Immunotherapy in Nonmelanoma Skin Cancer | Actas Dermo-Sifiliográficas

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Bassas Freixas, G. Aparicio Español, V. García-Patos Briones" "autores" => array:3 [ 0 => array:4 [ "nombre" => "P." "apellidos" => "Bassas Freixas" "email" => array:1 [ 0 => "patriciabassas@hotmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "G." "apellidos" => "Aparicio Español" ] 2 => array:2 [ "nombre" => "V." "apellidos" => "García-Patos Briones" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Dermatología, Hospital Universitari Vall d’Hebron, Barcelona, España" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Inmunoterapia en cáncer cutáneo no melanoma" ] ] "resumenGrafico" => array:2 [ "original" => 1 "multimedia" => array:5 [ "identificador" => "fig0015" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx1.jpeg" "Alto" => 658 "Ancho" => 1333 "Tamanyo" => 56428 ] ] ] ] "textoCompleto" => "IntroductionThe interaction between tumor initiation and propagation strategies and host antitumor mechanisms is key in the development of cancer. The concept of immune surveillance refers to the mechanism by which the immune system can recognize and eliminate tumor cells. However, tumors use a range of mechanisms to evade detection and so persist.The most important antitumor immune activity is that mediated by cell response. The process of T-cell activation requires 2 signals, an initial one mediated by recognition of an antigen presented by the major histocompatibility complex to the T cell receptor (TCR), and a second signal, known as a coregulatory signal, which modulates clonal expansion and a specific effector response. The coregulatory molecules are essential glycoproteins for communication between T cells and other immune cells; there are costimulatory molecules that trigger T-cell activation and other coinhibitory ones that minimize the damage to healthy tissue (peripheral tolerance mechanism).<a class="elsevierStyleCrossRef" href="#bib0220">1</a> Among these coinhibitory molecules, cytotoxic T lymphocyte associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and its corresponding ligand (PD-L1) are of particular note.One of the mechanisms of action of immune therapies for cancer is recruitment of immune cells to the tumor microenvironment and/or block of coinhibitory molecules, thereby enhancing antitumor cell response. Drugs that target the CTLA-4 and PD-1/PD-L1 axes are thus gaining traction in the treatment of a range of skin tumors such as malignant melanoma (MM), Merkel cell carcinoma (MCC), and, more recently, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC).Cytotoxic T Lymphocyte AntigenCTLA-4 belongs to the immunoglobin superfamily of coinhibitory receptors. It is expressed on the surface of T cells between 24 and 48h after activation. In a first phase of immune response, antigen presenting cells (APCs) expose tumor antigens to T cells in lymphoid tissue. The T-cell receptors, CTLA-4 (inhibitory molecule) and CD28 (stimulatory molecule) compete to bind with the B7-1 (CD80) and B7-2 (CD86) molecules of the APCs. Binding of CTLA-4 to its B7 ligand triggers an inhibitory signal that blocks T-cell response in early phases of lymph node priming (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0225">2,3</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>CTLA-4 is also implicated in other immune surveillance processes. Regulatory T cells (Treg) are a T-cell subpopulation that play a key role in the prevention of autoimmunity, promoting immune tolerance to autoantigens. They constitutively express CTLA-4 and exercise their suppressor function on CD4+an CD8+autoreactive T cells through a range of mechanisms, including secretion of regulatory cytokines.<a class="elsevierStyleCrossRef" href="#bib0225">2</a> However, their presence in peritumoral and intratumoral infiltrate can suppress the effector function of tumor-specific CD4+and CD8+T-cells, enabling tumor development.Ipilimumab (Yervoy®) and tremelimumab were the first antibodies used, in 2000, to block the CTLA-4 receptor and maintain the activity of specific T-cells in patients with advanced cancer, including MM.<a class="elsevierStyleCrossRef" href="#bib0235">4</a> Since its introduction, CTLA-4 blockade in patients with metastatic MM has achieved radiological response in 15% and lasting response of more than 10 years in some patients.<a class="elsevierStyleCrossRefs" href="#bib0235">4,5</a> Later, ipilimumab demonstrated longer survival in patients treated with this agent compared with those on conventional chemotherapy with dacarbazine and glycoprotein 100 peptide vaccine in 2 phase 3 studies.<a class="elsevierStyleCrossRefs" href="#bib0245">6,7</a> It was approved by the American Food and Drug Administration (FDA) in 2011 for the treatment of advanced MM and a few months later, the European Medicines Agency (EMA) also granted approval. In the phase 3 study of tremelimumab, no significant differences were found compared with chemotherapy, and so this agent is not available for use in MM, but its application in other types of tumors is under investigation.Programmed Cell Death 1 Protein and Its LigandIn healthy tissue, the PD-1 pathway in T cells regulates immune response to minimize damage to adjacent tissue and prevent autoimmunity from developing by enhancing autoallergen tolerance. PD-1 (or CD279) is a cosignalling immune receptor expressed by activated T cells. It operates essentially in peripheral tissues where T cells are brought into contact with their immunosuppressive ligands, PD-L1 (or B7-H1 or CD274) and PD-L2 (programmed cell death 1 protein ligand 2 or B7-DC). PD-L2 is expressed by APCs and epithelial cells, whereas PD-L1 is expressed by a wide range of immune and nonimmune cells, including some tumor cells, as a response to certain proinflammatory cytokines (interferon γ) or oncogenic processes caused by activating mutations. Binding of PD-1 to PD-L1 inhibits the production of several cytokines (interferon γ, tumor necrosis factor α, interleukin 2) and T-cell proliferation, and triggers T-cell apoptosis.<a class="elsevierStyleCrossRefs" href="#bib0225">2,8–11</a>Inhibition of this pathway can occur through block of PD-1, such that binding to both PD-L1 and PD-L2 is inhibited, or through block of PD-L1, which would only block interaction with PD-1. Currently, there are 5 anti-PD-1 or anti-PD-L1 antibodies approved by the FDA for treatment of 11 types cancer: nivolumab (Opdivo®), pembrolizumab (Keytruda®), atezolizumab (Tecentriq®), durvalumab (Imfinzi®), and avelumab (Bavencio®). The first ones to be approved in 2014 were nivolumab and pembrolizumab for the treatment of patients with advanced MM (unresectable or metastatic). In 2017, avelumab was approved for the treatment of patients with metastatic MCC (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>, <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia>Although these treatments provide hope for patients with advanced tumors, many do not respond. Strategies are being designed to improve response to prolong disease-free survival by testing combinations of drugs.<a class="elsevierStyleCrossRefs" href="#bib0275">12–14</a> Block of the PD-1/PD-L1 axis leads to a greater antitumor effect and lower toxicity than block of the CTLA-4 axis, given that this latter axis plays a role in the first phase of immune response. Among the most frequent side effects, of note are those related to autoimmunity in nontumor cells. In most cases, the effects are self-limiting or resolve with immunosuppressive treatment such as corticosteroids. It appears that the type of tumor, associated diseases, and prior treatments administered influence the profile of side effects arising with these therapies.<a class="elsevierStyleCrossRef" href="#bib0290">15</a> The combination of inhibitory treatments targeting these immune checkpoints to enhance the antitumor effect leads to a higher number of immune-mediated adverse effects, some of which are potentially serious.<a class="elsevierStyleCrossRef" href="#bib0275">12</a> Currently, the combination of nivolumab and ipilimumab is approved by the EMA for the treatment of advanced MM in adults.Immunotherapy in Nonmelanoma Skin CancerImmunotherapy for nonmelanoma skin cancer (NMSC) is emerging as a promising therapeutic tool. This type of therapy is used in the treatment of locally advanced and metastatic MCC, SCC, BCC, and occasionally in cutaneous angiosarcoma.<a class="elsevierStyleCrossRef" href="#bib0295">16</a>Immunotherapy in Merkel Cell CarcinomaMCC is an uncommon and aggressive neuroendocrine tumor, with a higher mortality rate (30%) than MM.<a class="elsevierStyleCrossRef" href="#bib0300">17</a> It is associated with a polyomavirus in 80% of cases and has a low mutational load, unlike ultraviolet-induced MCC, which has no relationship with polyomavirus and many more genetic abnormalities.<a class="elsevierStyleCrossRef" href="#bib0305">18</a> Traditionally, patients with disseminated disease receive chemotherapy. According to published results, nivolumab, avelumab, and pembrolizumab are currently preferred alternatives in patients with metastatic diseases. Longer-lasting response than that offered by conventional chemotherapy (in which disease-free survival is only 3 months) has been demonstrated.<a class="elsevierStyleCrossRefs" href="#bib0305">18–20</a>Pembrolizumab was the first inhibitor of an immune checkpoint to show objective tumor regression in patients with advanced MCC in a phase 2, uncontrolled, multicenter study that included 26 patients who had not received chemotherapy. The objective response rate was 56% and complete response was reported in 16%. Among responders, the duration of response was variable, ranging from 2.2 and 9.7 months, and progression-free survival was 67% at 6 months. Interestingly, it was effective in polyomavirus-positive and -negative tumors and immunohistochemical expression of PD-L1 was not correlated with a greater probability of response to treatment.<a class="elsevierStyleCrossRef" href="#bib0305">18</a> According to the findings of a retrospective study presented at the American Society of Clinical Oncology (ASCO) this year, the presence of a high mutational load and prolonged exposure to UV are associated with a higher response rate to immunotherapy, but no association was found with presence or absence of Merkel cell polyomavirus.<a class="elsevierStyleCrossRef" href="#bib0320">21</a>In March 2017, the FDA approved the first anti-PD-L1 monoclonal antibody, avelumab (Bavencio®), for the treatment of patients with metastatic MCC, on the basis of results from the JAVELIN Merkel 200 clinical trial.<a class="elsevierStyleCrossRef" href="#bib0310">19</a>Immunotherapy in Squamous Cell CarcinomaAs with MCC, SCC is also an immunogenic tumor considered a good candidate for immunotherapy treatment. There is evidence that PD-L1 and PD-L2 play an important role in tumor progression, and so they are considered possible therapeutic targets.<a class="elsevierStyleCrossRefs" href="#bib0325">22,23</a> Experience with the use of immunotherapy in oncology in this tumor is limited to anecdotal observations and the preliminary results of some clinical trials. All these encourage further study.<a class="elsevierStyleCrossRefs" href="#bib0335">24,25</a>Of note is an article published in April 2017 in which 38 biopsies of patients with SCC were evaluated with NanoString technology, which allows study of messenger RNA (mRNA) expression in paraffin-embedded tumor samples. Ten samples of SCC with perineural invasion, 12 infiltrating tumors, 6 superficial tumors, 10 tumors from solid organ transplant recipients (SOTR) and 7 samples from normal skin as control were selected. Of all the subgroups, those with greatest expression of PD-1 and PD-L2 compared to controls were those SCC samples with perineural invasion. Greater expression of PD-1 was also observed in samples from stage 2B SCC (2 of the 3 high-risk factors for metastasis, recurrence, or death) and stage 3 SCC (4 additional high-risk factors for metastasis, recurrence, or death) according to the Brigham and Women's Hospital Tumor Staging. The findings from study of mRNA coding for PD-1 and PD-L2 were correlated with their immunohistochemical expression in tumor samples. The authors concluded that SCC samples express higher levels of PD-1 and their ligands (PD-L1 and PD-L2) than samples of normal skin. Perhaps blockade of PD-L1 with monoclonal antibodies is useful for activating host immune response to the tumor and offers a therapeutic alternative to patients with advanced and/or metastatic SCC without any other treatment options. Considering the above, immunohistochemical expression of PD-L1 could be a biomarker to identify those patients who may stand to benefit from these drugs.<a class="elsevierStyleCrossRef" href="#bib0345">26</a>At this year's ASCO meeting, the preliminary results were presented of a phase 2 study in which 59 patients with metastatic SCC had been treated with cemiplimab (anti-PD-1). The objective response rate was 47.5% (28 out of 59 patients), with a response duration of more than 6 months in 57% of responders and an acceptable safety profile.<a class="elsevierStyleCrossRef" href="#bib0350">27</a> These results have been published recently.<a class="elsevierStyleCrossRef" href="#bib0355">28</a>Immunotherapy in Basal Cell CarcinomaAlthough the different subtypes of BCC have aberrant activation of the Hedgehog signaling pathway in common, the immune system may play an important role in the development of some of these tumors. There are several observations that point to the importance of antitumoral immunity in BCC. First, RUV-B, one of the main pathogenic factors, has long-term immunosuppressive effects, mainly T-cell-mediated immune reactions.<a class="elsevierStyleCrossRef" href="#bib0360">29</a> It also induces the production of CD4/CD25+T regulatory cells able to inhibit antitumor effector functions and favor an immunosuppressive microenvironment.<a class="elsevierStyleCrossRefs" href="#bib0360">29–31</a> Second, SOTRs are at 10 to 16 times higher risk of developing BCC than the general population. These figures increase with increasing extent and duration of immunosuppressive therapy. These are the most aggressive, invasive, and recurrent tumors.<a class="elsevierStyleCrossRefs" href="#bib0360">29,32</a> Third, partial spontaneous regression is a relatively common phenomenon in BCC, but one that has not been extensively studied. It appears that secretion of certain cytokines by activated CD4+T-cells could induce an antitumor response.<a class="elsevierStyleCrossRefs" href="#bib0380">33–35</a> Fourth, we often find accompanying peritumoral infiltrate, formed mainly of T cells, although little is known of the significance of this finding. Finally, topical immunomodulators are curative therapeutic options in some cases of BCC.There are few publications on the role of antibodies against immunological molecular targets for the treatment of patients with locally advanced and metastatic BCC. In January 2016, Mohan et al.<a class="elsevierStyleCrossRef" href="#bib0395">36</a> reported the case of a patient with metastatic MM treated with ipilimumab in whom incidental regression of locally advanced BCC was observed. Later, Ikeda et al.<a class="elsevierStyleCrossRef" href="#bib0400">37</a> published a similar case. The patient was a 58-year-old man with metastatic BCC, with bone, lung, brain, and hepatic involvement, who had received several treatments (vismodegib, cisplatin, paclitaxel, sonidegib, and buparlisib), all discontinued due to disease progression or toxicity. Intravenous nivolumab was administered every 2 weeks and after 4 months, almost complete resolution of the hepatic metastases was observed. In another patient with metastatic BCC in treatment with pembrolizumab, the disease remained stable for months.<a class="elsevierStyleCrossRef" href="#bib0405">38</a> In November 2016, Falchook et al.<a class="elsevierStyleCrossRef" href="#bib0410">39</a> published the case of another metastatic BCC treated with REGN2810, a monoclonal anti-PD-1 antibody in a phase 1 study (NCT02383212), with partial and sustained response. Shortly afterwards, Borradori et al.<a class="elsevierStyleCrossRef" href="#bib0415">40</a> presented the case of a patient with basosquamous carcinoma with lung metastases treated with nivolumab who maintained stable disease for a few months. Finally, Lipson et al.<a class="elsevierStyleCrossRef" href="#bib0420">41</a> published the case of a patient with locally advanced BCC for whom surgery was not an option and who had been treated previously with radiotherapy and a Hedgehog pathway inhibitor. She started treatment with intravenous pembrolizumab 2mg/kg every 3 weeks for 14 weeks, with partial sustained response. It is worth noting that the immunohistochemical study before starting treatment only showed PD-L1 expression in immune cells, not in tumor cells, and that approximately 50% of T cells expressed PD-1 (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Currently, there are 2 ongoing studies with immune control proteins in BCC; in the first, a PD-1 inhibitor (REGN2810) is being used in patients with locally advanced or metastatic BCC not responsive or refractory to Hedgehog signaling pathway inhibitors, and in the second, nivolumab is being used in monotherapy or in combination with ipilimumab in patients with unresectable locally advanced BCC or metastatic disease.<a class="elsevierStyleCrossRefs" href="#bib0425">42,43</a>ConclusionsEnhancement of the immune system in the treatment of cancer is shaping up as an effective and promising alternative. As dermatologists, we have experience with these therapies in patients with advanced MM and, more recently, in MCC. It is worth focusing our efforts on common tumors such as BCC and SCC and conducting controlled studies to investigate their efficacy, as such agents may be a therapeutic alternative for some patients. We should also try to identify biomarkers that could enable us to select those patients who may benefit from these treatments, in monotherapy or in combination, and thus avoid side effects on those expected to be nonresponders.Conflicts of InterestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:15 [ 0 => array:3 [ "identificador" => "xres1199769" "titulo" => "Graphical abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:3 [ "identificador" => "xres1199770" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 2 => array:2 [ "identificador" => "xpalclavsec1118212" "titulo" => "Keywords" ] 3 => array:3 [ "identificador" => "xres1199771" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0015" ] ] ] 4 => array:2 [ "identificador" => "xpalclavsec1118213" "titulo" => "Palabras clave" ] 5 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 6 => array:2 [ "identificador" => "sec0010" "titulo" => "Cytotoxic T Lymphocyte Antigen" ] 7 => array:2 [ "identificador" => "sec0015" "titulo" => "Programmed Cell Death 1 Protein and Its Ligand" ] 8 => array:2 [ "identificador" => "sec0020" "titulo" => "Immunotherapy in Nonmelanoma Skin Cancer" ] 9 => array:2 [ "identificador" => "sec0025" "titulo" => "Immunotherapy in Merkel Cell Carcinoma" ] 10 => array:2 [ "identificador" => "sec0030" "titulo" => "Immunotherapy in Squamous Cell Carcinoma" ] 11 => array:2 [ "identificador" => "sec0035" "titulo" => "Immunotherapy in Basal Cell Carcinoma" ] 12 => array:2 [ "identificador" => "sec0040" "titulo" => "Conclusions" ] 13 => array:2 [ "identificador" => "sec0045" "titulo" => "Conflicts of Interest" ] 14 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-06-13" "fechaAceptado" => "2018-09-03" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1118212" "palabras" => array:5 [ 0 => "Nonmelanoma skin cancer" 1 => "Immunotherapy" 2 => "Programmed cell death protein 1 (PD-1)" 3 => "Programmed death ligand 1 (PD-L1)" 4 => "Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1118213" "palabras" => array:5 [ 0 => "Cáncer cutáneo no melanoma" 1 => "Inmunoterapia" 2 => "Molécula" 3 => "Ligando" 4 => "Antígeno citotóxico de los linfocitos T (CTLA-4)" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Immunotherapy is emerging as a new and promising treatment for a great variety of tumors, including nonmelanoma skin cancer. Checkpoint inhibitors —antibodies that block proteins that regulate the immune system—mainly target the surface protein CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4) and the PD-1/PD-L1 (programmed cell death protein 1/PD-ligand 1) axis. We review the CTLA-4 and PD-1/PD-L1 pathways and current evidence supporting checkpoint inhibitor therapy in the main types of nonmelanoma skin cancer." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La inmunoterapia en el cáncer emerge como un tratamiento novedoso y prometedor en una gran variedad de tumores, incluido el cáncer cutáneo no melanoma. Los anticuerpos inhibidores de proteínas de control inmunitario están dirigidos fundamentalmente a las moléculas de superficie CTLA-4 (antígeno citotóxico de los linfocitos T) y PD-1 (molécula de muerte programada 1). En el presente artículo se revisan las vías de CTLA-4 y PD-1/PD-L1 (PD-1/ligando de la PD-1) y las evidencias actuales de tratamiento con inhibidores de puntos de control inmunitario en los principales tipos de cáncer cutáneo no melanoma." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Bassas Freixas P, Aparicio Español G, García-Patos Briones V. Inmunoterapia en cáncer cutáneo no melanoma. Actas Dermosifiliogr. 2019;110:353–359." ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1365 "Ancho" => 1504 "Tamanyo" => 122938 ] ] "descripcion" => array:1 [ "en" => "Schematic representation of T cell activation after interaction between the T-cell receptor and major histocompatibility complex and between B7 costimulatory molecules and CD28 (top panel). Inhibition of response after binding of cytotoxic T lymphocyte antigen to B7 (bottom panel). Abbreviations APC: antigen presenting cells; CD28 cluster of differentiation 28; CTLA-4: cytotoxic T lymphocyte antigen; TCR: T-cell receptor; MHC: major histocompatibility complex." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 744 "Ancho" => 1504 "Tamanyo" => 71424 ] ] "descripcion" => array:1 [ "en" => "Schematic representation of T cell inhibition mediated by programmed cell death 1 protein ligand. Binding of programmed cell death 1 protein to its corresponding ligand inhibits the positive signal mediated by interaction between the T cell receptor and major histocompatibility complex. Nivolumab and pembrolizumab bind to PD-1. Atezolizumab, avelumab, and durvalumab bind to PD-L1. Abbreviations MHC: major histocompatibility complex; PD-1: programmed cell death 1 protein; PD-L1: programmed death ligand 1; TCR: T cell receptor." ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: HNSCC, head and neck squamous cell carcinoma; MCC, Merkel cell carcinoma; MM, malignant melanoma; NSCLC, nonsmall cell lung cancer; RCC, renal cell carcinoma; PD-1, programmed cell death 1 protein; PD-L1, programmed death ligand 1." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Antibody \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Specificity \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Indication \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nivolumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-PD-1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Classic Hodgkin lymphoma, MM, NSCLC, HNSCC, RCC, urothelial carcinoma \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pembrolizumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-PD-1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NSCLC, MM, classic Hodgkin lymphoma, urothelial carcinoma \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Atezolizumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-PD-L1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NSCLC, urothelial carcinoma \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Avelumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-PD-L1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MCC \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Durvalumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-PD-L1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NSCLC (pending definitive approval) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2049321.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Anti-PD-1 or Anti-PD-L1 Agents Approved by the European Medicines Agency." ] ] 3 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: BCC, basal cell carcinoma; CTLA-4, cytotoxic T lymphocyte antigen; laBCC, locally advanced basal cell carcinoma; mBCC, metastatic basal cell carcinoma; MM, malignant melanoma; PD-1, programmed cell death 1 protein; PR, partial response; SD, stable disease." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Author \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Year \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Treatment \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mechanism of Action \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Duration \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No. Patients \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Tumor \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Response \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ikeda et al. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2016 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nivolumab 240mg/2 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-PD-1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">mBCC (head, liver, lung, and bone) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PR (liver metastasis) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mohan et al.</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2016</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ipilimumab (3mg/kg/3 weeks)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-CTLA-4</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 weeks</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">laBCC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PR</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Metastatic MM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Falchook et al. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2016 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">REGN2810 (10mg/kg/2 weeks) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-PD-1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">48 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">mBCC (lung) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PR \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Borradori et al. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2016 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nivolumab (3mg/kg/3 weeks) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-PD-1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Basosquamous carcinoma with lung metastasis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SD (lung) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Winkler et al.</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2017</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pembrolizumab</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 cycles (12-16 weeks)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">mBCC (lung)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SD (pulmonary) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sarcoidosis-like granulomatous reaction \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lipson et al.</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2017</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pembrolizumab (2mg/kg/3 weeks)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-PD-1</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14 weeks</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">laBCC</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PR \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Subclinical hypothyroidism \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2049322.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Summary of BCC Treated With Immune Control Proteins." ] ] 4 => array:5 [ "identificador" => "fig0015" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx1.jpeg" "Alto" => 658 "Ancho" => 1333 "Tamanyo" => 56428 ] ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:43 [ 0 => array:3 [ "identificador" => "bib0220" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "B.T. 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Novelties in Dermatology

Immunotherapy in Nonmelanoma Skin Cancer

Inmunoterapia en cáncer cutáneo no melanoma

P. Bassas Freixas

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patriciabassas@hotmail.com

Corresponding author.

, G. Aparicio Español, V. García-Patos Briones

Servicio de Dermatología, Hospital Universitari Vall d’Hebron, Barcelona, España

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The interaction between tumor initiation and propagation strategies and host antitumor mechanisms is key in the development of cancer&#46; The concept of <span class="elsevierStyleItalic">immune surveillance</span> refers to the mechanism by which the immune system can recognize and eliminate tumor cells&#46; However&#44; tumors use a range of mechanisms to evade detection and so persist&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The most important antitumor immune activity is that mediated by cell response&#46; The process of T-cell activation requires 2 signals&#44; an initial one mediated by recognition of an antigen presented by the major histocompatibility complex to the T cell receptor &#40;TCR&#41;&#44; and a second signal&#44; known as a coregulatory signal&#44; which modulates clonal expansion and a specific effector response&#46; The coregulatory molecules are essential glycoproteins for communication between T cells and other immune cells&#59; there are costimulatory molecules that trigger T-cell activation and other coinhibitory ones that minimize the damage to healthy tissue &#40;peripheral tolerance mechanism&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">1</span></a> Among these coinhibitory molecules&#44; cytotoxic T lymphocyte associated protein 4 &#40;CTLA-4&#41;&#44; programmed cell death protein 1 &#40;PD-1&#41;&#44; and its corresponding ligand &#40;PD-L1&#41; are of particular note&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">One of the mechanisms of action of immune therapies for cancer is recruitment of immune cells to the tumor microenvironment and&#47;or block of coinhibitory molecules&#44; thereby enhancing antitumor cell response&#46; Drugs that target the CTLA-4 and PD-1&#47;PD-L1 axes are thus gaining traction in the treatment of a range of skin tumors such as malignant melanoma &#40;MM&#41;&#44; Merkel cell carcinoma &#40;MCC&#41;&#44; and&#44; more recently&#44; squamous cell carcinoma &#40;SCC&#41; and basal cell carcinoma &#40;BCC&#41;&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Cytotoxic T Lymphocyte Antigen</span><p id="par0020" class="elsevierStylePara elsevierViewall">CTLA-4 belongs to the immunoglobin superfamily of coinhibitory receptors&#46; It is expressed on the surface of T cells between 24 and 48<span class="elsevierStyleHsp" style=""></span>h after activation&#46; In a first phase of immune response&#44; antigen presenting cells &#40;APCs&#41; expose tumor antigens to T cells in lymphoid tissue&#46; The T-cell receptors&#44; CTLA-4 &#40;inhibitory molecule&#41; and CD28 &#40;stimulatory molecule&#41; compete to bind with the B7-1 &#40;CD80&#41; and B7-2 &#40;CD86&#41; molecules of the APCs&#46; Binding of CTLA-4 to its B7 ligand triggers an inhibitory signal that blocks T-cell response in early phases of lymph node priming &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">2&#44;3</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">CTLA-4 is also implicated in other immune surveillance processes&#46; Regulatory T cells &#40;Treg&#41; are a T-cell subpopulation that play a key role in the prevention of autoimmunity&#44; promoting immune tolerance to autoantigens&#46; They constitutively express CTLA-4 and exercise their suppressor function on CD4<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>an CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>autoreactive T cells through a range of mechanisms&#44; including secretion of regulatory cytokines&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">2</span></a> However&#44; their presence in peritumoral and intratumoral infiltrate can suppress the effector function of tumor-specific CD4<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>and CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>T-cells&#44; enabling tumor development&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Ipilimumab &#40;Yervoy&#174;&#41; and tremelimumab were the first antibodies used&#44; in 2000&#44; to block the CTLA-4 receptor and maintain the activity of specific T-cells in patients with advanced cancer&#44; including MM&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">4</span></a> Since its introduction&#44; CTLA-4 blockade in patients with metastatic MM has achieved radiological response in 15&#37; and lasting response of more than 10 years in some patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">4&#44;5</span></a> Later&#44; ipilimumab demonstrated longer survival in patients treated with this agent compared with those on conventional chemotherapy with dacarbazine and glycoprotein 100 peptide vaccine in 2 phase 3 studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">6&#44;7</span></a> It was approved by the American Food and Drug Administration &#40;FDA&#41; in 2011 for the treatment of advanced MM and a few months later&#44; the European Medicines Agency &#40;EMA&#41; also granted approval&#46; In the phase 3 study of tremelimumab&#44; no significant differences were found compared with chemotherapy&#44; and so this agent is not available for use in MM&#44; but its application in other types of tumors is under investigation&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Programmed Cell Death 1 Protein and Its Ligand</span><p id="par0035" class="elsevierStylePara elsevierViewall">In healthy tissue&#44; the PD-1 pathway in T cells regulates immune response to minimize damage to adjacent tissue and prevent autoimmunity from developing by enhancing autoallergen tolerance&#46; PD-1 &#40;or CD279&#41; is a cosignalling immune receptor expressed by activated T cells&#46; It operates essentially in peripheral tissues where T cells are brought into contact with their immunosuppressive ligands&#44; PD-L1 &#40;or B7-H1 or CD274&#41; and PD-L2 &#40;programmed cell death 1 protein ligand 2 or B7-DC&#41;&#46; PD-L2 is expressed by APCs and epithelial cells&#44; whereas PD-L1 is expressed by a wide range of immune and nonimmune cells&#44; including some tumor cells&#44; as a response to certain proinflammatory cytokines &#40;interferon &#947;&#41; or oncogenic processes caused by activating mutations&#46; Binding of PD-1 to PD-L1 inhibits the production of several cytokines &#40;interferon &#947;&#44; tumor necrosis factor &#945;&#44; interleukin 2&#41; and T-cell proliferation&#44; and triggers T-cell apoptosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">2&#44;8&#8211;11</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Inhibition of this pathway can occur through block of PD-1&#44; such that binding to both PD-L1 and PD-L2 is inhibited&#44; or through block of PD-L1&#44; which would only block interaction with PD-1&#46; Currently&#44; there are 5 anti-PD-1 or anti-PD-L1 antibodies approved by the FDA for treatment of 11 types cancer&#58; nivolumab &#40;Opdivo&#174;&#41;&#44; pembrolizumab &#40;Keytruda&#174;&#41;&#44; atezolizumab &#40;Tecentriq&#174;&#41;&#44; durvalumab &#40;Imfinzi&#174;&#41;&#44; and avelumab &#40;Bavencio&#174;&#41;&#46; The first ones to be approved in 2014 were nivolumab and pembrolizumab for the treatment of patients with advanced MM &#40;unresectable or metastatic&#41;&#46; In 2017&#44; avelumab was approved for the treatment of patients with metastatic MCC &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#44; <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">Although these treatments provide hope for patients with advanced tumors&#44; many do not respond&#46; Strategies are being designed to improve response to prolong disease-free survival by testing combinations of drugs&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">12&#8211;14</span></a> Block of the PD-1&#47;PD-L1 axis leads to a greater antitumor effect and lower toxicity than block of the CTLA-4 axis&#44; given that this latter axis plays a role in the first phase of immune response&#46; Among the most frequent side effects&#44; of note are those related to autoimmunity in nontumor cells&#46; In most cases&#44; the effects are self-limiting or resolve with immunosuppressive treatment such as corticosteroids&#46; It appears that the type of tumor&#44; associated diseases&#44; and prior treatments administered influence the profile of side effects arising with these therapies&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">15</span></a> The combination of inhibitory treatments targeting these immune checkpoints to enhance the antitumor effect leads to a higher number of immune-mediated adverse effects&#44; some of which are potentially serious&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">12</span></a> Currently&#44; the combination of nivolumab and ipilimumab is approved by the EMA for the treatment of advanced MM in adults&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Immunotherapy in Nonmelanoma Skin Cancer</span><p id="par0050" class="elsevierStylePara elsevierViewall">Immunotherapy for nonmelanoma skin cancer &#40;NMSC&#41; is emerging as a promising therapeutic tool&#46; This type of therapy is used in the treatment of locally advanced and metastatic MCC&#44; SCC&#44; BCC&#44; and occasionally in cutaneous angiosarcoma&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Immunotherapy in Merkel Cell Carcinoma</span><p id="par0055" class="elsevierStylePara elsevierViewall">MCC is an uncommon and aggressive neuroendocrine tumor&#44; with a higher mortality rate &#40;30&#37;&#41; than MM&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">17</span></a> It is associated with a polyomavirus in 80&#37; of cases and has a low mutational load&#44; unlike ultraviolet-induced MCC&#44; which has no relationship with polyomavirus and many more genetic abnormalities&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">18</span></a> Traditionally&#44; patients with disseminated disease receive chemotherapy&#46; According to published results&#44; nivolumab&#44; avelumab&#44; and pembrolizumab are currently preferred alternatives in patients with metastatic diseases&#46; Longer-lasting response than that offered by conventional chemotherapy &#40;in which disease-free survival is only 3 months&#41; has been demonstrated&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">18&#8211;20</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Pembrolizumab was the first inhibitor of an immune checkpoint to show objective tumor regression in patients with advanced MCC in a phase 2&#44; uncontrolled&#44; multicenter study that included 26 patients who had not received chemotherapy&#46; The objective response rate was 56&#37; and complete response was reported in 16&#37;&#46; Among responders&#44; the duration of response was variable&#44; ranging from 2&#46;2 and 9&#46;7 months&#44; and progression-free survival was 67&#37; at 6 months&#46; Interestingly&#44; it was effective in polyomavirus-positive and -negative tumors and immunohistochemical expression of PD-L1 was not correlated with a greater probability of response to treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">18</span></a> According to the findings of a retrospective study presented at the American Society of Clinical Oncology &#40;ASCO&#41; this year&#44; the presence of a high mutational load and prolonged exposure to UV are associated with a higher response rate to immunotherapy&#44; but no association was found with presence or absence of Merkel cell polyomavirus&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">21</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">In March 2017&#44; the FDA approved the first anti-PD-L1 monoclonal antibody&#44; avelumab &#40;Bavencio&#174;&#41;&#44; for the treatment of patients with metastatic MCC&#44; on the basis of results from the JAVELIN Merkel 200 clinical trial&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">19</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Immunotherapy in Squamous Cell Carcinoma</span><p id="par0070" class="elsevierStylePara elsevierViewall">As with MCC&#44; SCC is also an immunogenic tumor considered a good candidate for immunotherapy treatment&#46; There is evidence that PD-L1 and PD-L2 play an important role in tumor progression&#44; and so they are considered possible therapeutic targets&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">22&#44;23</span></a> Experience with the use of immunotherapy in oncology in this tumor is limited to anecdotal observations and the preliminary results of some clinical trials&#46; All these encourage further study&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">24&#44;25</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Of note is an article published in April 2017 in which 38 biopsies of patients with SCC were evaluated with NanoString technology&#44; which allows study of messenger RNA &#40;mRNA&#41; expression in paraffin-embedded tumor samples&#46; Ten samples of SCC with perineural invasion&#44; 12 infiltrating tumors&#44; 6 superficial tumors&#44; 10 tumors from solid organ transplant recipients &#40;SOTR&#41; and 7 samples from normal skin as control were selected&#46; Of all the subgroups&#44; those with greatest expression of PD-1 and PD-L2 compared to controls were those SCC samples with perineural invasion&#46; Greater expression of PD-1 was also observed in samples from stage 2<span class="elsevierStyleHsp" style=""></span>B SCC &#40;2 of the 3 high-risk factors for metastasis&#44; recurrence&#44; or death&#41; and stage 3 SCC &#40;4 additional high-risk factors for metastasis&#44; recurrence&#44; or death&#41; according to the Brigham and Women&#39;s Hospital Tumor Staging&#46; The findings from study of mRNA coding for PD-1 and PD-L2 were correlated with their immunohistochemical expression in tumor samples&#46; The authors concluded that SCC samples express higher levels of PD-1 and their ligands &#40;PD-L1 and PD-L2&#41; than samples of normal skin&#46; Perhaps blockade of PD-L1 with monoclonal antibodies is useful for activating host immune response to the tumor and offers a therapeutic alternative to patients with advanced and&#47;or metastatic SCC without any other treatment options&#46; Considering the above&#44; immunohistochemical expression of PD-L1 could be a biomarker to identify those patients who may stand to benefit from these drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">26</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">At this year&#39;s ASCO meeting&#44; the preliminary results were presented of a phase 2 study in which 59 patients with metastatic SCC had been treated with cemiplimab &#40;anti-PD-1&#41;&#46; The objective response rate was 47&#46;5&#37; &#40;28 out of 59 patients&#41;&#44; with a response duration of more than 6 months in 57&#37; of responders and an acceptable safety profile&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">27</span></a> These results have been published recently&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">28</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Immunotherapy in Basal Cell Carcinoma</span><p id="par0085" class="elsevierStylePara elsevierViewall">Although the different subtypes of BCC have aberrant activation of the Hedgehog signaling pathway in common&#44; the immune system may play an important role in the development of some of these tumors&#46; There are several observations that point to the importance of antitumoral immunity in BCC&#46; First&#44; RUV-B&#44; one of the main pathogenic factors&#44; has long-term immunosuppressive effects&#44; mainly T-cell-mediated immune reactions&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">29</span></a> It also induces the production of CD4&#47;CD25<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>T regulatory cells able to inhibit antitumor effector functions and favor an immunosuppressive microenvironment&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">29&#8211;31</span></a> Second&#44; SOTRs are at 10 to 16 times higher risk of developing BCC than the general population&#46; These figures increase with increasing extent and duration of immunosuppressive therapy&#46; These are the most aggressive&#44; invasive&#44; and recurrent tumors&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">29&#44;32</span></a> Third&#44; partial spontaneous regression is a relatively common phenomenon in BCC&#44; but one that has not been extensively studied&#46; It appears that secretion of certain cytokines by activated CD4<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>T-cells could induce an antitumor response&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">33&#8211;35</span></a> Fourth&#44; we often find accompanying peritumoral infiltrate&#44; formed mainly of T cells&#44; although little is known of the significance of this finding&#46; Finally&#44; topical immunomodulators are curative therapeutic options in some cases of BCC&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">There are few publications on the role of antibodies against immunological molecular targets for the treatment of patients with locally advanced and metastatic BCC&#46; In January 2016&#44; Mohan et al&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">36</span></a> reported the case of a patient with metastatic MM treated with ipilimumab in whom incidental regression of locally advanced BCC was observed&#46; Later&#44; Ikeda et al&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">37</span></a> published a similar case&#46; The patient was a 58-year-old man with metastatic BCC&#44; with bone&#44; lung&#44; brain&#44; and hepatic involvement&#44; who had received several treatments &#40;vismodegib&#44; cisplatin&#44; paclitaxel&#44; sonidegib&#44; and buparlisib&#41;&#44; all discontinued due to disease progression or toxicity&#46; Intravenous nivolumab was administered every 2 weeks and after 4 months&#44; almost complete resolution of the hepatic metastases was observed&#46; In another patient with metastatic BCC in treatment with pembrolizumab&#44; the disease remained stable for months&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">38</span></a> In November 2016&#44; Falchook et al&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">39</span></a> published the case of another metastatic BCC treated with REGN2810&#44; a monoclonal anti-PD-1 antibody in a phase 1 study &#40;NCT02383212&#41;&#44; with partial and sustained response&#46; Shortly afterwards&#44; Borradori et al&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">40</span></a> presented the case of a patient with basosquamous carcinoma with lung metastases treated with nivolumab who maintained stable disease for a few months&#46; Finally&#44; Lipson et al&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">41</span></a> published the case of a patient with locally advanced BCC for whom surgery was not an option and who had been treated previously with radiotherapy and a Hedgehog pathway inhibitor&#46; She started treatment with intravenous pembrolizumab 2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg every 3 weeks for 14 weeks&#44; with partial sustained response&#46; It is worth noting that the immunohistochemical study before starting treatment only showed PD-L1 expression in immune cells&#44; not in tumor cells&#44; and that approximately 50&#37; of T cells expressed PD-1 &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">Currently&#44; there are 2 ongoing studies with immune control proteins in BCC&#59; in the first&#44; a PD-1 inhibitor &#40;REGN2810&#41; is being used in patients with locally advanced or metastatic BCC not responsive or refractory to Hedgehog signaling pathway inhibitors&#44; and in the second&#44; nivolumab is being used in monotherapy or in combination with ipilimumab in patients with unresectable locally advanced BCC or metastatic disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">42&#44;43</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conclusions</span><p id="par0100" class="elsevierStylePara elsevierViewall">Enhancement of the immune system in the treatment of cancer is shaping up as an effective and promising alternative&#46; As dermatologists&#44; we have experience with these therapies in patients with advanced MM and&#44; more recently&#44; in MCC&#46; It is worth focusing our efforts on common tumors such as BCC and SCC and conducting controlled studies to investigate their efficacy&#44; as such agents may be a therapeutic alternative for some patients&#46; We should also try to identify biomarkers that could enable us to select those patients who may benefit from these treatments&#44; in monotherapy or in combination&#44; and thus avoid side effects on those expected to be nonresponders&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflicts of Interest</span><p id="par0105" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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        3 => array:3 [
          "identificador" => "xres1199771"
          "titulo" => "Resumen"
          "secciones" => array:1 [
            0 => array:1 [
              "identificador" => "abst0015"
            ]
          ]
        ]
        4 => array:2 [
          "identificador" => "xpalclavsec1118213"
          "titulo" => "Palabras clave"
        ]
        5 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        6 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Cytotoxic T Lymphocyte Antigen"
        ]
        7 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Programmed Cell Death 1 Protein and Its Ligand"
        ]
        8 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Immunotherapy in Nonmelanoma Skin Cancer"
        ]
        9 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Immunotherapy in Merkel Cell Carcinoma"
        ]
        10 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Immunotherapy in Squamous Cell Carcinoma"
        ]
        11 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "Immunotherapy in Basal Cell Carcinoma"
        ]
        12 => array:2 [
          "identificador" => "sec0040"
          "titulo" => "Conclusions"
        ]
        13 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Conflicts of Interest"
        ]
        14 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2018-06-13"
    "fechaAceptado" => "2018-09-03"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1118212"
          "palabras" => array:5 [
            0 => "Nonmelanoma skin cancer"
            1 => "Immunotherapy"
            2 => "Programmed cell death protein 1 &#40;PD-1&#41;"
            3 => "Programmed death ligand 1 &#40;PD-L1&#41;"
            4 => "Cytotoxic T-lymphocyte-associated antigen 4 &#40;CTLA-4&#41;"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1118213"
          "palabras" => array:5 [
            0 => "C&#225;ncer cut&#225;neo no melanoma"
            1 => "Inmunoterapia"
            2 => "Mol&#233;cula"
            3 => "Ligando"
            4 => "Ant&#237;geno citot&#243;xico de los linfocitos T &#40;CTLA-4&#41;"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Immunotherapy is emerging as a new and promising treatment for a great variety of tumors&#44; including nonmelanoma skin cancer&#46; Checkpoint inhibitors &#8212;antibodies that block proteins that regulate the immune system&#8212;mainly target the surface protein CTLA-4 &#40;cytotoxic T-lymphocyte-associated antigen 4&#41; and the PD-1&#47;PD-L1 &#40;programmed cell death protein 1&#47;PD-ligand 1&#41; axis&#46; We review the CTLA-4 and PD-1&#47;PD-L1 pathways and current evidence supporting checkpoint inhibitor therapy in the main types of nonmelanoma skin cancer&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0015" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">La inmunoterapia en el c&#225;ncer emerge como un tratamiento novedoso y prometedor en una gran variedad de tumores&#44; incluido el c&#225;ncer cut&#225;neo no melanoma&#46; Los anticuerpos inhibidores de prote&#237;nas de control inmunitario est&#225;n dirigidos fundamentalmente a las mol&#233;culas de superficie CTLA-4 &#40;ant&#237;geno citot&#243;xico de los linfocitos T&#41; y PD-1 &#40;mol&#233;cula de muerte programada 1&#41;&#46; En el presente art&#237;culo se revisan las v&#237;as de CTLA-4 y PD-1&#47;PD-L1 &#40;PD-1&#47;ligando de la PD-1&#41; y las evidencias actuales de tratamiento con inhibidores de puntos de control inmunitario en los principales tipos de c&#225;ncer cut&#225;neo no melanoma&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Bassas Freixas P&#44; Aparicio Espa&#241;ol G&#44; Garc&#237;a-Patos Briones V&#46; Inmunoterapia en c&#225;ncer cut&#225;neo no melanoma&#46; Actas Dermosifiliogr&#46; 2019&#59;110&#58;353&#8211;359&#46;</p>"
      ]
    ]
    "multimedia" => array:5 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1365
            "Ancho" => 1504
            "Tamanyo" => 122938
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Schematic representation of T cell activation after interaction between the T-cell receptor and major histocompatibility complex and between B7 costimulatory molecules and CD28 &#40;top panel&#41;&#46; Inhibition of response after binding of cytotoxic T lymphocyte antigen to B7 &#40;bottom panel&#41;&#46;</p> <p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Abbreviations APC&#58; antigen presenting cells&#59; CD28 cluster of differentiation 28&#59; CTLA-4&#58; cytotoxic T lymphocyte antigen&#59; TCR&#58; T-cell receptor&#59; MHC&#58; major histocompatibility complex&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 744
            "Ancho" => 1504
            "Tamanyo" => 71424
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Schematic representation of T cell inhibition mediated by programmed cell death 1 protein ligand&#46; Binding of programmed cell death 1 protein to its corresponding ligand inhibits the positive signal mediated by interaction between the T cell receptor and major histocompatibility complex&#46;</p> <p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Nivolumab and pembrolizumab bind to PD-1&#46; Atezolizumab&#44; avelumab&#44; and durvalumab bind to PD-L1&#46;</p> <p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Abbreviations MHC&#58; major histocompatibility complex&#59; PD-1&#58; programmed cell death 1 protein&#59; PD-L1&#58; programmed death ligand 1&#59; TCR&#58; T cell receptor&#46;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at1"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; HNSCC&#44; head and neck squamous cell carcinoma&#59; MCC&#44; Merkel cell carcinoma&#59; MM&#44; malignant melanoma&#59; NSCLC&#44; nonsmall cell lung cancer&#59; RCC&#44; renal cell carcinoma&#59; PD-1&#44; programmed cell death 1 protein&#59; PD-L1&#44; programmed death ligand 1&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Antibody&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Specificity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Indication&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nivolumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti-PD-1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Classic Hodgkin lymphoma&#44; MM&#44; NSCLC&#44; HNSCC&#44; RCC&#44; urothelial carcinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pembrolizumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti-PD-1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NSCLC&#44; MM&#44; classic Hodgkin lymphoma&#44; urothelial carcinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Atezolizumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti-PD-L1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NSCLC&#44; urothelial carcinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Avelumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti-PD-L1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MCC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Durvalumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti-PD-L1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NSCLC &#40;pending definitive approval&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2049321.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Anti-PD-1 or Anti-PD-L1 Agents Approved by the European Medicines Agency&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; BCC&#44; basal cell carcinoma&#59; CTLA-4&#44; cytotoxic T lymphocyte antigen&#59; laBCC&#44; locally advanced basal cell carcinoma&#59; mBCC&#44; metastatic basal cell carcinoma&#59; MM&#44; malignant melanoma&#59; PD-1&#44; programmed cell death 1 protein&#59; PR&#44; partial response&#59; SD&#44; stable disease&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Author&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Year&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mechanism of Action&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Duration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No&#46; Patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Tumor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Response&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ikeda et al&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nivolumab 240<span class="elsevierStyleHsp" style=""></span>mg&#47;2 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti-PD-1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">mBCC &#40;head&#44; liver&#44; lung&#44; and bone&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PR &#40;liver metastasis&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mohan et al&#46;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2016</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ipilimumab &#40;3<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;3 weeks&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti-CTLA-4</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8 weeks</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">laBCC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PR</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Metastatic MM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Falchook et al&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">REGN2810 &#40;10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;2 weeks&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti-PD-1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">mBCC &#40;lung&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Borradori et al&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nivolumab &#40;3<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;3 weeks&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti-PD-1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Basosquamous carcinoma with lung metastasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD &#40;lung&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Winkler et al&#46;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2017</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pembrolizumab</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 cycles &#40;12-16 weeks&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">mBCC &#40;lung&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SD &#40;pulmonary&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sarcoidosis-like granulomatous reaction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lipson et al&#46;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2017</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pembrolizumab &#40;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;3 weeks&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti-PD-1</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14 weeks</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">laBCC</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Subclinical hypothyroidism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                    0 => array:2 [
                      "titulo" => "Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
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                      "doi" => "10.1111/j.1600-065X.2008.00662.x"
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                        "tituloSerie" => "Immunol Rev&#46;"
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                        "volumen" => "224"
                        "paginaInicial" => "166"
                        "paginaFinal" => "182"
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                          0 => array:2 [
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                      "titulo" => "CTLA-4 and PD-1 pathways similarities&#44; differences&#44; and implications of their inhibition"
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                          "etal" => false
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                      "doi" => "10.1097/COC.0000000000000239"
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                        "tituloSerie" => "Am J Clin Oncol&#46;"
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                          "etal" => true
                          "autores" => array:6 [
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                            3 => "J&#46;S&#46; Weber"
                            4 => "K&#46; Margolin"
                            5 => "O&#46; Hamid"
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                    0 => array:2 [
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                      "titulo" => "Long term survival with cytotoxic T lymphocyte-associated antigen 4 blockade using tremelimumab"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Z&#46; Eroglu"
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                            2 => "X&#46; Wang"
                            3 => "L&#46;H&#46; Camacho"
                            4 => "B&#46; Chmielowski"
                            5 => "E&#46; Seja"
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                        "tituloSerie" => "Eur J Cancer&#46;"
                        "fecha" => "2015"
                        "volumen" => "51"
                        "paginaInicial" => "2689"
                        "paginaFinal" => "2697"
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                          0 => array:2 [
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                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "Improved survival with ipilimumab in patients with metastatic melanoma"
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                          "etal" => true
                          "autores" => array:6 [
                            0 => "F&#46;S&#46; Hodi"
                            1 => "S&#46;J&#46; O&#8217;Day"
                            2 => "D&#46;F&#46; McDermott"
                            3 => "R&#46;W&#46; Weber"
                            4 => "J&#46;A&#46; Sosman"
                            5 => "J&#46;B&#46; Haanen"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1003466"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med&#46;"
                        "fecha" => "2010"
                        "volumen" => "363"
                        "paginaInicial" => "711"
                        "paginaFinal" => "723"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ipilimumab plus dacarbazine for previously untreated metastatic melanoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Robert"
                            1 => "L&#46; Thomas"
                            2 => "I&#46; Bondarenko"
                            3 => "S&#46; O&#8217;Day"
                            4 => "J&#46; Weber"
                            5 => "C&#46; Garbe"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med&#46;"
                        "fecha" => "2011"
                        "volumen" => "364"
                        "paginaInicial" => "2517"
                        "paginaFinal" => "2526"
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Article information

ISSN: 15782190
Original language: English

DOI:10.1016/j.adengl.2019.04.002

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Year/Month	Html	Pdf	Total

2024 November	16	12	28
2024 October	83	38	121
2024 September	89	24	113
2024 August	114	64	178
2024 July	102	44	146
2024 June	93	34	127
2024 May	105	43	148
2024 April	113	31	144
2024 March	108	33	141
2024 February	114	33	147
2024 January	96	30	126
2023 December	97	28	125
2023 November	95	32	127
2023 October	83	32	115
2023 September	81	37	118
2023 August	52	13	65
2023 July	68	48	116
2023 June	71	40	111
2023 May	68	25	93
2023 April	49	23	72
2023 March	103	30	133
2023 February	63	28	91
2023 January	42	39	81
2022 December	70	46	116
2022 November	54	40	94
2022 October	36	29	65
2022 September	38	38	76
2022 August	32	36	68
2022 July	30	43	73
2022 June	26	36	62
2022 May	69	47	116
2022 April	83	45	128
2022 March	67	61	128
2022 February	49	37	86
2022 January	55	38	93
2021 December	78	40	118
2021 November	76	46	122
2021 October	78	66	144
2021 September	67	43	110
2021 August	70	36	106
2021 July	54	27	81
2021 June	57	30	87
2021 May	82	58	140
2021 April	190	58	248
2021 March	144	43	187
2021 February	97	48	145
2021 January	81	18	99
2020 December	62	22	84
2020 November	41	18	59
2020 October	35	23	58
2020 September	28	17	45
2020 August	35	17	52
2020 July	45	22	67
2020 June	37	27	64
2020 May	31	12	43
2020 April	21	12	33
2020 March	15	4	19
2020 February	4	0	4
2019 October	1	0	1
2019 May	1	0	1

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