Combined targeted therapy and immunotherapy in the treatment of advanced melanoma.

2012·0.57 MB·English

by  Wilmott, James S.

AuthOr’S VIew AuthOr’S VIew
OncoImmunology 1:6, 997-999; September 2012; © 2012 Landes Bioscience
Combined targeted therapy and immunotherapy
in the treatment of advanced melanoma
James S. wilmott,1,2,* richard A. Scolyer,1,2,3 Georgina V. Long1,2,4 and Peter hersey1,2,5
1Melanoma Institute Australia; Sydney, NSw Australia; 2university of Sydney; Sydney, NSw Australia; 3royal Prince Alfred hospital; Sydney, NSw Australia; 4westmead hospital;
Sydney, NSw Australia; 5Kolling Institute; royal North Shore hospital; Sydney, NSw Australia
Keywords: BRAF, BRAF mutation, CTLA-4, immunotherapy, immune response, melanoma, pathology, tumor infiltrating
lymphocytes, targeted therapy
recently, a CtLA-4 antibody and BrAF inhibitors showed survival benefits in advance melanoma treatment. the
documentation of immune infiltrates in melanomas early during BrAF inhibitor therapy provides a scientific rationale
for combination therapy with both treatments with possible synergistic benefits. this commentary reviews immune
responses induced by BrAF inhibitors.
After decades of negative clinical trials in oncogenic-rerouting.5 These two new samples. Our findings lead us to conclude
patients with advanced melanoma, two clinically efficacious agents have differ- that BRAFi may increase the ability of
agents have recently shown a significant ent mechanisms of action in treatment of cytotoxic T-cells to infiltrate metastatic
survival benefit in separate Phase 3 clinical metastatic melanoma; one is an immune- melanoma and hence the combination
trials. One agent is the immune-stimulat- modulator enhancing the body’s immune- with immunotherapies may lead to more
ing human anti-CTLA-4 antibody ipi- response against the tumor and the other favorable outcomes in BRAF-mutant met-
limumab. Ipilimumab binds to CTLA-4, inhibits a signal transduction pathway astatic melanoma patients.
thereby blocking negative immunogenic and directly inhibits tumor proliferation. The mechanisms responsible for this
signaling stimulated by B7 molecules on Ipilimumab has low but durable response increase in T-cell infiltration following
antigen-presenting cells (APCs). This rates, while BRAFi have high response commencement of BRAFi therapy remain
enables CD28 on T-cells to bind to rates and durability in few patients. unknown. The melanoma may become
CD80/86 on APCs, leading to activation Currently interest has turned to combin- more “visible” to the immune system
and proliferation of T-cells. Clinical trials ing both agents to achieve more durable following BRAF inhibition. Boni et al.
evaluating ipilimumab in metastatic mela- responses in BRAF mutant melanoma reported that in vitro treatment of BRAF
noma patients have shown response rates of patients. To investigate the effects of the mutant cell lines with a BRAFi induced the
10–15%1,2 with significant improvements selective BRAFi on immune-responses, expression of melanoma cell surface anti-
in median overall survival when com- we recently analyzed biopsies of meta- gens GP-100/MART-1, which increased
pared with a GP-100 vaccine (27.8 vs. 17.2 static melanoma patients taken before and the recognition of the melanoma cells by
mo),1 or in combination with dacarbazine early during treatment with a BRAFi.6 antigen-specific T-cells. Additionally, our
chemotherapy compared with dacarba- These studies showed, a dramatic increase study and those of other authors showed
zine alone (19.3 vs. 8.1 mo).2 The second in the number of tumor-infiltrating lym- increased levels of necrosis and apoptosis in
agent to show a significant improvement phocytes (TILS) in biopsies following response to BRAFi and both forms of cell
in overall survival when compared with commencement of BRAFi treatment. death are known to induce an immune-
dacarbazine was BRAF inhibitor (BRAFi) Using immunohistochemistry, we showed response.7 Other mechanisms of increased
targeted therapy. Selective BRAFi target that intratumoral density of CD4/CD8+ immune-reaction may result from the
V600-mutated-BRAF, which constitu- T-cells significantly increased with BRAFi disruption of the immunosuppressive
tively activates the mitogen-activated-pro- treatment. The increase in intratumoral tumor-stroma microenvironment that
tein-kinase (MAPK) pathway and occurs T-cell density following BRAFi treatment MAPK overexpression has helped main-
in approximately 50% of metastatic mela- correlated with a reduction in tumor-size tain. This hypothesis is supported by data
noma patients.3 BRAFi have response and an increase in necrosis. Furthermore, from Suminoto et al. who demonstrated
rates of approximately 50%, although in biopsies of progressing lesions, the den- that BRAF shRNA reduced the secre-
V600E
by 6 mo 50% of patients develop resis- sity of the CD4/CD8+ T-cells reduced to tion of immunosuppressive chemokines
tance4 to the BRAFi principally through levels observed in the pre-BRAF inhibitor IL-6/10 by BRAF-mutant cell lines.8
*Correspondence to: James S. Wilmott; Email: [email protected]
Submitted: 02/29/12; Accepted: 03/12/12
http://dx.doi.org/10.4161/onci.19865
www.landesbioscience.com OncoImmunology 997
Figure 1. Disruption to the tumor microenvironment through BrAF inhibition may improve immunotherapy efficacy. (A) the immunosuppressive
tumor microenvironment is maintained by the tumor and stroma which release immunosuppressive chemokines and through the negative regulation
of t-cells. (B) BrAF inhibitors may be used to sensitize melanomas to immunotherapies such as anti-CtLA-4 and anti-PD-1 antibodies. BrAF inhibi-
tion may reduce tumor suppressive chemokines produced by the tumor and recruited monocytes. Additionally, BrAF inhibitors induce necrosis and
increase cell surface antigens which may increase the visibility of the tumor to the immune system. BrAF inhibitors can be combined with immuno-
therapies which may increase tumor specific t-cell activation and proliferation. (C) Pre-treatment biopsy showing a low density of CD8+ lymphocytes.
(D) Pre-treatment biopsy showing a low density of Granzyme B+ lymphocytes. (E) Post BrAF inhibitor biopsy showing a high density of CD8+ lympho-
cytes. (F) Post BrAF inhibitor biopsy showing a high density of Granzyme B+ lymphocytes.
Furthermore, the supernatant from these B expression identifies activated T-cells that the increase in TILS was lost once
untreated cell lines inhibited the produc- in the tumor-microenvironment and the tumor progresses on BRAFi therapy,
tion of inflammatory chemokines IL-12 importantly we observed an increase in suggesting that an immunotherapy with
and TNFa by dendritic cells.8 Also dis- Granzyme B expressing T-cells in mela- a shorter latency period may be needed
ruption to the tumor-stroma maintained nomas with BRAFi therapy. However, the to exploit the BRAFi response. The
immunosuppressive and anti-inflamma- magnitude of the increase was less than obvious choice would appear to be the
tory microenvironment by BRAFi therapy that of the total CD8+ T-cells possibly CTLA-4 antibody Ipilimumab as it has
may have allowed T-cells to infiltrate the indicating at least a portion of the T-cells proven efficacy and responses can be
tumor more readily (Fig. 1). may be non-functional. Understanding rapid. Initial clinical trials are under-
A potentially more clinically impor- the functional status of these T-cells may way which combine BRAFi and ipi-
tant issue is whether the CD8+ T-cells provide important insights into the selec- limumab (ClinicalTrials.gov Identifier:
seen in BRAFi-treated melanoma biopsies tion of the most effective immunotherapy NCT01400451). Another possible com-
are functionally active. Lymphocytes may combination. bination is the antibody against PD1, an
be rendered anergic by a variety of mech- The optimal criteria for the most immune antagonist, which has shown
anisms including contact with ligands appropriate drug to be combined with a similar responses but lower toxicity than
of negative signaling receptors PD-1, BRAFi would include low/absent toxic- Ipilimumab in early phase clinical trials.
CTLA-4, TIM-3 as well as activation ity, induction of strong responses and a In addition, in vitro studies have shown
of FoxP3+ T regulatory cells. Granzyme short latency period. Our study showed that the combination of CTLA-4 and
998 OncoImmunology Volume 1 Issue 6
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