期刊
CANCER RESEARCH
卷 72, 期 16, 页码 3928-3937出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-11-2837
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资金
- NIH [P50 CA086306, P01 CA132681]
- Seaver Institute
- Louise Belley and Richard Schnarr Fund
- Wesley Coyle Memorial Fund
- Garcia-Corsini Family Fund
- Fred L. Hartley Family Foundation
- Ruby Family Foundation
- Jonsson Cancer Center Foundation
- Caltech-UCLA Joint Center for Translational Medicine
- UCLA
- US Department of Health and Human Services
- Ruth L. Kirschstein Institutional National Research Service Award [T32 CA009056]
- Eugene V. Cota-Robles Fellowship
- Competitive Edge Fellowship
- NSF AGEP
- [K08 AI091663]
Combining immunotherapy with targeted therapy blocking oncogenic BRAF(V600) may result in improved treatments for advanced melanoma. In this study, we developed a BRAF(V600E)-driven murine model of melanoma, SM1, which is syngeneic to fully immunocompetent mice. SM1 cells exposed to the BRAF inhibitor vemurafenib (PLX4032) showed partial in vitro and in vivo sensitivity resulting from the inhibition of MAPK pathway signaling. Combined treatment of vemurafenib plus adoptive cell transfer therapy with lymphocytes genetically modified with a T-cell receptor (TCR) recognizing chicken ovalbumin (OVA) expressed by SM1-OVA tumors or pmel-1 TCR transgenic lymphocytes recognizing gp100 endogenously expressed by SM1 resulted in superior antitumor responses compared with either therapy alone. T-cell analysis showed that vemurafenib did not significantly alter the expansion, distribution, or tumor accumulation of the adoptively transferred cells. However, vemurafenib paradoxically increased mitogen-activated protein kinase (MAPK) signaling, in vivo cytotoxic activity, and intratumoral cytokine secretion by adoptively transferred cells. Taken together, our findings, derived from 2 independent models combining BRAF-targeted therapy with immunotherapy, support the testing of this therapeutic combination in patients with BRAF(V600) mutant metastatic melanoma. Cancer Res; 72(16); 3928-37. (C) 2012 AACR.
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