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1.
Curr Oncol Rep ; 22(3): 25, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32048065

RESUMO

PURPOSE OF REVIEW: Recent developments in immunotherapy have transformed the landscape of melanoma therapy. Here, we review markers for response to immunotherapy. RECENT FINDINGS: Current immunotherapies disable immune checkpoints on T cells and other immune cells and allow immune rejection of tumor. This process depends crucially on a preexisting response to the development of the melanoma. Here we describe the complexity of the anti-tumor immune response and the links to the development of markers that are currently used or under investigation in the clinic. We describe immune response biomarkers along with new developments that could translate into advances.

2.
Clin Cancer Res ; 26(3): 598-607, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31582519

RESUMO

PURPOSE: IL12 promotes adaptive type I immunity and has demonstrated antitumor efficacy, but systemic administration leads to severe adverse events (AE), including death. This pilot trial investigated safety, efficacy, and immunologic activity of intratumoral delivery of IL12 plasmid DNA (tavo) via in vivo electroporation (i.t.-tavo-EP) in patients with Merkel cell carcinoma (MCC), an aggressive virus-associated skin cancer. PATIENTS AND METHODS: Fifteen patients with MCC with superficial injectable tumor(s) received i.t.-tavo-EP on days 1, 5, and 8 of each cycle. Patients with locoregional MCC (cohort A, N = 3) received one cycle before definitive surgery in week 4. Patients with metastatic MCC (cohort B, N = 12) received up to four cycles total, administered at least 6 weeks apart. Serial tumor and blood samples were collected. RESULTS: All patients successfully completed at least one cycle with transient, mild (grades 1 and 2) AEs and without significant systemic toxicity. Sustained (day 22) intratumoral expression of IL12 protein was observed along with local inflammation and increased tumor-specific CD8+ T-cell infiltration, which led to systemic immunologic and clinical responses. The overall response rate was 25% (3/12) in cohort B, with 2 patients experiencing durable clinical benefit (16 and 55+ months, respectively). Two cohort A patients (1 with pathologic complete remission) were recurrence-free at 44+ and 75+ months, respectively. CONCLUSIONS: I.t.-tavo-EP was safe and feasible without systemic toxicity. Sustained local expression of IL12 protein and local inflammation led to systemic immune responses and clinically meaningful benefit in some patients. Gene electrotransfer, specifically i.t.-tavo-EP, warrants further investigation for immunotherapy of cancer.

3.
Clin Cancer Res ; 26(1): 46-53, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31732523

RESUMO

PURPOSE: To report the 5-year overall survival (OS) landmark and the long-term safety profile of vemurafenib plus cobimetinib (BRAF plus MEK inhibition, respectively) in the BRIM7 study. PATIENTS AND METHODS: This phase Ib, dose-finding, and expansion study evaluated combination treatment with vemurafenib and cobimetinib in two cohorts of patients with advanced BRAF V600-mutated melanoma: patients who were BRAF inhibitor (BRAFi)-naïve (n = 63) or patients who had progressed on prior treatment with BRAFi monotherapy [vemurafenib monotherapy-progressive disease (PD); n = 66]. Patients in the dose-escalation phase received vemurafenib at 720 or 960 mg twice daily in combination with cobimetinib at 60, 80, or 100 mg/d for 14 days on/14 days off, 21 days on/7 days off, or continuously. Two regimens were selected for expansion: vemurafenib (720 and 960 mg twice daily) and cobimetinib (60 mg/d 21/7). RESULTS: Median OS was 31.8 months [95% confidence interval (CI), 24.5-not estimable] in the BRAFi-naïve cohort. The landmark OS rate plateaued at 39.2% at years 4 and 5 of follow-up. In the vemurafenib monotherapy-PD cohort, the median OS was 8.5 months (95% CI, 6.7-11.1), and the landmark OS rate plateaued at 14.0% from 3 years of follow-up. No increase was observed in the frequency and severity of adverse events with long-term follow-up. No new toxicities were detected, and there was no increase in the frequency of symptomatic MEK inhibitor class-effect adverse events. CONCLUSIONS: A subset of patients with advanced BRAF V600-mutated melanoma treated with a combination regimen of vemurafenib and cobimetinib achieve favorable long-term outcomes.

4.
Cancer Immunol Res ; 8(2): 246-254, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31852717

RESUMO

Whereas systemic IL12 is associated with potentially life-threatening toxicity, intratumoral delivery of IL12 through tavokinogene telseplasmid electroporation (tavo) is safe and can induce tumor regression at distant sites. The mechanism by which these responses are mediated is unknown but is presumed to result from a cellular immune response. In a phase II clinical trial of tavo (NCT01502293), samples from 29 patients with cutaneous melanoma with in-transit disease were assessed for immune responses induced with this treatment. Within the blood circulating immune cell population, we found that the frequencies of circulating PD-1+ CD4+ and CD8+ T cells declined with treatment. Circulating immune responses to gp100 were also detected following treatment as measured by IFNγ ELISpot. Patients with a greater antigen-specific circulating immune response also had higher numbers of CD8+ T cells within the tumor. Clinical response was also associated with increased intratumoral CD3+ T cells. Finally, intratumoral T-cell clonality and convergence were increased after treatment, indicating a focusing of the T-cell receptor repertoire. These results indicated that local treatment with tavo can induce a systemic T-cell response and recruit T cells to the tumor microenvironment.

5.
JCI Insight ; 4(24)2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31852848

RESUMO

Distinct subsets of Tregs reside in nonlymphoid tissues where they mediate unique functions. To interrogate the biology of tissue Tregs in human health and disease, we phenotypically and functionally compared healthy skin Tregs with those in peripheral blood, inflamed psoriatic skin, and metastatic melanoma. The mitochondrial enzyme, arginase 2 (ARG2), was preferentially expressed in Tregs in healthy skin, increased in Tregs in metastatic melanoma, and reduced in Tregs from psoriatic skin. ARG2 enhanced Treg suppressive capacity in vitro and conferred a selective advantage for accumulation in inflamed tissues in vivo. CRISPR-mediated deletion of this gene in primary human Tregs was sufficient to skew away from a tissue Treg transcriptional signature. Notably, the inhibition of ARG2 increased mTOR signaling, whereas the overexpression of this enzyme suppressed it. Taken together, our results suggest that Tregs express ARG2 in human tissues to both regulate inflammation and enhance their metabolic fitness.

6.
Nat Rev Cancer ; 19(11): 639-650, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31455892

RESUMO

Genetic intratumoural heterogeneity is a natural consequence of imperfect DNA replication. Any two randomly selected cells, whether normal or cancerous, are therefore genetically different. Here, we review the different forms of genetic heterogeneity in cancer and re-analyse the extent of genetic heterogeneity within seven types of untreated epithelial cancers, with particular regard to its clinical relevance. We find that the homogeneity of predicted functional mutations in driver genes is the rule rather than the exception. In primary tumours with multiple samples, 97% of driver-gene mutations in 38 patients were homogeneous. Moreover, among metastases from the same primary tumour, 100% of the driver mutations in 17 patients were homogeneous. With a single biopsy of a primary tumour in 14 patients, the likelihood of missing a functional driver-gene mutation that was present in all metastases was 2.6%. Furthermore, all functional driver-gene mutations detected in these 14 primary tumours were present among all their metastases. Finally, we found that individual metastatic lesions responded concordantly to targeted therapies in 91% of 44 patients. These analyses indicate that the cells within the primary tumours that gave rise to metastases are genetically homogeneous with respect to functional driver-gene mutations, and we suggest that future efforts to develop combination therapies have the potential to be curative.


Assuntos
Heterogeneidade Genética , Mutação , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Animais , Biópsia , Ensaios Clínicos como Assunto , Epigênese Genética , Humanos , Oncologia , Metástase Neoplásica
7.
Lancet Oncol ; 20(7): e378-e389, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31267972

RESUMO

Advances in the treatment of metastatic melanoma have improved responses and survival. However, many patients continue to experience resistance or toxicity to treatment, highlighting a crucial need to identify biomarkers and understand mechanisms of response and toxicity. Neoadjuvant therapy for regional metastases might improve operability and clinical outcomes over upfront surgery and adjuvant therapy, and has become an established role for drug development and biomarker discovery in other cancers (including locally advanced breast cancer, head and neck squamous cell carcinomas, gastroesophageal cancer, and anal cancer). Patients with clinically detectable stage III melanoma are ideal candidates for neoadjuvant therapy, because they represent a high-risk patient population with poor outcomes when treated with upfront surgery alone. Neoadjuvant therapy is now an active area of research for melanoma with numerous completed and ongoing trials (since 2014) with disparate designs, endpoints, and analyses under investigation. We have, therefore, established the International Neoadjuvant Melanoma Consortium with experts in medical oncology, surgical oncology, pathology, radiation oncology, radiology, and translational research to develop recommendations for investigating neoadjuvant therapy in melanoma to align future trial designs and correlative analyses. Alignment and consistency of neoadjuvant trials will facilitate optimal data organisation for future regulatory review and strengthen translational research across the melanoma disease continuum.

8.
J Natl Compr Canc Netw ; 17(7): 778-783, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31319387

RESUMO

Clear cell basal cell carcinoma (BCC) is an unusual variant of BCC. Its pathogenesis, prognosis, and optimal management remain poorly described due to its rarity. This report presents a 51-year-old man with a history of excised BCC and cutaneous squamous cell carcinomas of the face, with multiple recurrent poorly differentiated carcinomas with clear cell changes of the shoulder for which further classification using conventional histologic means was not possible. His tumor tissue was sent to Foundation Medicine for testing, which revealed a high number of pathogenic genomic alterations, including a mutation in PTCH1. He was diagnosed with dedifferentiated BCC and started on vismodegib. He developed lung metastases while receiving vismodegib, and his disease continued to progress while he was undergoing treatment in a phase I clinical trial. Given the high number of pathogenic alterations suggestive of high tumor mutational burden, immunotherapy was considered and off-label authorization was obtained for treatment with a PD-1 antibody (pembrolizumab). He had a dramatic disease response after 4 infusions of pembrolizumab. Molecular testing was instrumental in determining the correct diagnosis and formulating appropriate treatment options for this patient. Molecular profiling of metastatic BCCs and its subtypes is essential to the development of effective targeted therapies and combination approaches.

9.
Lancet Oncol ; 20(9): 1239-1251, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31345627

RESUMO

BACKGROUND: Pembrolizumab improved progression-free survival and overall survival versus ipilimumab in patients with advanced melanoma and is now a standard of care in the first-line setting. However, the optimal duration of anti-PD-1 administration is unknown. We present results from 5 years of follow-up of patients in KEYNOTE-006. METHODS: KEYNOTE-006 was an open-label, multicentre, randomised, controlled, phase 3 study done at 87 academic institutions, hospitals, and cancer centres in 16 countries. Patients aged at least 18 years with Eastern Cooperative Oncology Group performance status of 0 or 1, ipilimumab-naive histologically confirmed advanced melanoma with known BRAFV600 status and up to one previous systemic therapy were randomly assigned (1:1:1) to intravenous pembrolizumab 10 mg/kg every 2 weeks or every 3 weeks or four doses of intravenous ipilimumab 3 mg/kg every 3 weeks. Treatments were assigned using a centralised, computer-generated allocation schedule with blocked randomisation within strata. Exploratory combination of data from the two pembrolizumab dosing regimen groups was not protocol-specified. Pembrolizumab treatment continued for up to 24 months. Eligible patients who discontinued pembrolizumab with stable disease or better after receiving at least 24 months of pembrolizumab or discontinued with complete response after at least 6 months of pembrolizumab and then progressed could receive an additional 17 cycles of pembrolizumab. Co-primary endpoints were overall survival and progression-free survival. Efficacy was analysed in all randomly assigned patients, and safety was analysed in all randomly assigned patients who received at least one dose of study treatment. Exploratory assessment of efficacy and safety at 5 years' follow-up was not specified in the protocol. Data cutoff for this analysis was Dec 3, 2018. Recruitment is closed; the study is ongoing. This study is registered with ClinicalTrials.gov, number NCT01866319. FINDINGS: Between Sept 18, 2013, and March 3, 2014, 834 patients were enrolled and randomly assigned to receive pembrolizumab (every 2 weeks, n=279; every 3 weeks, n=277), or ipilimumab (n=278). After a median follow-up of 57·7 months (IQR 56·7-59·2) in surviving patients, median overall survival was 32·7 months (95% CI 24·5-41·6) in the combined pembrolizumab groups and 15·9 months (13·3-22·0) in the ipilimumab group (hazard ratio [HR] 0·73, 95% CI 0·61-0·88, p=0·00049). Median progression-free survival was 8·4 months (95% CI 6·6-11·3) in the combined pembrolizumab groups versus 3·4 months (2·9-4·2) in the ipilimumab group (HR 0·57, 95% CI 0·48-0·67, p<0·0001). Grade 3-4 treatment-related adverse events occurred in 96 (17%) of 555 patients in the combined pembrolizumab groups and in 50 (20%) of 256 patients in the ipilimumab group; the most common of these events were colitis (11 [2%] vs 16 [6%]), diarrhoea (ten [2%] vs seven [3%]), and fatigue (four [<1%] vs three [1%]). Any-grade serious treatment-related adverse events occurred in 75 (14%) patients in the combined pembrolizumab groups and in 45 (18%) patients in the ipilimumab group. One patient assigned to pembrolizumab died from treatment-related sepsis. INTERPRETATION: Pembrolizumab continued to show superiority over ipilimumab after almost 5 years of follow-up. These results provide further support for use of pembrolizumab in patients with advanced melanoma. FUNDING: Merck Sharp & Dohme.

10.
Am J Clin Dermatol ; 20(6): 781-796, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31228012

RESUMO

Skin cancer, as the most physically accessible malignancy, allows for the greatest variety in treatment innovation. The last 2 decades have seen striking increases in the life expectancies of those diagnosed with malignant melanoma. However, many cases remain in which disease prevails against standard treatment, and those patients rely on continuing ingenuity. Drugs that can be injected directly into patients' tumors have become increasingly promising, not least for the reduction in side effects observed. Intratumoral therapy encompasses a wide array of agents, from chemotherapeutic drugs to cancer vaccines. While each show some efficacy, those agents which regulate the immune system likely have the greatest potential for preventing disease progression or recurrence. Recent research has highlighted the importance of the presence of cytotoxic T cells and of keeping regulatory T cells in check. Thus, manipulating the tumor microenvironment is a need in skin cancer therapy, which intratumoral delivery can potentially address. In order to find the best approach to each person's disease, more studies are needed to test intralesional agents in combination with currently approved therapies and with each other.

11.
Cell ; 177(3): 556-571.e16, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-30955881

RESUMO

Differentiation of proinflammatory CD4+ conventional T cells (Tconv) is critical for productive antitumor responses yet their elicitation remains poorly understood. We comprehensively characterized myeloid cells in tumor draining lymph nodes (tdLN) of mice and identified two subsets of conventional type-2 dendritic cells (cDC2) that traffic from tumor to tdLN and present tumor-derived antigens to CD4+ Tconv, but then fail to support antitumor CD4+ Tconv differentiation. Regulatory T cell (Treg) depletion enhanced their capacity to elicit strong CD4+ Tconv responses and ensuing antitumor protection. Analogous cDC2 populations were identified in patients, and as in mice, their abundance relative to Treg predicts protective ICOS+ PD-1lo CD4+ Tconv phenotypes and survival. Further, in melanoma patients with low Treg abundance, intratumoral cDC2 density alone correlates with abundant CD4+ Tconv and with responsiveness to anti-PD-1 therapy. Together, this highlights a pathway that restrains cDC2 and whose reversal enhances CD4+ Tconv abundance and controls tumor growth.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Animais , Antígenos de Neoplasias/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Citocinas/metabolismo , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Toxina Diftérica/imunologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Linfonodos/imunologia , Linfonodos/metabolismo , Ativação Linfocitária , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Quimiocinas/metabolismo , Linfócitos T Reguladores/imunologia , Microambiente Tumoral
12.
Immunity ; 50(2): 477-492.e8, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30737146

RESUMO

Resistance to checkpoint-blockade treatments is a challenge in the clinic. We found that although treatment with combined anti-CTLA-4 and anti-PD-1 improved control of established tumors, this combination compromised anti-tumor immunity in the low tumor burden (LTB) state in pre-clinical models as well as in melanoma patients. Activated tumor-specific T cells expressed higher amounts of interferon-γ (IFN-γ) receptor and were more susceptible to apoptosis than naive T cells. Combination treatment induced deletion of tumor-specific T cells and altered the T cell repertoire landscape, skewing the distribution of T cells toward lower-frequency clonotypes. Additionally, combination therapy induced higher IFN-γ production in the LTB state than in the high tumor burden (HTB) state on a per-cell basis, reflecting a less exhausted immune status in the LTB state. Thus, elevated IFN-γ secretion in the LTB state contributes to the development of an immune-intrinsic mechanism of resistance to combination checkpoint blockade, highlighting the importance of achieving the optimal magnitude of immune stimulation for successful combination immunotherapy strategies.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígeno CTLA-4/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Interferon gama/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Animais , Anticorpos Monoclonais/imunologia , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Linhagem Celular Tumoral , Deleção Clonal/efeitos dos fármacos , Deleção Clonal/imunologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/metabolismo , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/imunologia
13.
J Clin Oncol ; 37(9): 693-702, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30726175

RESUMO

PURPOSE: Merkel cell carcinoma (MCC) is an aggressive skin cancer often caused by the Merkel cell polyomavirus. Clinical trials of programmed cell death-1 pathway inhibitors for advanced MCC (aMCC) demonstrate increased progression-free survival (PFS) compared with historical chemotherapy data. However, response durability and overall survival (OS) data are limited. PATIENTS AND METHODS: In this multicenter phase II trial (Cancer Immunotherapy Trials Network-09/Keynote-017), 50 adults naïve to systemic therapy for aMCC received pembrolizumab (2 mg/kg every 3 weeks) for up to 2 years. Radiographic responses were assessed centrally per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. RESULTS: Among 50 patients, the median age was 70.5 years, and 64% had Merkel cell polyomavirus-positive tumors. The objective response rate (ORR) to pembrolizumab was 56% (complete response [24%] plus partial response [32%]; 95% CI, 41.3% to 70.0%), with ORRs of 59% in virus-positive and 53% in virus-negative tumors. Median follow-up time was 14.9 months (range, 0.4 to 36.4+ months). Among 28 responders, median response duration was not reached (range, 5.9 to 34.5+ months). The 24-month PFS rate was 48.3%, and median PFS time was 16.8 months (95% CI, 4.6 months to not estimable). The 24-month OS rate was 68.7%, and median OS time was not reached. Although tumor viral status did not correlate with ORR, PFS, or OS, there was a trend toward improved PFS and OS in patients with programmed death ligand-1-positive tumors. Grade 3 or greater treatment-related adverse events occurred in 14 (28%) of 50 patients and led to treatment discontinuation in seven (14%) of 50 patients, including one treatment-related death. CONCLUSION: Here, we present the longest observation to date of patients with aMCC receiving first-line anti-programmed cell death-1 therapy. Pembrolizumab demonstrated durable tumor control, a generally manageable safety profile, and favorable OS compared with historical data from patients treated with first-line chemotherapy.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma de Célula de Merkel/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Carcinoma de Célula de Merkel/patologia , Feminino , Seguimentos , Humanos , Hipotireoidismo/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Pneumonia/induzido quimicamente , Intervalo Livre de Progressão , Indução de Remissão , Critérios de Avaliação de Resposta em Tumores Sólidos , Neoplasias Cutâneas/patologia
16.
Immunity ; 49(6): 1148-1161.e7, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30552023

RESUMO

Anti-PD-1 immune checkpoint blockers can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Here, we combined intravital real-time imaging with single-cell RNA sequencing analysis and mouse models to uncover anti-PD-1 pharmacodynamics directly within tumors. We showed that effective antitumor responses required a subset of tumor-infiltrating dendritic cells (DCs), which produced interleukin 12 (IL-12). These DCs did not bind anti-PD-1 but produced IL-12 upon sensing interferon γ (IFN-γ) that was released from neighboring T cells. In turn, DC-derived IL-12 stimulated antitumor T cell immunity. These findings suggest that full-fledged activation of antitumor T cells by anti-PD-1 is not direct, but rather involves T cell:DC crosstalk and is licensed by IFN-γ and IL-12. Furthermore, we found that activating the non-canonical NF-κB transcription factor pathway amplified IL-12-producing DCs and sensitized tumors to anti-PD-1 treatment, suggesting a therapeutic strategy to improve responses to checkpoint blockade.


Assuntos
Células Dendríticas/imunologia , Interferon gama/imunologia , Interleucina-12/imunologia , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Células Dendríticas/metabolismo , Feminino , Humanos , Imunoterapia/métodos , Interferon gama/metabolismo , Interleucina-12/administração & dosagem , Interleucina-12/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , NF-kappa B/imunologia , NF-kappa B/metabolismo , Neoplasias/metabolismo , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
17.
Br J Cancer ; 119(6): 670-674, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30202085

RESUMO

BACKGROUND: Mucosal melanoma is an aggressive melanoma with poor prognosis. We assessed efficacy of pembrolizumab in patients with advanced mucosal melanoma in KEYNOTE-001 (NCT01295827), -002 (NCT01704287), and -006 (NCT01866319). METHODS: Patients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) or 10 mg/kg Q2W or Q3W. Response was assessed by independent central review per RECIST v1.1. RESULTS: 1567 patients were treated and 84 (5%) had mucosal melanoma. Fifty-one of 84 were ipilimumab-naive. In patients with mucosal melanoma, the objective response rate (ORR) was 19% (95% CI 11-29%), with median duration of response (DOR) of 27.6 months (range 1.1 + to 27.6). Median progression-free survival (PFS) was 2.8 months (95% CI 2.7-2.8), with median overall survival (OS) of 11.3 months (7.7-16.6). ORR was 22% (95% CI 11-35%) and 15% (95% CI 5-32%) in ipilimumab-naive and ipilimumab-treated patients. CONCLUSION: Pembrolizumab provides durable antitumour activity in patients with advanced mucosal melanoma regardless of prior ipilimumab.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Melanoma/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Esquema de Medicação , Feminino , Humanos , Ipilimumab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
18.
Eur J Cancer ; 101: 236-243, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30096704

RESUMO

BACKGROUND: Predictive biomarkers of patients likely to benefit from anti-programmed death 1 inhibitor therapy have clinical relevance. We examined whether line of therapy or tumour programmed death ligand 1 (PD-L1) expression affects the efficacy and safety of pembrolizumab, compared with ipilimumab, in advanced melanoma. METHODS: Of 834 patients enrolled in the randomised, open-label phase III KEYNOTE-006 study, 833 were included in this analysis. Patients were randomly assigned 1:1:1 to receive pembrolizumab 10 mg/kg every 2 or 3 weeks (for 24 months) or ipilimumab 3 mg/kg every 3 weeks (for four doses) until disease progression/intolerable toxicity. This analysis evaluated progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). Data cut-off: 03 November 2016. RESULTS: Of the patients, 60.3% were male, 65.9% were treatment naive and 80.6% had PD-L1-positive tumours (median follow-up was 33.9 months). Twenty-four-month survival rates were higher with pembrolizumab than with ipilimumab in treatment-naive (PFS 31.0% versus 14.6%; OS 58.0% versus 44.7%) and previously treated patients (PFS 25.7% versus 11.3%; OS 49.2% versus 37.9%). Twenty-four-month survival rates were higher with pembrolizumab than with ipilimumab in patients with PD-L1-positive tumours (PFS 33.2% versus 13.1%; OS 58.4% versus 45.0%) and similar in PD-L1-negative tumours (PFS 14.9% versus NR [no data at 24 months for a PFS estimate]; OS 43.6% versus 31.8%). Safety of pembrolizumab by subgroup was consistent with previous reports. CONCLUSIONS: Findings support pembrolizumab monotherapy as standard of care in patients with advanced melanoma, regardless of first- or second-line therapy or PD-L1 status. CLINICALTRIALS. GOV IDENTIFIER: NCT01866319.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Ipilimumab/uso terapêutico , Melanoma/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/metabolismo , Esquema de Medicação , Feminino , Humanos , Ipilimumab/efeitos adversos , Estimativa de Kaplan-Meier , Masculino , Melanoma/metabolismo , Melanoma/patologia , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
19.
Sci Rep ; 8(1): 10902, 2018 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-30026510

RESUMO

Despite major advances in targeted melanoma therapies, drug resistance limits their efficacy. Long noncoding RNAs (lncRNAs) are transcriptome elements that do not encode proteins but are important regulatory molecules. LncRNAs have been implicated in cancer development and response to different therapeutics and are thus potential treatment targets; however, the majority of their functions and molecular interactions remain unexplored. In this study, we identify a novel cytoplasmic intergenic lincRNA (MIRAT), which is upregulated following prolonged MAPK inhibition in NRAS mutant melanoma and modulates MAPK signaling by binding to the MEK scaffold protein IQGAP1. Collectively, our results present MIRAT's direct modulatory effect on the MAPK pathway and highlight the relevance of cytoplasmic lncRNAs as potential targets in drug resistant cancer.


Assuntos
Resistencia a Medicamentos Antineoplásicos , GTP Fosfo-Hidrolases/genética , Melanoma/genética , Proteínas de Membrana/genética , Mutação , RNA Longo não Codificante/genética , Proteínas Ativadoras de ras GTPase/genética , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Sistema de Sinalização das MAP Quinases , Inibidores de Proteínas Quinases/farmacologia , Análise de Sequência de RNA , Bibliotecas de Moléculas Pequenas/farmacologia , Regulação para Cima
20.
Clin Cancer Res ; 24(21): 5250-5260, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30021908

RESUMO

Purpose: PD-1/L1 axis-directed therapies produce clinical responses in a subset of patients; therefore, biomarkers of response are needed. We hypothesized that quantifying key immunosuppression mechanisms within the tumor microenvironment by multiparameter algorithms would identify strong predictors of anti-PD-1 response.Experimental Design: Pretreatment tumor biopsies from 166 patients treated with anti-PD-1 across 10 academic cancer centers were fluorescently stained with multiple markers in discovery (n = 24) and validation (n = 142) cohorts. Biomarker-positive cells and their colocalization were spatially profiled in pathologist-selected tumor regions using novel Automated Quantitative Analysis algorithms. Selected biomarker signatures, PD-1/PD-L1 interaction score, and IDO-1/HLA-DR coexpression were evaluated for anti-PD-1 treatment outcomes.Results: In the discovery cohort, PD-1/PD-L1 interaction score and/or IDO-1/HLA-DR coexpression was strongly associated with anti-PD-1 response (P = 0.0005). In contrast, individual biomarkers (PD-1, PD-L1, IDO-1, HLA-DR) were not associated with response or survival. This finding was replicated in an independent validation cohort: patients with high PD-1/PD-L1 and/or IDO-1/HLA-DR were more likely to respond (P = 0.0096). These patients also experienced significantly improved progression-free survival (HR = 0.36; P = 0.0004) and overall survival (HR = 0.39; P = 0.0011). In the combined cohort, 80% of patients exhibiting higher levels of PD-1/PD-L1 interaction scores and IDO-1/HLA-DR responded to PD-1 blockers (P = 0.000004). In contrast, PD-L1 expression was not predictive of survival.Conclusions: Quantitative spatial profiling of key tumor-immune suppression pathways by novel digital pathology algorithms could help more reliably select melanoma patients for PD-1 monotherapy. Clin Cancer Res; 24(21); 5250-60. ©2018 AACR.


Assuntos
Antígeno B7-H1/metabolismo , Antígenos HLA-DR/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Melanoma/metabolismo , Melanoma/mortalidade , Receptor de Morte Celular Programada 1/metabolismo , Adulto , Idoso , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais , Biópsia , Linhagem Celular Tumoral , Feminino , Humanos , Imuno-Histoquímica , Masculino , Melanoma/tratamento farmacológico , Melanoma/patologia , Pessoa de Meia-Idade , Modelos Biológicos , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Ligação Proteica , Retratamento , Resultado do Tratamento
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