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

  • New England Journal of Medicine


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 . . .
n engl j med 372;4 january 22, 2015
new england journal
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.
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.
describe improved survival
among patients with metastatic melanoma who
received the anti–PD-1 drug nivolumab. Ansell
et al.
describe a remarkably high objective re-
sponse rate of 87% among heavily pretreated
patients with Hodgkin’s lymphoma receiving
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.
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
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Copyright © 2015 Massachusetts Medical Society. All rights reserved.
n engl j med 372;4 january 22, 2015
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
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
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
1. Pardoll DM. The blockade of immune checkpoints in cancer
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4. Sznol M, Kluger HM, Callahan MK, et al. Survival, response
duration, and activity by BRAF mutation (MT) status of nivolu-
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DOI: 10.1056/NEJMe1413488
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... Immunity homeostasis requires orchestrating the interaction and modulation of these immune checkpoint mediators to optimize normal and appropriate immune responses and avoid autoimmune disorders in normal tissues as well (Reinherz and Schlossman, 1980;Harshyne et al., 2015;Baruch et al., 2016;Hutchinson, 2016;Jiang et al., 2016). CD28, a type of co-stimulatory molecules which is expressed in 90% CD4+ T-cell and 50% CD8+ T-cell, binds to cofactor B7 and up-regulates the effector T-cell activation (Ardon et al., 2012;Topalian et al., 2012;Hamid et al., 2013;Asaoka et al., 2015;Sznol and Longo, 2015;Wolchok, 2015). Conversely, Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), also known as CD152, is capable of competitively binding to B7 and blocking co-stimulatory signals. ...
... It also improved immune related progression free survival greatly in non-small cell lung cancer (NSCLC) when combined with chemotherapy. Another humanized anti-CTLA-4 antibody, tremelimumab obtained durable responses in phase I/II clinical studies with melanoma but fell short in Phase III randomized clinical trial (Boussiotis, 2014;Deng et al., 2015;Sznol and Longo, 2015;Kataoka et al., 2016). ...
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Glioblastoma (GBM) is a severe malignant brain cancer with poor overall survival. Conventional intervention remains dismal to prevent recurrence and deterioration of GBM cell. Recent years have witnessed exciting breakthroughs in novel immune strategies, especially checkpoint inhibitors, some of which have become adjuvant setting after standard of care in melanoma. Several clinical trials of checkpoint inhibitors are ongoing in glioblastoma and other brain carcinomas. Plus, synergistic combinations of checkpoint inhibitors with conventional therapy strategies—radiotherapy, temozolomide, bevacizumab, and corticosteroids are now being exploited and applied in clinical settings. This review highlights the recent developments of checkpoints in GBM immunotherapy to provide a brief and comprehensive review of current treatment options. Furthermore, we will discuss challenges remained, such as unique immune system of central nervous system (CNS), immune-related toxicities, synergies, and adverse interactions of combination therapies.
... In the last two decades several clinical trials have investigated these immunotherapy merthods and their potential in cancer patients. [14][15][16][17][18] Some of the results were very promissing and effective for cancer treatment. The famous research journal Science (American Association for the Advancement of Science) witnessing the amazing effect of cancer immunotherapy selected the method as "2013's Breakthrough of the Year". ...
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Cancer comprises many different diseases (estimated at more than 200 types of malignancies), all characterized by accumulation of DNA damage and uncontrolled proliferation of abnormal cells with capacity for spread to healthy organs and form malignant tumours. The therapeutic approaches in the last decades included surgery, radiation, chemotherapy and other advanced medical strategies. The scientists who contributed to these discoveries and improved therapeutic approaches to cancer treatment have been awarded Nobel prizes in the past. In 2018 the Nobel Prize in Physiology or Medicine was awarded to an American and a Japanese scientist for their discovery of a revolutionary approach to cancer treatment. Their revolutionary discovery proved that the human body's immune system can be harnessed to attack cancer cells 20 years ago. It was known for many years before that the human immune system under normal physiological conditions seeks out and destroys mutated cells, but cancer cells find sophisticated ways to hide from immune attacks, allowing them to thrive and grow. Many types of cancer do this by ramping up a braking mechanism that keeps immune cells in check. In 2011, new anticancer drugs have been approved by the Food and Drug Administration (FDA, USA) as a therapeutic antibody drug ipilimumab (trade name Yervoy ® Bristol-Myers Squibb Co) which is a monoclonal antibody that works to activate the immune system by targeting CTLA-4 (T-lymphocyte-associated protein). Also, in 2014 FDA approved PD-1 inhibitor pembrolizumab (trade name Keytruda ® , Merck Sharp & Dohme Corp.) which is used in cancer immunotherapy. It is an IgG4 isotype antibody that blocks a protective mechanism of cancer cells, and allows the immune system to destroy those cancer cells. Prof. J. Allison's research was fundamental. It focused on the question of how T cells worked in the fight against cancer cells because this basic knowledge was instrumental in developing the therapeutic aspects of immuno therapy. Prof. Tasuku Honjo (Department of Immunology at Kyoto University, Japan) and co-researchers discovered (1992) another protein PD-1 which functions in a similar way blocking the anticancer function of the immune system's T cells. Prof. Honjo and his co-workers performed research to unravel PD-1 role. Meticulously explored its function in elegant experiments performed over many years. The results showed that PD-1, similar to CTLA-4, functions as a T cell brake, but operates by a different mechanism. The 2018 Nobel prize was a justified reward for professors J. Allison and T. Honjo for their revolutionary approach to cancer treatment by using the capacity of the immune system. This review describes the process of the discovery and the drugs that were approved for the immunotherapy trteatment of cancer. The discovery of immunotherapy has become the fourth pillar of cancer treatment via the adaptive immune responses.. 2
... Most recently, cancer immunotherapy field is growing tremendously, such as utilization of cancer vaccinations, chimeric antigen receptor (CAR) T-cell therapy and immune checkpoint blockade therapy [10,11]. Several clinical trials have investigated their potentials in cancer patients lifesavings [12][13][14][15][16], and after witnessing the amazing effect of cancer immunotherapy it was selected as "2013's Breakthrough of the Year" by Science magazine [17]. ...
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In the past decades, our knowledge about the relationship between cancer and the immune system has increased considerably. Recent years' success of cancer immunotherapy including monoclonal antibodies (mAbs), cancer vaccines, adoptive cancer therapy and the immune checkpoint therapy has revolutionized traditional cancer treatment. However, challenges still exist in this field. Personalized combination therapies via new techniques will be the next promising strategies for the future cancer treatment direction.
... Introduction Activation of the immune system is a key component of mounting an effective durable anti-tumor response. The successful clinical use of checkpoint blockade antibodies to overcome immune suppressive mechanisms in the tumor microenvironment has transformed patient care [1][2][3][4][5]. However, most patients do not benefit from antagonist checkpoint blockade, suggesting that certain tumor microenvironments may require the addition of complementary immune agonist mechanisms to overcome tolerance and suppression [6]. ...
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Cytokines are potent immune modulating agents but are not ideal medicines in their natural form due to their short half-life and pleiotropic systemic effects. NKTR-214 is a clinical-stage biologic that comprises interleukin-2 (IL2) protein bound by multiple releasable polyethylene glycol (PEG) chains. In this highly PEG-bound form, the IL2 is inactive; therefore, NKTR- 214 is a biologic prodrug. When administered in vivo, the PEG chains slowly release, creating a cascade of increasingly active IL2 protein conjugates bound by fewer PEG chains. The 1-PEG-IL2 and 2-PEG-IL2 species derived from NKTR-214 are the most active conjugated- IL2 species. Free-IL2 protein is undetectable in vivo as it is eliminated faster than formed. The PEG chains on NKTR-214 are located at the region of IL2 that contacts the alpha (α) subunit of the heterotrimeric IL2 receptor complex, IL2Rαβγ, reducing its ability to bind and activate the heterotrimer. The IL2Rαβγ complex is constitutively expressed on regulatory T cells (Tregs). Therefore, without the use of mutations, PEGylation reduces the affinity for IL2Rαβγ to a greater extent than for IL2Rβγ, the receptor complex predominant on CD8 T cells. NKTR-214 treatment in vivo favors activation of CD8 T cells over Tregs in the tumor microenvironment to provide anti-tumor efficacy in multiple syngeneic models. Mechanistic modeling based on in vitro and in vivo kinetic data provides insight into the mechanism of NKTR-214 pharmacology. The model reveals that conjugated-IL2 protein derived from NKTR-214 occupy IL-2Rβγ to a greater extent compared to free-IL2 protein. The model accurately describes the sustained in vivo signaling observed after a single dose of NKTR- 214 and explains how the properties of NKTR-214 impart a unique kinetically-controlled immunological mechanism of action.
... Understanding the complex interplay and coevolution between the host immune system of different species and tumor cells can help to direct future treatments that harness the cytotoxic abilities of the immune system to seek and destroy neoplastic growths. Already, we are seeing a surge in clinical immunotherapy for cancer with great promise (Allison, 2015;Economopoulou et al., 2016;Jacob, 2015;Ribas, 2015;Sznol and Longo, 2015). ...
Increases in organismal complexity come at the cost of an increased likelihood of developing cancer. As complex multicellular organisms evolve, concomitant mechanisms of cancer suppression evolve as well. Over the evolutionary timescale, organisms with the ability to renew somatic tissue needed to evolve tumor suppressor mechanisms to regulate and control cellular proliferation in order to avoid unregulated cell growth leading to cancer. Cells invest in careful control of growth-promoting signals (i.e., growth inhibitors) and multiple cell-cycle checkpoints to coordinate orderly progression of cell division. Additionally, cells have multiple redundant pathways to reduce the risk of any errors in DNA replication and multiple DNA repair mechanisms when DNA damage does occur (e.g., DNA mismatch repair, double-stranded break repair). These mechanisms help sustain normal tissue architecture and function and dysregulation can lead to uncontrolled cellular proliferation and cellular growth, fundamental characteristics of cancer (Hanahan, D., Weinberg, R.A., 2011. Hallmarks of cancer: the next generation. Cell 144 (5), 646–674). In the first part of this chapter, we provide a brief overview of the mechanisms that complex multicellular organisms use to suppress neoplastic growth. We divide these areas of cancer defense mechanisms into three (nonmutually exclusive) main categories: (1) physical mechanisms, (2) molecular mechanisms, and (3) microenvironmental mechanisms. While majority of the work in the past has focused on the molecular mechanisms of cancer defense, we observe a trend in the past decade to focus on microenvironmental influences, and most recently, physical mechanisms, such as tissue architecture and stem cell dynamics. In the second part of this chapter, we discuss that despite hundreds of millions of years of multicellular evolution and cancer suppression, we still find reports of cancer in many organisms, which is likely due to trade-offs that may increase the organism’s fitness.
Background: Trials of immune checkpoint inhibitors (ICIs) have published patient-reported quality of life (QOL), but the size and heterogeneity of this literature can make patient education difficult. This meta-analysis aimed to describe change in QOL and symptomatology in patients receiving ICIs for cancer. Methods: Following PRISMA guidelines, databases were searched through November 2019 for articles or abstracts of prospective, original studies reporting longitudinal QOL in adult cancer patients treated with ICIs. The prespecified primary outcomes were change in global QOL among patients treated with ICIs and difference in change since baseline in global QOL between patients treated with ICI vs. non-ICI active treatment. Secondary outcomes included physical functioning and symptomatology. All statistical tests were 2-sided. Results: Twenty-six of 20,323 publications met inclusion criteria. Global QOL did not change over time in patients treated with ICIs (k = 26, n = 6,974, P = .19). Larger improvements in global QOL was observed in patients receiving ICI vs. non-ICI regimens (k = 16, ICI n = 3,588, non-ICI n = 2,948, P < .001). Physical functioning did not change in patients treated with ICIs (k = 14, n = 3,169, P=.47); there were no differences in mean change between ICI vs. non-ICI regimens (k = 11, n = 4,630, P=.94. Regarding symptoms, appetite loss, insomnia, and pain severity decreased but dyspnea severity increased in patients treated with ICIs (k = 14, n = 3,243-3,499) (Ps < 0.001). Insomnia severity was higher in patients treated with ICIs than non-ICI regimens (k = 11, n = 4,791) (P < .001). Conclusions: This study is among the first to quantitatively summarize QOL in patients treated with ICIs. Findings suggest ICI recipients report no change in global QOL and higher QOL than patients treated with non-ICI regimens.
Response assessment in malignant lymphoma has progressively evolved in the last 20 years, leading to continuous adaptations to clinical requirements and technology improvements. The latest challenge in treatment evaluation is represented by immunomodulatory drugs, capable of stimulating response to cancer by unleashing the immune system of the host. Despite the consolidated consensus on the use of Deauville score and Lugano criteria for the assessment of first-line therapeutic regimens, during other lines of treatment and, particularly, during the course of immunotherapy, response parameters and clinical evidence appear less clear.
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This chapter discusses the role of nanovesicles (NVs) in inflammation and coagulation, provide representative examples of their biological function and place them in clinical context. NVs are nanosized spherical vesicles defined by a lipid bilayer and continuously shed from the surfaces of both quiescent and stimulated cells. For years, the release of NVs by living cells has been considered a mechanism to dispose of unnecessary or damaged intracellular or membrane-bound molecules. Erythrocytes, leukocytes, platelets, and endothelial cells release NVs in blood, even under normal conditions. NVs convey intercellular signals either by the surface interactions or by the transfer of surface molecules and intravesicular content, such as mRNA, micro-RNA, proteins, lipids, and metabolites. The transfer of miRNA between malignant cells and cells of the immune system has widespread implications in cancer immunology. NVs released by dendritic cells might induce efficient T-cell immune response when loaded with a cognate antigen.
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Background: In patients with melanoma, ipilimumab (an antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) prolongs overall survival, and nivolumab (an antibody against the programmed death 1 [PD-1] receptor) produced durable tumor regression in a phase 1 trial. On the basis of their distinct immunologic mechanisms of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab combined with ipilimumab in patients with advanced melanoma. Methods: We administered intravenous doses of nivolumab and ipilimumab in patients every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (concurrent regimen). The combined treatment was subsequently administered every 12 weeks for up to 8 doses. In a sequenced regimen, patients previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses. Results: A total of 53 patients received concurrent therapy with nivolumab and ipilimumab, and 33 received sequenced treatment. The objective-response rate (according to modified World Health Organization criteria) for all patients in the concurrent-regimen group was 40%. Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ≥24 weeks) was observed in 65% of patients. At the maximum doses that were associated with an acceptable level of adverse events (nivolumab at a dose of 1 mg per kilogram of body weight and ipilimumab at a dose of 3 mg per kilogram), 53% of patients had an objective response, all with tumor reduction of 80% or more. Grade 3 or 4 adverse events related to therapy occurred in 53% of patients in the concurrent-regimen group but were qualitatively similar to previous experience with monotherapy and were generally reversible. Among patients in the sequenced-regimen group, 18% had grade 3 or 4 adverse events related to therapy and the objective-response rate was 20%. Conclusions: Concurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy, with rapid and deep tumor regression in a substantial proportion of patients. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; number, NCT01024231.).
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B7-H1 is an immunoglobulin-like immune suppressive molecule broadly detectable on the majority of human and rodent cancers, and its functions have been attributed to delivering an inhibitory signal to its counter-receptor programmed death-1 (PD-1) on T cells. Here we report that B7-H1 on cancer cells receives a signal from PD-1 to rapidly induce resistance against T cell-mediated killing because crippling signaling capacity of B7-H1 but not PD-1 ablates this resistance. Importantly, loss of B7-H1 signaling is accompanied by increased susceptibility to immune-mediated tumoricidal activity. In addition to resistance against T-cell destruction, B7-H1+ cancer cells also become refractory to apoptosis induced by Fas ligation or the protein kinase inhibitor Staurosporine. Our study reveals a new mechanism by which cancer cells use a receptor on immune cells as a ligand to induce resistance to therapy.
LBA9003^ Background: We report updated survival and clinical activity in initially enrolled cohorts and activity by BRAF MT status in a phase I trial of concurrent and sequenced NIVO + IPI. Methods: MEL pts (n=53, enrolled 2009-2012, data analysis Dec 2013) with ≤3 prior therapies received IV concurrent NIVO + IPI, Q3Wk × 4 doses, followed by NIVO Q3Wk × 4. At wk 24, NIVO + IPI continued Q12Wk × 8 in pts with disease control and no DLT. Tumor responses were evaluated by WHO and immune-related criteria. Results: Pt characteristics included stage M1c: 55% and prior systemic therapy: 40%. Across doses, 1- and 2-y OS rates were 82% and 75%. Clinical activity was similar to previous reports except CRs rose to 9/53 (17%). Pts with/without tumor BRAF MT (n=36) had similar activity (Table). By wk 36, 42% demonstrated ≥80% tumor reduction. Median duration of response (DOR) was not reached (NR). Of 22 pts with objective response, 14 (64%) had DOR ≥24 wk (range: 25+, 106+). Treatment-related adverse events were as reported previously: grade 3-4, 53% of pts; most common: ↑ lipase and AST (13% ea). Data for sequenced cohorts are shown (Table). Conclusions: Concurrent NIVO + IPI therapy showed encouraging survival and a manageable safety profile in advanced MEL pts. Responses were observed regardless of BRAF MT status and were durable in the majority of pts. Forty additional pts were enrolled (last pt: Nov 2013) on a cohort of NIVO 1 mg/kg + IPI 3 mg/kg Q3Wk × 4 doses, followed by NIVO 3mg/kg Q2Wk (the selected regimen for phase II/III trials). Clinical trial information: NCT01024231. [Table: see text]
Background: Preclinical studies suggest that Reed-Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. In classic Hodgkin's lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. We hypothesized that nivolumab, a PD-1-blocking antibody, could inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin's lymphoma. Methods: In this ongoing study, 23 patients with relapsed or refractory Hodgkin's lymphoma that had already been heavily treated received nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks until they had a complete response, tumor progression, or excessive toxic effects. Study objectives were measurement of safety and efficacy and assessment of the PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression. Results: Of the 23 study patients, 78% were enrolled in the study after a relapse following autologous stem-cell transplantation and 78% after a relapse following the receipt of brentuximab vedotin. Drug-related adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively. An objective response was reported in 20 patients (87%), including 17% with a complete response and 70% with a partial response; the remaining 3 patients (13%) had stable disease. The rate of progression-free survival at 24 weeks was 86%; 11 patients were continuing to participate in the study. Reasons for discontinuation included stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients). Analyses of pretreatment tumor specimens from 10 patients revealed copy-number gains in PDL1 and PDL2 and increased expression of these ligands. Reed-Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling. Conclusions: Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin's lymphoma. (Funded by Bristol-Myers Squibb and others; number, NCT01592370.).
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; number, NCT01597908.).
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 number, NCT01721772.).
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.