Date of Graduation
12-2013
Document Type
Dissertation (PhD)
Program Affiliation
Immunology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Patrick Hwu
Committee Member
Gregory Lizee
Committee Member
Stephen Ullrich
Committee Member
Shao-cong Sun
Committee Member
Scott Woodman
Abstract
Targeted therapy and immunotherapy eradicate malignant cells through different mechanisms, and the strengths and weaknesses of these two approaches are potentially complementary. Therefore, the combination of molecular targeted drugs with immune- based therapies is considered an attractive approach for improving the therapeutic efficacy of cancer treatment. The mutation and amplification of the c-KIT proto- oncogene are associated with multiple different cancer types, and multiple c-KIT inhibitors have been tested clinically. In spite of some encouraging results using these agents, most patients with c-KIT mutant cancers still relapse due to drug resistance. This also demonstrates the inherent limitation of molecular targeted drugs as mono-therapies, and highlights the need for combinatorial therapeutic approaches.
In this study, we show in the c-KIT mutant mastocytoma P815 mouse model that the therapeutic effect of the c-KIT inhibitor dasatinib is substantially dependent on the anti- tumor T cell response. Even though the direct effect of dasatinib on antigen-driven T cell expansion is inhibitory, 3-day dasatinib treatment significantly increased the proportion of tumor-specific T cells in the circulation of the treated mice. We also found that dasatinib augmented the priming of T cells through inhibition of immunosuppressive components, including down-regulation of Treg cells and IL-10. When dasatinib was combined with anti-OX40, an agonistic antibody that provides T cells with a potent costimulatory signal, we found that the two agents together gave a much better therapeutic effect compared with either therapy alone, leading to complete tumor eradication in most of the treated mice. Anti-OX40 alone enhanced the infiltration of CD8+ T cells within the tumor microenvironment. Furthermore, the combination of dasatinib and anti-OX40 significantly up-regulated the expression of IFN-γ-induced Th1 chemokines CXCL 9, 10 and 11, which was consistent with the enrichment of tumor- specific T cells at the tumor sites and better therapeutic effect. This study demonstrates that combinations of molecular targeted agents with immunotherapeutic approaches may result in superior therapeutic effects, suggesting that employing a similar combination strategy may provide clinical benefits to patients with c-KIT mutant cancers.
Keywords
C-KIT, mastocytoma, P815, dasatinib, anti-OX40, T cell