Date

January 2009

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Molecular and Medical Genetics

Institution

Oregon Health & Science University

Abstract

Recent results demonstrated that adoptive T cell immunotherapy of cancer is a potent treatment for patients with advanced melanoma. 52 percent of patients who failed standard treatments achieved objective clinical responses after receipt of adoptively transferred tumor-specific T cells. The marked improvement compared to previous adoptive transfer trials was due to nonmyeloablative lymphopenic conditioning prior to the adoptive transfer. Further studies are necessary to understand the nature of T cell populations which mediate the most effective anti-tumor response in a lymphopenic host. Moreover, novel strategies which enhance the anti-tumor function of the adoptively transferred T cells are also needed. This body of work presents data which address ways to enhance the anti-tumor efficacy of adoptively transferred T cells. We found that the most potent long-term anti-tumor response exerted specifically by the adoptively transferred T cells in a lymphopenic conditioned host required both tumor-specific CD4+ and CD8+ T cells. To elucidate strategies which enhance the T cell’s anti-tumor function, we next determined whether a molecular mechanism of enhanced anti-viral potential could in-turn enhance T cell-mediated anti-tumor response. Based on enhanced anti-viral potential previously observed in mice deficient in ubiquitin-specific protease 43 (Ubp43), we found that adoptively transferred tumor-specific Ubp43-/- T cells are significantly more therapeutic then wild type T cells. Taken together these data inform future adoptive T cell transfer clinical trials the necessity of ensuring that tumor-specific CD4+ T cells are contained within the population of transferred tumor-specific CD8+ cells. Further, these data elucidate a strategy to enhance their anti-tumor effect based on the elimination of Ubp43 expression.

Identifier

doi:10.6083/M4QV3JHF

School

School of Medicine

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