Evaluation of Adoptive T Cell Therapy and Oncolytic Virotherapy for Treatment of Brain Tumors

brain tumors;immunotherapy;oncolytic virotherapy;Melanoma;Adoptive T Cell Therapy

Thomas, Diana L.

关键词: brain tumors;    immunotherapy;    oncolytic virotherapy;    Melanoma;    Adoptive T Cell Therapy;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/18568/Thomas_Diana.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Adoptive immunotherapy and oncolytic virotherapy are two promising strategies fortreating primary and metastatic malignant brain tumors. We demonstrate the ability ofadoptively transferred tumor-specific T cells to rapidly mediate the clearance of established braintumors in several mouse models. Similar to the clinical situation, tumor recurrences are frequentand result from immune editing of tumors. T cells can eliminate antigen-expressing tumor cellsbut are not effective against antigen loss variant (ALV) cancer cells that multiply and repopulatea tumor. We show that the level of tumor antigen present affects the success of adoptive T celltherapy. When high levels of antigen are present, tumor stromal cells such as microglia andmacrophages present tumor peptide on their surface. As a result, T cells directly eliminatecancer cells and cross-presenting stromal cells and indirectly eliminate ALV cells. We were ableto show the first direct evidence of tumor antigen cross-presentation by CD11b+ stromal cells inthe brain using soluble, high-affinity T cell receptor monomers. Strategies that target braintumor stroma or increase antigen shedding from tumor cells leading to increased crosspresentationby stromal cells may improve the clinical success of T cell adoptive therapies.We evaluated one potential strategy to complement adoptive T cell therapy bycharacterizing the oncolytic effects of myxoma virus (MYXV) in a syngeneic mouse brain tumormodel of metastatic melanoma. MYXV is a rabbit poxvirus with strict species tropism forEuropean rabbits. MYXV can also infect mouse and human cancer cell lines due to signalingdefects in innate antiviral mechanisms and hyperphosphorylation of Akt. MYXV kills B16.SIYmelanoma cells in vitro, and intratumoral injection of virus leads to robust, selective andtransient infection of the tumor. We observed that virus treatment recruits innate immune cellsiiito the tumor, induces TNFα and IFNβ production in the brain, and results in limited oncolyticeffects in vivo. To overcome this, we evaluated the safety and efficacy of co-administering 2C Tcells, MYXV, and neutralizing antibodies against IFNβ. Mice that received the triplecombination therapy survived significantly longer with no apparent side effects, but eventuallyrelapsed. Based on these findings, methods to enhance viral replication in the tumor and limitimmune clearance of the virus will be pursued. We conclude that myxoma virus should befurther explored as a vector for transient delivery of therapeutic genes to a tumor to enhance Tcell responses.