BRAF Inhibitor Vemurafenib Improves the Antitumor Activity of Adoptive Cell Immunotherapy

Abstract

Combining immunotherapy with targeted therapy blocking oncogenic BRAFV600 may result in improved treatments for advanced melanoma. Here, 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 (ACT) 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 demonstrated that vemurafenib did not significantly alter the expansion, distribution, or tumor accumulation of the adoptively transferred cells. However, vemurafenib paradoxically increased MAPK signaling, in vivo cytotoxic activity, and intratumoral cytokine secretion by adoptively transferred cells. Together, our findings, derived from two independent models combining BRAF-targeted therapy with immunotherapy, support the testing of this therapeutic combination in patients with BRAFV600 mutant metastatic melanoma.

Prospects for personalized combination immunotherapy for solid tumors based on adoptive cell therapies and immune checkpoint blockade therapies

“…Based on current knowledge, it is conceivable that combination therapies of ACT with inhibition of the activated oncogene pathways using small molecule inhibitors could work synergistically to exhibit anti-tumor effects through mechanisms that restore T-cell infiltration. In a recent study, BRAF inhibitors improved the anti-tumor activity of ACT in mouse models 62) .…”

The importance for immunoregulation for long-term cancer control

“…The Phase I study combining ipilimumab and vemurafenib had to be stopped due to the high liver toxicity despite a strong rationale of using this combination. The BRAFi vemurafenib has shown in fact to enhance T-cell recognition of melanoma [40] improves anti tumor activity of adoptive cell immunotherapy [41], and it increases tumor infiltration by T cells [42].…”

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

“…Chemo-, radio-, targeted and anti-angiogenic therapies have all been shown to increase recruitment of adoptively transferred T cells to transplanted tumors and enhance anti-tumor responses [96,[176][177][178][179][180][181][182][183], but the mechanism by which this occurs has not been fully elucidated. One recent report showed that irradiation of spontaneous pancreatic tumors in RIP1-Tag5 mice increases recruitment of adoptively transferred CD8 + T cells and T cellmediated tumor rejection, which depended on repolarization of TAMs towards an antitumorigenic phenotype [184].…”