Rehabilitation for oncogene addiction: role of immunity in cellular sobriety.

Clinical responses to oncogene inhibitors result from direct effects on cell-intrinsic growth signals and disruption of downstream messages that produce a protumor immunosuppressive microenvironment. Combining oncogene-targeted and immunomodulatory therapies may result in synergistic effects, producing increased response rates and longer periods of tumor control than can be achieved with either class alone.

In this issue of Clinical Cancer Research, Wilmott and colleagues report that the administration of selective BRAF inhibitors in patients with metastatic melanoma results in early infiltration of CD4+ and CD8+ T lymphocytes. The magnitude of CD8+ lymphocyte infiltration correlates with tumor shrinkage, but at the time of tumor progression the immune infiltrate is most often lost (1). These data are important because they support the hypothesis that immune activation plays a role in the antitumor activity of targeting the BRAF oncogene in patients.
Metastatic melanoma is a notoriously deadly malignancy, and until recently, there were no therapies capable of extending patient survival. In 2011, two agents with different mechanisms of action were approved in the United States for use in melanoma based on evidence that they each prolong overall survival in selected populations.
Ipilimumab, a fully human monoclonal antibody, antagonizes CTLA-4 on T lymphocytes thereby silencing a negative regulator of T cell response. CTLA-4 blockade allows T cell activation and leads to immune-mediated destruction of melanoma cells. When used as a single agent, the objective response rate for ipilimumab is <15%, but for a minority of patients, clinical response can be sustained long-term (2). The selective BRAF inhibitor vemurafenib was also approved last year, and the drug has emerged as a highly active and well-tolerated treatment that improves survival for patients whose tumors harbor a BRAF mutation. Despite multiple genetic abnormalities in cancer cells, single mutations such as the constitutively active BRAF V600E in melanoma can be so crucial to growth and survival that their blockade results in tumor cell death, a phenomenon termed "oncogene addiction" (3). Responses to selective BRAF inhibition are often dramatic in terms of reduction of overall tumor burden but unfortunately, these transient responses do not typically lead to long-term disease control (4). Fundamental principles of clinical oncology suggest utility in testing combinations of treatments that exhibit single agent activity but have different mechanisms of action and non-overlapping toxicities. By Research.
on March 18, 2020. © 2012 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Author Manuscript Published OnlineFirst on January 20, 2012; DOI: 10.1158/1078-0432.CCR-  showing that BRAF inhibition is associated with an influx of T lymphocytes, Wilmott et al further fuel the notion that combining targeted therapy and immunotherapy may be able to yield synergistic responses in melanoma (5).
The presence of intratumoral T cells in primary melanoma is a positive prognostic biomarker. This may also be the case in metastatic melanoma. Wilmott et al now report that selective BRAF inhibition in patients with metastatic melanoma results in a marked increase in tumor-infiltrating T cells. Although not addressed specifically in this study, at least two mechanisms could explain this immunological effect. First, tumor cell death in the wake of a therapy that is not itself overtly immunotoxic or immunosuppressive may produce a "vaccine effect" insofar as tumor antigens shed after therapy may be processed and presented by host antigen presenting cells (APC) to drive tumor-specific adaptive immune responses. Second, the influx of T cells during treatment may also occur as a direct response to changes in the tumor microenvironment caused by BRAF inhibition. For example, the production of the immunomodulatory cytokines IL-10, VEGF and IL-6 by melanoma cell lines is controlled by the mitogen-activated protein kinase (MAPK) pathway and decreased in vitro by treatment with MEK inhibition or BRAF V600E RNA interference (6). Thus, treatment with selective BRAF inhibitors in vivo may alter this immunosuppressive cytokine milieu and permit enhanced infiltration of T cells. In addition, dying tumor cells may also release ATP (7) and other cellular contents that act as strong chemoattractants for T cells not otherwise present in the tumor microenvironment. In this case, T cells may be actively recruited to regressing melanoma as clearly documented in this study, although it remains to be shown that tumor infiltrating T cells following BRAF inhibition are tumor-specific. The key point, however, is that vemurafenib does not appear to be immunosuppressive, and in fact, may promote T cell responses by enhancing antigen presentation by tumor cells (8,9). Other immunological effects of BRAF inhibition on the tumor microenvironment may be highly nuanced and intertwined. Macrophages, for example, are generally considered to be tumor promoting leukocytes through their roles in angiogenesis, metastasis, and production of a T cell suppressive microenvironment. Growth of melanoma cell lines in the mouse is enhanced by tumor-associated macrophages (TAMs) (10) and the production of macrophage chemoattractant protein 1 (MCP-1), the major chemokine for macrophages, is upregulated in part by the MAPK pathway (11), suggesting that its production may be decreased by selective BRAF inhibition.
UnderstandingTAMs in patients receiving selective BRAF inhibitors would be a valuable next step in elucidating the interplay between oncogene inhibition and the innate To the extent that such murine models demonstrate that an immune response is important or even required for optimal tumor regression following oncogene inactivation, strategies to add potent immunomodulatory drugs (e.g. anti-CTLA-4 mAb) to oncogenetargeted cancer therapies have merit. This is particularly true in melanoma for which ipilimumab is clinically approved. Indeed, a phase I/II trial combining ipilimumab and vemurafenib has recently begun accrual. In one proposed mechanism of action (Fig 1), showing promise in clinical investigation in melanoma and other malignancies (Fig. 1), and many of these can be seen as potential partners with oncogene-targeted therapy.
With the increasing development of targeted therapies for for multiple types of tumors, the combination of these agents with immune therapy represents an exciting clinical frontier with a sound scientific rationale.    Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) . http://clincancerres.aacrjournals.org/content/early/2012/01/20/1078-0432.CCR-  To request permission to re-use all or part of this article, use this link Research.
on March 18, 2020. © 2012 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.