Liu C.,University of Houston |
Peng W.,University of Houston |
Xu C.,University of Houston |
Lou Y.,University of Houston |
And 17 more authors.
Clinical Cancer Research | Year: 2013
Purpose: Treatment of melanoma patients with selective BRAF inhibitors results in objective clinical responses in the majority of patients with BRAF-mutant tumors. However, resistance to these inhibitors develops within a few months. In this study, we test the hypothesis that BRAF inhibition in combination with adoptive T-cell transfer (ACT) will be more effective at inducing long-term clinical regressions of BRAFmutant tumors. Experimental Design: BRAF-mutated human melanoma tumor cell lines transduced to express gp100 and H-2Db to allow recognition by gp100-specific pmel-1 T cells were used as xenograft models to assess melanocyte differentiation antigen-independent enhancement of immune responses by BRAF inhibitor PLX4720. Luciferase-expressing pmel-1 T cells were generated to monitor T-cell migration in vivo. The expression of VEGF was determined by ELISA, protein array, and immunohistochemistry. Importantly, VEGF expression after BRAF inhibition was tested in a set of patient samples. Results: We found that administration of PLX4720 significantly increased tumor infiltration of adoptively transferred T cells in vivo and enhanced the antitumor activity of ACT. This increased T-cell infiltration was primarily mediated by the ability of PLX4720 to inhibit melanoma tumor cell production of VEGF by reducing the binding of c-myc to the VEGF promoter. Furthermore, analysis of human melanoma patient tumor biopsies before and during BRAF inhibitor treatment showed downregulation of VEGF consistent with the preclinical murine model. Conclusion: These findings provide a strong rationale to evaluate the potential clinical application of combining BRAF inhibition with T-cell-based immunotherapy for the treatment of patients with melanoma. © 2012 AACR.
Lizee G.,Center for Cancer Immunology Research |
Overwijk W.W.,Center for Cancer Immunology Research |
Radvanyi L.,Center for Cancer Immunology Research |
Gao J.,University of Texas M. D. Anderson Cancer Center |
And 2 more authors.
Annual Review of Medicine | Year: 2013
For many years, immunotherapeutic approaches for cancer held more promise than actual clinical benefit for the majority of patients. However, several recent key advances in tumor immunology have now turned the tide in favor of immunotherapy for the treatment of many different cancer types. In this review, we describe four of the most effective immunotherapeutic approaches currently used in the clinic: cancer vaccines, immunostimulatory agents, adoptive T cell therapy, and immune checkpoint blockade. In addition, we discuss some of the most promising future strategies that aim to utilize multiple immunotherapies or combine them with other approaches to more effectively target cancer. Copyright © 2013 by Annual Reviews.