CNS tumors remain a significant health concern despite decades of vaccine research. For this reason, understanding the cellular immune response that is mounted towards CNS cancers is of paramount importance in the development of immunotherapeutic strategies to treat these conditions. Glioblastoma multiforme (GBM) is among the most lethal of cancers, which despite treatment, presents with an average survival of 12-15 months. Complete surgical resection of the tumor is not feasible in the vast majority of cases. Therefore, it is critical to develop novel vaccines to generate tumor antigen specific T cel responses in vivo. Our central hypothesis is that is effective glioma-specific CD8 T cell-mediated immunity is achieved through appropriate tumor antigen processing To address our central hypothesis, we will use the established GL261 model systems to analyze anti-glioma killer T cell responses in vivo using novel recombinant picornaviruses and conditional knockout mice generated by our laboratory. We will also assess the route of injection of picornavirus vaccine in promoting protective immunity in vivo, as well as the mechanism of tumor antigen presentation and processing. Using an engineered GL261 cell line (termed """"""""Quad Cassette"""""""") that expresses model T cell epitopes, we have determined in our preliminary studies that tumor-specific killer T cell response can be generated towards this glioma in vivo. Furthermore, we present that the proposed picornavirus vaccination approach can halt or eradicate progression of established tumors in the CNS using this model. Therefore, the novel reagents and techniques we have generated for this model system of glioma will enable us to address our central hypothesis through conducting the following specific aims:
Specific Aim #1 - Optimize CD8 T cell responses to endogenous tumor antigens using novel picornavirus vaccination.
Specific Aim #2 - Define the mechanism by which protective CD8 T cell mediated immunity against gliomas is generated through conditional silencing of tumor antigen processing and presenting in various antigen presenting cells (APCs). This project is innovative because it provides a multidisciplinary approach to generate CNS derived tumor- specific antigens in vivo using a novel picornavirus vaccination approach. In the process, the capacity of professional antigen presenting cells to illicit CD8 T cell immunity against brain cancer will also be determined. We have established the methodology to monitor growth kinetics of the GL261 glioma in vivo using bioluminescence imaging and MRI in live animals. Our expectation is that picornavirus based vaccines will prove to be effective in generating anti-tumor CD8 T cell responses. However, the importance of all APCs in CNS immunity to tumors will also be assessed in this proposal. This would have significant impact in that novel immunotherapeutic strategies to enhance anti-tumor killer T cell responses could be optimized using this system. Furthermore, the proposed studies are translational in that modifiable human picornaviruses could be employed as novel clinical approach to an as yet incurable cancer. To accomplish these aims, we will employ: (a) flow cytometry, (b) behavioral studies, (c) high resolution confocal microscopy and immunohistochemistry, (d) virology, (e) protein biochemistry, (f) bioluminescence imaging, and (g) small mammal MRI.
In this proposal, we put forward a novel vaccination strategy involving the use of recombinant picornaviruses as a creative immunotherapeutic approach to treating CNS tumors including glioblastoma multiforme. We will also determine the mechanism by which this vaccination approach confers protective immunity through defining the contribution of antigen presenting cell subsets.
|Kim, Minjee; Ma, Daniel J; Calligaris, David et al. (2018) Efficacy of the MDM2 Inhibitor SAR405838 in Glioblastoma Is Limited by Poor Distribution Across the Blood-Brain Barrier. Mol Cancer Ther 17:1893-1901|
|Hardcastle, Jayson; Mills, Lisa; Malo, Courtney S et al. (2017) Immunovirotherapy with measles virus strains in combination with anti-PD-1 antibody blockade enhances antitumor activity in glioblastoma treatment. Neuro Oncol 19:493-502|
|Cumba Garcia, Luz M; Huseby Kelcher, April M; Malo, Courtney S et al. (2016) Superior isolation of antigen-specific brain infiltrating T cells using manual homogenization technique. J Immunol Methods 439:23-28|
|Renner, Danielle N; Malo, Courtney S; Jin, Fang et al. (2016) Improved Treatment Efficacy of Antiangiogenic Therapy when Combined with Picornavirus Vaccination in the GL261 Glioma Model. Neurotherapeutics 13:226-36|
|Malo, Courtney S; Renner, Danielle N; Huseby Kelcher, April M et al. (2016) The Effect of Vector Silencing during Picornavirus Vaccination against Experimental Melanoma and Glioma. PLoS One 11:e0162064|
|Renner, Danielle N; Jin, Fang; Litterman, Adam J et al. (2015) Effective Treatment of Established GL261 Murine Gliomas through Picornavirus Vaccination-Enhanced Tumor Antigen-Specific CD8+ T Cell Responses. PLoS One 10:e0125565|
|Chae, Michael; Peterson, Timothy E; Balgeman, Alexis et al. (2015) Increasing glioma-associated monocytes leads to increased intratumoral and systemic myeloid-derived suppressor cells in a murine model. Neuro Oncol 17:978-91|