Browsing by Author "Hopewell, Emily L."

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    Development of Cancer-Genomics-Guided Precision Immunotherapy for Triple-Negative Breast Cancer
    (2023-05) Sun, Yifan; Lu, Xiongbin; Kaplan, Mark H.; Hopewell, Emily L.; Zhang, Chi; Yang, Kai
    Triple-negative breast cancer (TNBC), which accounts for 15-20% of all breast cancers, is highly aggressive and metastatic with the poorest overall rates. While surgery, radiation, and chemotherapy remain the main treatment options, TNBC represents an unmet medical need for better treatment strategies. Tremendous efforts have been made to develop effective therapies over the past years. However, TNBC treatment options are still very limited due to the lack of good drug targets and the low response rate of current therapies. In this study, we developed two different strategies to treat TNBC based on its cancer genomic features: 1) heterozygous loss of chromosome 17p (17p loss) and 2) high mutation load. 17p loss is one of the most frequent genomic events in breast cancer including TNBC, rendering cancer cells vulnerable to the inhibition of POLR2A via α-amanitin (POLR2A-specific inhibitor). Here, we developed a new drug T-Ama (α-amanitin-conjugated trastuzumab) targeting HER2-low TNBC with 17p loss by combining the effects of α-amanitin and trastuzumab (HER2+ breast cancer therapy). Our results showed that T-Ama exhibited superior efficacy in treating HER2-low TNBC with 17p loss in vitro and in vivo, and surprisingly induced immunogenic cell death (ICD) which further enhanced T cell infiltration and cytotoxicity levels and delivered greater efficacy in combination with immune checkpoint blockade therapy. Collectively, the therapeutic window created by 17p loss and HER2 expression will make HER2-low TNBC clinically feasible targets of T-Ama. As another genetic feature of TNBC, the higher genomic instability and mutational burden results in more neoantigens presented on MHC-I, along with the higher level of tumor-infiltrating T cells, making TNBC a perfect model for immunotherapy compared to the other breast cancer subtypes. Here, we designed a deconvolution-algorithm-derived library screening to find new therapeutic targets and identified PIK3C2α as a key player that determines MHC-I turnover and reduces the MHC-I-restricted antigen presentation on tumor cells. In preclinical models, inhibition of PIK3C2α profoundly suppressed breast tumor growth, increased tumor-infiltrating CD8+ T cells, and showed high potential enhancing the efficacy of anti-PD-1 therapy, suggesting that PIK3C2α is a potential therapeutic target for TNBC immunotherapy.
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    Manufacturing Dendritic Cells for Immunotherapy: Monocyte Enrichment
    (Elsevier, 2020-01-15) Hopewell, Emily L.; Cox, Cheryl; Medical and Molecular Genetics, School of Medicine
    Dendritic cells play a key role in activation of the immune system as potent antigen-presenting cells. This pivotal position, along with the ability to generate dendritic cells from monocytes and ready uptake of antigen, makes them an intriguing vehicle for immunotherapy for a variety of indications. Since the first reported trial using dendritic cells in 1995, they have been used in trials all over the world for a plethora of indications. Monocyte-derived dendritic cells are generated from whole blood or apheresis products by culturing enriched monocytes in the presence of interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF). A variety of methods can be used for enrichment of monocytes for generation of clinical-grade dendritic cells and are summarized herein.
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    Tumor-infiltrating lymphocytes: Streamlining a complex manufacturing process
    (Elsevier, 2019-03) Hopewell, Emily L.; Cox, Cheryl; Pilon-Thomas, Shari; Kelley, Linda L.; Medical and Molecular Genetics, School of Medicine
    Adoptive cell therapy of tumor-infiltrating lymphocytes has shown promise for treatment of refractory melanoma and other solid malignancies; however, challenges to manufacturing have limited its widespread use. Traditional manufacturing efforts were lengthy, cumbersome and used open culture systems. We describe changes in testing and manufacturing that decreased the process cycle time, enhanced the robustness of critical quality attribute testing and facilitated a functionally closed system. These changes have enabled export of the manufacturing process to support multi-center clinical trials.