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Item reinstated by Sarah Shreeves (sshreeve@illinois.edu) on 2013-01-22T11:00:26Z Item was in collections: University of Illinois Dissertations and Theses (ID: 204) Neuroscience Program Dissertations (ID: 630) No. of bitstreams: 3 Thomas_Diana.pdf.txt: 257425 bytes, checksum: 0b304c0b6c5cbb693c600467c7bb0e5c (MD5) Thomas_Diana.pdf: 3038640 bytes, checksum: 896d6ad276ecbc2554d446038b108c2a (MD5) license.txt: 4062 bytes, checksum: 4c7d41c5e204a627318cfde2b8a34868 (MD5) Roy, Edward J. Roy, Edward J. Kranz, David M. MacNeill, Amy L. Ceman, Stephanie S. George, Julia M. Thomas, Diana L. 2011-01-21T22:46:51Z 2013-01-22T11:00:26Z 2011-01-21T22:46:51Z 2010-12 Adoptive immunotherapy and oncolytic virotherapy are two promising strategies for treating primary and metastatic malignant brain tumors. We demonstrate the ability of adoptively transferred tumor-specific T cells to rapidly mediate the clearance of established brain tumors in several mouse models. Similar to the clinical situation, tumor recurrences are frequent and result from immune editing of tumors. T cells can eliminate antigen-expressing tumor cells but are not effective against antigen loss variant (ALV) cancer cells that multiply and repopulate a tumor. We show that the level of tumor antigen present affects the success of adoptive T cell therapy. When high levels of antigen are present, tumor stromal cells such as microglia and macrophages present tumor peptide on their surface. As a result, T cells directly eliminate cancer cells and cross-presenting stromal cells and indirectly eliminate ALV cells. We were able to show the first direct evidence of tumor antigen cross-presentation by CD11b+ stromal cells in the brain using soluble, high-affinity T cell receptor monomers. Strategies that target brain tumor stroma or increase antigen shedding from tumor cells leading to increased crosspresentation by stromal cells may improve the clinical success of T cell adoptive therapies. We evaluated one potential strategy to complement adoptive T cell therapy by characterizing the oncolytic effects of myxoma virus (MYXV) in a syngeneic mouse brain tumor model of metastatic melanoma. MYXV is a rabbit poxvirus with strict species tropism for European rabbits. MYXV can also infect mouse and human cancer cell lines due to signaling defects in innate antiviral mechanisms and hyperphosphorylation of Akt. MYXV kills B16.SIY melanoma cells in vitro, and intratumoral injection of virus leads to robust, selective and transient infection of the tumor. We observed that virus treatment recruits innate immune cells iii to the tumor, induces TNFα and IFNβ production in the brain, and results in limited oncolytic effects in vivo. To overcome this, we evaluated the safety and efficacy of co-administering 2C T cells, MYXV, and neutralizing antibodies against IFNβ. Mice that received the triple combination therapy survived significantly longer with no apparent side effects, but eventually relapsed. Based on these findings, methods to enhance viral replication in the tumor and limit immune clearance of the virus will be pursued. We conclude that myxoma virus should be further explored as a vector for transient delivery of therapeutic genes to a tumor to enhance T cell responses. Item withdrawn by Alexis Thompson (athmpsn1@illinois.edu) on 2010-11-30T21:16:48Z Item was in collections: University of Illinois Theses & Dissertations (ID: 1) No. of bitstreams: 1 Thomas_Diana.pdf: 3038382 bytes, checksum: 4728f91229fc62d8938269dfd70d744e (MD5) Made available in DSpace on 2011-01-21T22:46:51Z (GMT). No. of bitstreams: 2 Thomas_Diana.pdf: 3038640 bytes, checksum: 896d6ad276ecbc2554d446038b108c2a (MD5) license.txt: 4062 bytes, checksum: 4c7d41c5e204a627318cfde2b8a34868 (MD5) Item marked as restricted to the 'UIUC Users [automated]' Group (id=2) by William Ingram (wingram2@illinois.edu) on 2011-01-21T22:48:21Z Item is restricted until 2013-01-21T22:47:37Z Item released from any restrictions by Sarah Shreeves (sshreeve@illinois.edu) on 2013-01-22T11:00:26Z http://hdl.handle.net/2142/18568 en Copyright 2010 Diana L. Thomas brain tumors immunotherapy oncolytic virotherapy Melanoma Adoptive T Cell Therapy Evaluation of Adoptive T Cell Therapy and Oncolytic Virotherapy for Treatment of Brain Tumors School of Molecular & Cell Bio 1415 Neuroscience 0323 University of Illinois at Urbana-Champaign Dissertation Ph.D. PHD:Neuroscience -UIUC 10KS0323PHD