The Oncogenic BRAF Kinase Inhibitor PLX4032/RG7204 Does Not Affect the Viability or Function of Human Lymphocytes across a Wide Range of Concentrations

Comı́n-Anduix, Begoña; Chodon, Thinle; Sazegar, Hooman; Matsunaga, Douglas; Mock, Stephen; Jalil, Jason; Escuin-Ordinas, Helena; Chmielowski, Bartosz; Koya, Richard C.; Ribas, Antoni

doi:10.1158/1078-0432.ccr-10-1911

Cited by 126 publications

(98 citation statements)

References 37 publications

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“…Regarding the direct effect of kinase inhibition on healthy T lymphocytes, previous in vitro studies have shown that vemurafenib and its derivative (PLX4720) do not compromise T-lymphocyte function (21,32), whereas MEKi U0126 and PD0325901 are detrimental. We asked whether the function of normal healthy donor T lymphocytes was affected by direct dabrafenib or trametinib or combined treatment.…”

Section: Discussionmentioning

confidence: 99%

MEK Inhibition, Alone or in Combination with BRAF Inhibition, Affects Multiple Functions of Isolated Normal Human Lymphocytes and Dendritic Cells

Vella

Pasam

Dimopoulos

et al. 2014

Cancer Immunology Research

121

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Combination therapy with BRAF and MEK inhibition is currently in clinical development for the treatment of BRAF-mutated malignant melanoma. BRAF inhibitors are associated with enhanced antigen-specific T-lymphocyte recognition in vivo. Consequently, BRAF inhibition has been proposed as proimmunogenic and there has been considerable enthusiasm for combining BRAF inhibition with immunotherapy. MEK inhibitors inhibit ERK phosphorylation regardless of BRAF mutational status and have been reported to impair T-lymphocyte and modulate dendritic cell function. In this study, we investigate the effects on isolated T lymphocytes and monocytederived dendritic cells (moDC) of a MEK (trametinib) and BRAF (dabrafenib) inhibitor combination currently being evaluated in a randomized controlled clinical trial. The effects of dabrafenib and trametinib, alone and in combination, were studied on isolated normal T lymphocytes and moDCs. Lymphocyte viability, together with functional assays including proliferation, cytokine production, and antigen-specific expansion, were assessed. MoDC phenotype in response to lipopolysaccharide stimulation was evaluated by flow cytometry, as were effects on antigen cross-presentation. Dabrafenib did not have an impact on T lymphocytes or moDCs, whereas trametinib alone or in combination with dabrafenib suppressed T-lymphocyte proliferation, cytokine production, and antigenspecific expansion. However, no significant decrease in CD4 þ or CD8 þ T-lymphocyte viability was observed following kinase inhibition. MoDC cross-presentation was suppressed in association with enhanced maturation following combined inhibition of MEK and BRAF. The results of this study demonstrate that MEK inhibition, alone or in combination with BRAF inhibition, can modulate immune cell function, and further studies in vivo will be required to evaluate the potential clinical impact of these findings.

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Section: Discussionmentioning

confidence: 99%

MEK Inhibition, Alone or in Combination with BRAF Inhibition, Affects Multiple Functions of Isolated Normal Human Lymphocytes and Dendritic Cells

Vella

Pasam

Dimopoulos

et al. 2014

Cancer Immunology Research

121

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“…36 Targeted agents such as the BRAF inhibitor vemurafenib have also been associated with various immune effects. 26,41 One study suggested that vemurafenib promoted the development of an immune stimulatory microenvironment with increases in CD40L and IFN gamma and that this antitumor effect could be abrogated with CD40L and IFN gamma blockade. 42 Likewise, overall viability of human lymphocytes does not appear to be compromised by BRAF inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…42 Likewise, overall viability of human lymphocytes does not appear to be compromised by BRAF inhibitors. 41 In fact, vemurafenib has since been found to cause an increase in expression of melanoma antigens such as gp100 and MART1 accompanied with a noted increased response in CTL's specific for these antigens. 27,43 These results suggest that BRAF inhibitors should indeed be synergistic with immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Durable complete responses off all treatment in patients with metastatic malignant melanoma after sequential immunotherapy followed by a finite course of BRAF inhibitor therapy

Wyluda

Cheng

Schell

et al. 2015

Cancer Biology & Therapy

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Drabick (2015) Durable complete responses off all treatment in patients with metastatic malignant melanoma after sequential immunotherapy followed by a finite course of BRAF inhibitor therapy, Cancer Biology & Therapy, 16:5, 662-670, DOI: 10.1080/15384047.2015 We report 3 cases of durable complete response (CR) in patients with BRAF-mutated metastatic melanoma who were initially treated unsuccessfully with sequential immunotherapies (high dose interleukin 2 followed by ipilimumab with or without concurrent radiation therapy). After progression during or post immunotherapy, these patients were given BRAF inhibitor therapy and developed rapid CRs. Based on the concomitant presence of autoimmune manifestations (including vitiligo and hypophysitis), we postulated that there was a synergistic effect between the prior immune therapy and the BRAF targeting agents. Accordingly, the inhibitors were gradually weaned off beginning at 3 months and were stopped completely at 9-12 months. The three patients remain well and in CR off of all therapy at up to 15 months radiographic follow-up. The institution of the BRAF therapy was associated with development of severe rheumatoid-like arthritis in 2 patients which persisted for months after discontinuation of therapy, suggesting it was not merely a known toxicity of BRAF inhibitors (arthralgias). On immunologic analysis, these patients had high levels of non-T-regulatory, CD4 positive effector phenotype T-cells, which persisted after completion of therapy. Of note, we had previously reported a similar phenomenon in patients with metastatic melanoma who failed high dose interleukin-2 and were then placed on a finite course of temozolomide with rapid complete responses that have remained durable for many years after discontinuation of temozolomide. We postulate that a finite course of cytotoxic or targeted therapy specific for melanoma given after apparent failure of prior immunotherapy can result in complete and durable remissions that may persist long after the specific cytotoxic or targeted agents have been discontinued suggesting the existence of sequence specific synergism between immunotherapy and these agents. Here, we discuss these cases in the context of the literature on synergy between conventional or targeted cytotoxic therapy and immunotherapy in cancer treatment.

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“…The MAPK pathway when activated downregulates the expression of microphthalmiaassociated transcription factor (MITF) (16), which ultimately leads to suppression of melanocyte-lineage antigen expression [such as gp100, melan-A, tyrosinase related proteins 1 and 2 (17,18)] that are recognized by T-cells (Figure 1). It has been shown that BRAF inhibition has favorable effects in the tumor microenvironment, including increased HLA and antigen expression, increased T-cell infiltrate, improved T-cell function, reduced immunosuppressive cytokines and increased PD-L1 expression (18)(19)(20)(21)(22). TILs are increased early after the initiation of BRAF inhibitor therapy (18,21).…”

Section: Introductionmentioning

confidence: 99%

The combination of checkpoint immunotherapy and targeted therapy in cancer

Karachaliou¹,

Cao²,

Sosa³

et al. 2017

Ann. Transl. Med.

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Abstract:The therapeutic possibilities for patients with metastatic melanoma have changed due to the development of targeted therapies that inhibit oncogenic signaling pathways as well as immune modulating therapies that unleash the patient antitumor immunity. These therapeutic changes have impressively increased the median overall survival of the patients. Considering the dramatic but transient responses that occur with targeted therapies for a subgroup of patients and the durable responses that can be achieved with immunotherapy in a subset of patients, a lot of effort is ongoing for the clinical development of combinations of these two therapeutic approaches. Herein we discuss the existing preclinical and clinical data for the combination of targeted therapies and immunotherapy focusing mainly on melanoma and non-small cell lung cancer (NSCLC).

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The Oncogenic BRAF Kinase Inhibitor PLX4032/RG7204 Does Not Affect the Viability or Function of Human Lymphocytes across a Wide Range of Concentrations

Cited by 126 publications

References 37 publications

MEK Inhibition, Alone or in Combination with BRAF Inhibition, Affects Multiple Functions of Isolated Normal Human Lymphocytes and Dendritic Cells

MEK Inhibition, Alone or in Combination with BRAF Inhibition, Affects Multiple Functions of Isolated Normal Human Lymphocytes and Dendritic Cells

Durable complete responses off all treatment in patients with metastatic malignant melanoma after sequential immunotherapy followed by a finite course of BRAF inhibitor therapy

The combination of checkpoint immunotherapy and targeted therapy in cancer

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