells, as they have natural tropism for dendritic cells, preeminent inducers of CD8 T cell immunity; elicit Th1-promoting inflammation; and lack interference with innate or adaptive immunity. However, notorious genetic instability and underlying neuropathogenicity has hampered poliovirus-based vector applications. We devised a strategy based on the polio:rhinovirus chimera PVSRIPO, devoid of viral neuropathogenicity after intracerebral inoculation in human subjects, for stable expression of exogenous antigens. PVSRIPO vectors infect, activate, and induce epitope presentation in DCs in vitro; recruit and activate DCs with Th1-dominant cytokine profiles at the injection site in vivo. They efficiently prime tumor antigen-specific CD8 T cells in vivo, induce CD8 T cell migration to the tumor site, delay tumor growth and enhance survival in murine tumor models.