The long term goal of this proposal is to test the efficacy of OV-ChaseM virotherapy in combination with anti-CTLA-4 T-cell targeted immunotherapy for breast cancer brain metastases (BM). With a dismal one and two year survival of 20% and 2%, respectively, the development of novel therapeutic modalities is critical for BM. OV-ChaseM is a second generation oncolytic virus that expresses the Chondroitinase ABC (Chase), an enzyme that degrades the extra-cellular matrix. Anti-CTLA-4 is a monoclonal antibody directed against the CTLA-4 inhibitory receptor on T lymphocytes. Using murine models of brain cancer BM, we aim to characterize the anti-tumor immune responses evoked by both individual and combinatorial therapy. We hypothesize that Chondroitinase expression by OV-ChaseM will facilitate the influx of immune cells into the tumor stroma and alleviate microglia suppression. Here, activated microglia can then uptake virally infected cells, present tumor antigens and promote an anti-tumor microenvironment. This, in turn, will enhance T cell anti-tumor responses following anti-CTLA-4 blockade and result in overt immune cell activation and enhanced anti-tumor efficacy, as compared to controls. Overall, we aim to broaden the scope of treatment for brain cancer patients and provide pre-clinical evidence for individual and combinatory therapeutic regiments that may be implemented in the clinic.
Breast cancer is estimated to be the second leading cause of cancer death and source of brain metastases (BM) among women in the United States. With a dismal one and two year survival of 20% and 2%, respectively, the development of novel treatment modalities is critical. In this study, we will examine the first individual and combinatorial therapeutic effects of tumor targeting oncolytic virus therapy and immune enhancing antibody therapy in BM.
| Jaime-Ramirez, Alena C; Yu, Jun-Ge; Caserta, Enrico et al. (2017) Reolysin and Histone Deacetylase Inhibition in the Treatment of Head and Neck Squamous Cell Carcinoma. Mol Ther Oncolytics 5:87-96 |
| McMichael, Elizabeth L; Jaime-Ramirez, Alena Cristina; Guenterberg, Kristan D et al. (2017) IL-21 Enhances Natural Killer Cell Response to Cetuximab-Coated Pancreatic Tumor Cells. Clin Cancer Res 23:489-502 |
| Jaime-Ramirez, Alena Cristina; Dmitrieva, Nina; Yoo, Ji Young et al. (2017) Humanized chondroitinase ABC sensitizes glioblastoma cells to temozolomide. J Gene Med 19: |
| Lee, Tae Jin; Yoo, Ji Young; Shu, Dan et al. (2017) RNA Nanoparticle-Based Targeted Therapy for Glioblastoma through Inhibition of Oncogenic miR-21. Mol Ther 25:1544-1555 |
| Yoo, Ji Young; Jaime-Ramirez, Alena Cristina; Bolyard, Chelsea et al. (2016) Bortezomib Treatment Sensitizes Oncolytic HSV-1-Treated Tumors to NK Cell Immunotherapy. Clin Cancer Res 22:5265-5276 |
| Skinner, Cassandra C; McMichael, Elizabeth L; Jaime-Ramirez, Alena C et al. (2016) Folate-conjugated immunoglobulin targets melanoma tumor cells for NK cell effector functions. Melanoma Res 26:329-37 |
| Jaime-Ramirez, Alena C; McMichael, Elizabeth; Kondadasula, SriVidya et al. (2016) NK Cell-Mediated Antitumor Effects of a Folate-Conjugated Immunoglobulin Are Enhanced by Cytokines. Cancer Immunol Res 4:323-336 |
| Stiff, Andrew; Caserta, Enrico; Sborov, Douglas W et al. (2016) Histone Deacetylase Inhibitors Enhance the Therapeutic Potential of Reovirus in Multiple Myeloma. Mol Cancer Ther 15:830-41 |
| Martin del Campo, Sara E; Levine, Kala M; Mundy-Bosse, Bethany L et al. (2015) The Raf Kinase Inhibitor Sorafenib Inhibits JAK-STAT Signal Transduction in Human Immune Cells. J Immunol 195:1995-2005 |
| Meisen, W Hans; Wohleb, Eric S; Jaime-Ramirez, Alena Cristina et al. (2015) The Impact of Macrophage- and Microglia-Secreted TNF? on Oncolytic HSV-1 Therapy in the Glioblastoma Tumor Microenvironment. Clin Cancer Res 21:3274-85 |
