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

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.

"Am I Korean American?": beliefs and practices of parents and children living in two languages and two cultures

The purpose of this study is to explore attitudes and practices regarding their heritage language and the dominant English language among Korean American immigrant families. Using the framework of Language Ideology (Silverstein, 1979), I had three research questions: a) why do parents send their children to a Korean language school, b) what attitudes do immigrant parents and their children show toward Korean and English, and c) how are the parents and children involved in the practices of these two languages? I conducted a survey of parents whose children attended a Korean language school in Urbana-Champaign, Illinois, where the number of Korean sojourners (temporary residents) exceeds that of Korean immigrants. Forty participant parents provided demographic information. They described their children's language-use patterns depending on interlocutors as well as their language proficiency in both Korean and English. The reasons for sending their children to the Korean language school were significantly different depending on the respondents' residential status. In comparison to the sojourners, immigrants tended to give more priority to their children's oral language development and Korean identity construction. I also conducted case studies of three Korean immigrant families with 3- to 5-year-old children, using interviews, observations, and photographs of children's work. The collected data were analyzed according to themes such as daily life, parental beliefs about two languages, practices in two languages, children's attitudes toward two languages, and challenges and needs. Despite individual families' different immigration histories, the three families faced some common challenges. Because of their busy daily routines and different lifestyles, the immigrant families had limited interactions with other Koreans. The parents wanted their children to benefit from two communities and build a combined ethnic identity as Korean Americans. I argue that a Korean language school should expand its role as a comfort zone for all Koreans and Korean Americans. This study explores the heterogeneity among Korean sojourner and immigrant families and their language use and identity construction.