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Release the Hounds! Activating the T-Cell Response to Cancer

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  • New England Journal of Medicine

Abstract

Among the many subterfuges that cancer cells deploy to limit detection by host immune defenses, activation of so-called immune checkpoints is one that may be exploitable in activating a counterattack. Many complex multicellular regulatory events are involved in keeping the immune system from overreacting to a stimulus or mistaking a component of oneself for a dangerous invader. One such event that regulates inflammatory responses in the tissues involves the programmed death 1 (PD-1) pathway. One or both of the PD-1 ligands, PD-L1 and PD-L2, which are expressed on cells in the tissues, bind to PD-1 receptors on T cells and . . .
editorial
n engl j med 372;4 nejm.org january 22, 2015
374
The
new england journal
of
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Release the Hounds! Activating the T-Cell Response to Cancer
Mario Sznol, M.D., and Dan L. Longo, M.D.
Among the many subterfuges that cancer cells
deploy to limit detection by host immune de-
fenses, activation of so-called immune check-
points is one that may be exploitable in activat-
ing a counterattack. Many complex multicellular
regulatory events are involved in keeping the im-
mune system from overreacting to a stimulus or
mistaking a component of oneself for a danger-
ous invader. One such event that regulates in-
flammatory responses in the tissues involves the
programmed death 1 (PD-1) pathway. One or
both of the PD-1 ligands, PD-L1 and PD-L2,
which are expressed on cells in the tissues, bind
to PD-1 receptors on T cells and inhibit their
function. Blocking this interaction between PD-1
and its ligands can result in T-cell activation and
a more florid tissue inflammatory response.
1
Two reports now published in the Journal pro-
vide additional data on the emerging and impor-
tant role of immune therapy — and specifically,
on the role of antibodies blocking the PD-1 recep-
tor pathway — in the treatment of metastatic
cancer. Robert et al.
2
describe improved survival
among patients with metastatic melanoma who
received the anti–PD-1 drug nivolumab. Ansell
et al.
3
describe a remarkably high objective re-
sponse rate of 87% among heavily pretreated
patients with Hodgkin’s lymphoma receiving
nivolumab.
In September 2014, another anti–PD-1 drug,
pembrolizumab, was granted accelerated approv-
al in the United States but only for the treat-
ment of metastatic melanoma in patients with
progressive disease after treatment with the
current standard of care, ipilimumab (an anti–
CTLA-4 antibody), and a BRAF-targeted agent
(for tumors with a V600 mutation). The results
of the trial by Robert et al. strongly support the
approval and selection of anti–PD-1 therapy as
first-line treatment for metastatic melanoma in
patients with tumors containing unmutated
BRAF. Although nivolumab was compared with
dacarbazine, its activity and safety profile were
substantially superior to those of ipilimumab
in a very similar patient population. If the re-
cently reported results for ipilimumab in combi-
nation with nivolumab are confirmed in ran-
domized trials, further improvement in overall
survival and in durable long-term responses
could be achieved in the near future.
4,5
Previous studies of anti–PD-1 therapy in meta-
static melanoma have shown higher response
rates and improved progression-free survival in
patients with at least 5% of tumor cells staining
for membrane PD-L1 expression on immunohisto-
chemical analysis, as assessed in a pretreatment
metastatic lesion. In the study by Robert et al.,
patients were stratified according to tumor PD-L1
status. Nivolumab was superior to dacarbazine
and showed substantial benefit even in the group
with negative or indeterminate biomarkers. It
remains unclear whether the results reflect tech-
nical issues with the assay, heterogeneity in ex-
pression of tumor PD-L1 leading to a high per-
centage of false negative results, an effect of
anti–PD-1 therapy remote from the tumor, or an
outcome specific to melanoma. Clearly, improved
biomarkers for the selection of patients are re-
quired — for example, to select between target-
ed therapy and anti–PD-1 therapy in patients with
BRAF-mutated metastatic melanoma or to deter-
mine which patients might receive the most ef-
fective results from anti–PD-1 therapy alone, as
compared with a more toxic combination, or
perhaps to determine the best combination
therapy among the many potentially active ones
that will be developed over the coming years.
Recent findings that have been presented at
The New England Journal of Medicine
Downloaded from nejm.org at NIH Libary on September 23, 2015. For personal use only. No other uses without permission.
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editorial
n engl j med 372;4 nejm.org january 22, 2015
375
meetings examining the predictive value of fea-
tures related to the malignant cells or the tumor
immune infiltrate appear to be promising. How-
ever, the substantial complexity of the tumor–
host relationship and the large number of poten-
tial variables that might influence outcome with
respect to any single or combined intervention
suggest that development of reliable and afford-
able predictive biomarkers will be difficult and
will require a substantial investment in resources.
An important lesson from the trial by Robert
et al. is the need to validate the prospective pre-
dictive biomarker in a randomized, controlled
clinical trial.
The immediate clinical effects of the results
reported by Ansell et al. are clear and are par-
ticularly exciting in suggesting a future in which
anti–PD-1 therapy will become the foundation
for the treatment of Hodgkin’s lymphoma, pos-
sibly sparing patients both short- and long-term
toxic effects of combination chemotherapy. The
mechanism of response to anti–PD-1 therapy
in this population needs further study. Al-
though Hodgkins lymphoma is characterized by
genetically driven PD-L1 and PD-L2 overexpres-
sion and an intense inflammatory response in-
cluding the activation of PD-1–expressing CD4+
T cells, compelling evidence for a clonal tumor
antigen-specific response is not yet available.
Perhaps part of the anti–PD-1 antitumor effect
may be related to the blockade of reverse signal-
ing through PD-L1, which was previously de-
scribed to impart a general antiapoptotic cellular
response.
6
Studies of biopsy samples obtained
from patients with regressing lesions may lead
to a greater understanding of the mechanism,
which in turn could provide the scientific basis
for developing even more effective combination
treatment regimens.
With recent data showing impressive clinical
activity of PD-1 or PD-L1 antagonists in sub-
groups of patients with a variety of different
cancers, the critical and foundational role of
immune interventions in cancer treatment is
no longer deniable. The success that has been
achieved to date was accomplished with agents
directed against only two of the many potentially
important immune targets, which also include a
large number of coinhibitory and costimulatory
ligand–receptor pairs. The substantial investment
in immunology and tumor immunobiology by
the National Institutes of Health and the Nation-
al Cancer Institute is paying off, and the clinical
data that were sampled in these two studies
presage the substantial additional gains that
could be possible from continued investment in
this field.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
From the Section of Medical Oncology, Yale University School
of Medicine, New Haven, CT (M.S.).
This article was published on December 6, 2014, at NEJM.org.
1. Pardoll DM. The blockade of immune checkpoints in cancer
immunotherapy. Nat Rev Cancer 2012;12:252-64.
2. Robert C, Long GV, Brady B, et al. Nivolumab in previously
untreated melanoma without BRAF mutation. N Engl J Med 2015;
372:320-30.
3. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade
with nivolumab in relapsed or refractory Hodgkin’s lymphoma.
N Engl J Med 2015;372:311-9.
4. Sznol M, Kluger HM, Callahan MK, et al. Survival, response
duration, and activity by BRAF mutation (MT) status of nivolu-
mab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab
(IPI) concurrent therapy in advanced melanoma (MEL). J Clin
Oncol 2014;32:Suppl:LBA9003. abstract.
5. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus
ipilimumab in advanced melanoma. N Engl J Med 2013;369:122-
33.
6. Azuma T, Yao S, Zhu G, Flies AS, Flies SJ, Chen L. B7-H1 is
a ubiquitous antiapoptotic receptor on cancer cells. Blood 2008;
111:3635-43.
DOI: 10.1056/NEJMe1413488
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Background: The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations. Combining dabrafenib and the MEK inhibitor trametinib, as compared with dabrafenib alone, enhanced antitumor activity in this population of patients. Methods: In this open-label, phase 3 trial, we randomly assigned 704 patients with metastatic melanoma with a BRAF V600 mutation to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy. The primary end point was overall survival. Results: At the preplanned interim overall survival analysis, which was performed after 77% of the total number of expected events occurred, the overall survival rate at 12 months was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P=0.005). The prespecified interim stopping boundary was crossed, and the study was stopped for efficacy in July 2014. Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). The objective response rate was 64% in the combination-therapy group and 51% in the vemurafenib group (P<0.001). Rates of severe adverse events and study-drug discontinuations were similar in the two groups. Cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the combination-therapy group and 18% of those in the vemurafenib group. Conclusions: Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01597908.).
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Background: Nivolumab was associated with higher rates of objective response than chemotherapy in a phase 3 study involving patients with ipilimumab-refractory metastatic melanoma. The use of nivolumab in previously untreated patients with advanced melanoma has not been tested in a phase 3 controlled study. Methods: We randomly assigned 418 previously untreated patients who had metastatic melanoma without a BRAF mutation to receive nivolumab (at a dose of 3 mg per kilogram of body weight every 2 weeks and dacarbazine-matched placebo every 3 weeks) or dacarbazine (at a dose of 1000 mg per square meter of body-surface area every 3 weeks and nivolumab-matched placebo every 2 weeks). The primary end point was overall survival. Results: At 1 year, the overall rate of survival was 72.9% (95% confidence interval [CI], 65.5 to 78.9) in the nivolumab group, as compared with 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; P<0.001). The median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (hazard ratio for death or progression of disease, 0.43; 95% CI, 0.34 to 0.56; P<0.001). The objective response rate was 40.0% (95% CI, 33.3 to 47.0) in the nivolumab group versus 13.9% (95% CI, 9.5 to 19.4) in the dacarbazine group (odds ratio, 4.06; P<0.001). The survival benefit with nivolumab versus dacarbazine was observed across prespecified subgroups, including subgroups defined by status regarding the programmed death ligand 1 (PD-L1). Common adverse events associated with nivolumab included fatigue, pruritus, and nausea. Drug-related adverse events of grade 3 or 4 occurred in 11.7% of the patients treated with nivolumab and 17.6% of those treated with dacarbazine. Conclusions: Nivolumab was associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation. (Funded by Bristol-Myers Squibb; CheckMate 066 ClinicalTrials.gov number, NCT01721772.).
Article
Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.