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Published OnlineFirst January 20, 2012; DOI: 10.1158/1078-0432.CCR-11-3322
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CCR Translations
Commentary on Wilmott et al., p. 1386
Rehabilitation for Oncogene Addiction: Role of Immunity in
Cellular Sobriety
David L. Bajor and Robert H. Vonderheide
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. Clin Cancer Res; 18(5); 1–3. 2012 AACR.
In this issue of Clinical Cancer Research, Wilmott and
colleagues (1) report that the administration of selective
BRAF inhibitors in patients with metastatic melanoma
results in early infiltration of CD4þ and CD8þ T lymphocytes. The magnitude of CD8þ lymphocyte infiltration
correlates with tumor shrinkage, but at the time of tumor
progression the immune infiltrate is most often lost. 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, 2 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
cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) on
T lymphocytes, thereby silencing a negative regulator of Tcell 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. Although cancer cells possess
multiple genetic abnormalities, single mutations, such as
the constitutively active BRAFV600E in melanoma, can be so
crucial to growth and survival that their blockade results in
Authors' Affiliation: Abramson Family Cancer Research Institute, Hematology-Oncology Division, Department of Medicine, Perelman School of
Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
Corresponding Author: Robert H. Vonderheide, 551 BRB ii/iii, 421 Curie
Boulevard, Philadelphia, PA 19104. Phone: 215-573-4265; Fax: 215-5732652; E-mail: [email protected]
doi: 10.1158/1078-0432.CCR-11-3322
2012 American Association for Cancer Research.
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;
unfortunately, however, these transient responses do not
typically lead to long-term disease control (4). The fundamental principles of clinical oncology suggest the utility of
testing combinations of treatments that exhibit single-agent
activity but have different mechanisms of action and nonoverlapping toxicities. By showing that BRAF inhibition is
associated with an influx of T lymphocytes, Wilmott and
colleagues (1) 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 is a positive prognostic biomarker in primary melanoma. This may also be
the case in metastatic melanoma. Wilmott and colleagues
(1) now report that selective BRAF inhibition in patients
with metastatic melanoma results in a marked increase in
tumor-infiltrating T cells. Although they are not addressed
specifically in this study, at least 2 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 that are 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 interleukin 10
(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 mitogen-activated
protein–extracellular signal-regulated kinase (MEK) inhibition or BRAFV600E 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 that are not otherwise present in
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Published OnlineFirst January 20, 2012; DOI: 10.1158/1078-0432.CCR-11-3322
Bajor and Vonderheide
the tumor microenvironment. In this case, T cells may be
actively recruited to regressing melanoma, as clearly shown
in this study, although it remains to be shown that tumorinfiltrating 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. For example, macrophages are generally considered to be tumor-promoting leukocytes through their
roles in angiogenesis, metastasis, and production of a
T-cell–suppressive microenvironment. Melanoma cell line
growth in the mouse is enhanced by tumor-associated
macrophages (10), and the production of macrophage
chemoattractant protein 1, the major chemokine for macrophages, is upregulated in part by the MAPK pathway (11),
which suggests that its production may be decreased by
selective BRAF inhibition. Understanding the role of tumorassociated macrophages in patients receiving selective BRAF
inhibitors would be a valuable next step in elucidating the
interplay between oncogene inhibition and the innate
immune system.
The findings from Wilmott and colleagues fit nicely with
the increasing body of data regarding the importance of the
immune system in eradicating tumors following oncogene
inactivation. Using a mouse model of T-cell acute lympho-
blastic lymphoma (T-ALL) driven by the c-MYC oncogene,
Rakhra and colleagues (12) showed the necessity of the
immune system for eliminating tumors completely. In their
study, T-ALL tumors driven by the tetracycline-sensitive
c-MYC oncogene were implanted into wild-type mice or mice
with various forms of lymphocyte deficiency. Tumor growth
was monitored following oncogene inactivation, which was
accomplished experimentally by doxycycline administration. Partial regression was seen upon c-MYC inactivation
in all of the animals; however, in the absence of CD4þ T cells,
tumors failed to regress completely and began to grow
despite continued oncogene inactivation. The host immune
system was shown to produce antitumor cytokines in the
presence of c-MYC inactivation, which were necessary mediators of tumor elimination. Similar immune-mediated
responses were also seen in a BCR-ABL oncogene–induced
model of pro-B-cell acute lymphoblastic leukemia.
To the extent that such murine models show that an
immune response is important or even required for optimal
tumor regression following oncogene inactivation, strategies to add potent immunomodulatory drugs (e.g., antiCTLA-4 mAb) to oncogene-targeted 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 recently began
accrual. In one proposed mechanism of action (Fig. 1),
selective BRAF inhibition blocks the activated MAPK
pathway, resulting in tumor cell death by targeting
Tumor
antigen
release
T lymphocyte
Tumor antigen
presentation
APC
Tumor
“Vaccine effect”
Tumor death/clinical response
Melanoma
• BRAF inhibitor
resistance
• Immune escape
• Clinical relapse
Immune effector
response
BRAF
inhibition
Tumor
infiltrating
lymphocyte
(TIL)
No further
treatment
Associated with increased
T lymphocyte infiltrate
Addition of
immunotherapy
• Anti CTLA-4
• Anti CD40
• Anti PD-1
• Others
• Combinations
• Immunological
memory
• Sustained clinical
response
© 2012 American Association for Cancer Research
Figure 1. The prospect of immunotherapy cooperating with oncogene inhibition for optimal clinical outcome in metastatic melanoma. BRAF inhibition causes
tumor cell death, which is associated with increased lymphocyte infiltration. Tumor antigen released by dying tumor cells is presented to lymphocytes
by APCs. Without further treatment, tumors develop BRAF inhibitor resistance, leading to immune escape and relapse. The addition of immunotherapy such
as anti CTLA-4, anti CD40, or anti PD-1 (programmed death 1) monoclonal antibodies, or other types of immunotherapy alone or in combination may lead to a
more pronounced immune infiltrate, immunological memory, and sustained clinical response. TIL, tumor-infiltrating lymphocyte.
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Clinical Cancer Research
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Published OnlineFirst January 20, 2012; DOI: 10.1158/1078-0432.CCR-11-3322
Combining Targeted and Immune Therapy
oncogene-addicted cells. The concomitant release of tumorspecific antigens can then be picked up by APCs, which
present tumor antigen to T cells and produce cytokines and
chemokines that are capable of accelerating the antitumor
immune response. BRAF inactivation may also decrease
production of immunosuppressive cytokines that regulate
the tumor microenvironment, further driving intratumoral
infiltration of CD4þ and CD8þ T cells. Ultimately, and
unfortunately commonly, treatment resistance emerges,
leading to recapitulation of an immunosuppressive microenvironment, immunological escape, and clinical relapse.
Treatments such as ipilimumab may be able to fuel a more
robust immunological response and potentially clinical
responses as well, even perhaps preserving clinical activity
in the setting of resistance to BRAF inactivation. Several
immunomodulatory agents with different mechanisms of
action and more-muted toxicity profiles than ipilimumab
are currently showing promise in clinical investigations of
melanoma and other malignant diseases (Fig. 1), and many
of these can be seen as potential partners with oncogenetargeted therapy. With the increasing development of
targeted therapies for multiple types of tumors, the combination of these agents with immune therapy represents an
exciting clinical frontier with a sound scientific rationale.
Disclosure of Potential Conflicts of Interest
Dr. Vonderheide received research funding from Pfizer Corporation. No
other potential conflicts of interest were disclosed.
Grant Support
National Institutes of Health grants (T32 HL007775 to D.L. Bajor and
R01 CA158186 to R.H. Vonderheide).
Received December 23, 2011; accepted January 11, 2012; published
OnlineFirst January 20, 2012.
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Clin Cancer Res; 18(5) March 1, 2012
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Published OnlineFirst January 20, 2012; DOI: 10.1158/1078-0432.CCR-11-3322
Rehabilitation for Oncogene Addiction: Role of Immunity in
Cellular Sobriety
David L. Bajor and Robert H. Vonderheide
Clin Cancer Res Published OnlineFirst January 20, 2012.
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