BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy.

Combining immunotherapy with targeted therapy blocking oncogenic BRAFV600 may result in improved treatments for advanced melanoma. In this study, we developed a BRAFV600E-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 BRAFV600 mutant metastatic melanoma.

Koya RC ，Mok S ，Otte N ，Blacketor KJ ，Comin-Anduix B ，Tumeh PC ，Minasyan A ，Graham NA ，Graeber TG ，Chodon T ，Ribas A ... -  《-》

BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice.

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 BRAF-mutant tumors. BRAF-mutated human melanoma tumor cell lines transduced to express gp100 and H-2D(b) 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. 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. 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.

Liu C ，Peng W ，Xu C ，Lou Y ，Zhang M ，Wargo JA ，Chen JQ ，Li HS ，Watowich SS ，Yang Y ，Tompers Frederick D ，Cooper ZA ，Mbofung RM ，Whittington M ，Flaherty KT ，Woodman SE ，Davies MA ，Radvanyi LG ，Overwijk WW ，Lizée G ，Hwu P ... -  《-》

17-AAG inhibits vemurafenib-associated MAP kinase activation and is synergistic with cellular immunotherapy in a murine melanoma model.

Joshi SS ，Jiang S ，Unni E ，Goding SR ，Fan T ，Antony PA ，Hornyak TJ ... -  《PLoS One》

Inhibition of colony stimulating factor-1 receptor improves antitumor efficacy of BRAF inhibition.

Mok S ，Tsoi J ，Koya RC ，Hu-Lieskovan S ，West BL ，Bollag G ，Graeber TG ，Ribas A ... -  《BMC CANCER》

Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma.

Hu-Lieskovan S ，Mok S ，Homet Moreno B ，Tsoi J ，Robert L ，Goedert L ，Pinheiro EM ，Koya RC ，Graeber TG ，Comin-Anduix B ，Ribas A ... -  《-》