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1.
Lancet Oncol ; 25(7): 853-864, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38834087

RESUMO

BACKGROUND: Current systemic therapies for metastatic pancreatic ductal adenocarcinoma are associated with poor outcomes with a 5-year overall survival rate under 5%. We aimed to assess the safety and antitumour activity of mitazalimab, a human CD40 agonistic IgG1 antibody, with modified FOLFIRINOX (mFOLFIRINOX; fluorouracil, leucovorin, oxaliplatin, and irinotecan), in chemotherapy-naive patients with metastatic pancreatic ductal adenocarcinoma. METHODS: OPTIMIZE-1 was a single-arm, multicentre, phase 1b/2 study which enrolled adults with histologically-confirmed metastatic pancreatic ductal adenocarcinoma and European Cooperative Oncology Group performance status 0 or 1 in 14 university hospitals in Belgium, France, and Spain. The primary endpoint of phase 1b was to determine the recommended phase 2 dose of intravenous mitazalimab (450 µg/kg or 900 µg/kg) when combined with intravenous mFOLFIRINOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2, fluorouracil 2400 mg/m2). In the first 21-day treatment cycle, mitazalimab was administered on days 1 and 10, and mFOLFIRINOX on day 8. In subsequent 14-day cycles mitazalimab was administered 2 days after mFOLFIRINOX. The phase 2 primary endpoint was objective response rate. Activity and safety analyses were conducted on the full analysis set (all patients who received the combination of mitazalimab at the recommended phase 2 dose and mFOLFIRINOX for at least two treatment cycles) and safety set (all patients who received any study treatment), respectively. Enrolment is complete, and data represents a primary analysis of the ongoing trial. The trial is registered at Clinicaltrials.gov (NCT04888312). FINDINGS: Between Sept 29, 2021, and March 28, 2023, 88 patients were screened and 70 patients were enrolled (40 [57%] were female and 30 [43%] were male). In phase 1b, 900 µg/kg mitazalimab was determined as the recommended phase 2 dose. Overall, five patients received 450 µg/kg mitazalimab; 65 received 900 µg/kg mitazalimab. No dose-limiting toxicities were observed at 450 µg/kg, and one dose-limiting toxicity was observed at 900 µg/kg. 57 patients were evaluated for activity, and all 70 patients were included in the safety set. At data cutoff on Nov 14, 2023, median follow-up was 12·7 months (95% CI 11·1-15·7). Of the 57 patients, 29 (51%) remained on study and 18 (32%) remained on treatment. The primary endpoint (objective response rate >30%) was met (objective response rates in 23 [40%]; one-sided 90% CI ≥32 of 57 patients). The most common grade 3 or worse adverse events were neutropenia (18 [26%] of 70 patients), hypokalaemia (11 patients [16%]), and anaemia and thrombocytopenia (eight patients [11%]). Serious adverse events were reported in 29 (41%) of 70 patients, the most common being vomiting (five [7%] of 70 patients), decreased appetite (four [6%]), and diarrhoea and cholangitis (three [4%] of 70 patients for each), none considered related to mitazalimab. No treatment-related deaths were reported. INTERPRETATION: Mitazalimab with mFOLFIRINOX demonstrated manageable safety and encouraging activity, warranting continued development in a phase 3, randomised, controlled trial. The results from OPTIMIZE-1 pave the way for further exploration and confirmation of a novel immunotherapy treatment regimen for metastatic pancreatic ductal adenocarcinoma, which is a complex and aggressive cancer with very low survival rates and restricted treatment options. FUNDING: Alligator Bioscience.


Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Ductal Pancreático , Fluoruracila , Irinotecano , Leucovorina , Oxaliplatina , Neoplasias Pancreáticas , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Pessoa de Meia-Idade , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Leucovorina/administração & dosagem , Leucovorina/uso terapêutico , Idoso , Irinotecano/administração & dosagem , Fluoruracila/administração & dosagem , Oxaliplatina/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Adulto
2.
Gastric Cancer ; 26(3): 425-437, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36881202

RESUMO

BACKGROUND: The optimal treatment strategy after first-line induction therapy in advanced HER2-positive oeso-gastric adenocarcinoma (OGA) remains challenging. METHODS: Patients treated with trastuzumab (T) plus platinum salts and fluoropyrimidine (F) as first-line chemotherapy between 2010 and 2020 for HER2-positive advanced OGA at 17 academic care centers in France, Italy, and Austria were included. The primary objective was the comparison of F + T vs T alone as maintenance regimen in terms of progression-free survival (PFS) and overall survival (OS) after a platinum-based chemotherapy induction + T. As secondary objective, PFS and OS between patients treated with reintroduction of initial chemotherapy or standard second-line chemotherapy at progression were assessed. RESULTS: Among the 157 patients included, 86 (55%) received F + T and 71 (45%) T alone as a maintenance regimen after a median of 4 months of induction chemotherapy. Median PFS from start of maintenance therapy was 5.1 months in both groups (95% CI 4.2-7.7 for F + T and 95% CI 3.7-7.5 for T alone; p = 0.60) and median OS was 15.2 (95% CI 10.9-19.1) and 17.0 months (95% CI 15.5-21.6) for F + T and T alone, respectively (p = 0.40). Of 112/157 patients (71%) receiving systemic therapy after progression under maintenance, 26/112 (23%) were treated with a reintroduction of initial chemotherapy + T and 86/112 (77%) with a standard second-line regimen. Here, median OS was significantly longer with the reintroduction (13.8 (95% CI 12.1-19.9) vs 9.0 months (95% CI 7.1-11.9); p = 0.007) as confirmed by multivariate analysis (HR 0.49; 95% CI 0.28-0.85; p = 0.01). CONCLUSION: No additional benefit of adding F to T monotherapy as a maintenance treatment could be observed. Reintroduction of initial therapy at first progression may be a feasible approach to preserve later treatment lines.


Assuntos
Adenocarcinoma , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , Estudos Retrospectivos , Quimioterapia de Indução , Receptor ErbB-2 , Protocolos de Quimioterapia Combinada Antineoplásica , Trastuzumab/uso terapêutico
3.
Int J Cancer ; 132(11): 2557-66, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23151995

RESUMO

Cancer vaccines have recently been shown to induce some clinical benefits. The relationship between clinical activity and anti-vaccine T cell responses is somewhat controversial. Indeed, in many trials it has been documented that the induction of vaccine-specific T cells exceeds the clinical responses observed. Here, we evaluate immunological and clinical responses in 23 MAGE-A3(+) melanoma patients treated with autologous lymphocytes genetically engineered to express the tumor antigen MAGE-A3 and the viral gene product thymidine kinase of the herpes simplex virus (HSV-TK). HSV-TK was used as safety system in case of adverse events and as tracer antigen to monitor the immune competence of treated patients. The increase of anti-TK and anti-MAGE-A3 T-cells after vaccination was observed in 90 and 27% of patients, respectively. Among 19 patients with measurable disease, we observed a disease control rate of 26.3%, with one objective clinical response, and four durable, stable diseases. Three patients out of five with no evidence of disease (NED) at the time of vaccination remained NED after 73+, 70+ and 50+ months. Notably, we report that only patients experiencing MAGE-A3-specific immune responses showed a clinical benefit. Additionally, we report that responder and non-responder patients activate and expand T cells against the tracer antigen TK in a similar way, suggesting that local rather than systemic immune suppression might be involved in limiting clinically relevant antitumor immune responses.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/uso terapêutico , Terapia Genética , Melanoma/imunologia , Proteínas de Neoplasias/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/terapia , Ensaios Clínicos Fase II como Assunto , Feminino , Seguimentos , Humanos , Hipersensibilidade Tardia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Masculino , Melanoma/mortalidade , Melanoma/terapia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/terapia , Linfócitos T/metabolismo , Timidina Quinase/imunologia , Timidina Quinase/metabolismo
4.
Cancer Immunol Immunother ; 62(5): 897-908, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23589107

RESUMO

The frequency and function of regulatory T cells (Tregs) were studied in stage II-III melanoma patients who were enrolled in a phase II randomized trial of vaccination with HLA-A*0201-modified tumor peptides versus observation. The vaccinated patients received low-dose cyclophosphamide (CTX) and low-dose interleukin-2 (IL-2). Tregs were analyzed in the lymph nodes (LNs) of stage III patients who were undergoing complete lymph node dissection and in peripheral blood mononuclear cells (PBMCs) collected before vaccination and at different time points during the vaccination period. The LNs of the vaccinated patients, which were surgically removed after two rounds of vaccination and one dose of CTX, displayed a low frequency of Tregs and a less immunosuppressive environment compared with those of the untreated patients. The accurate time-course analysis of the PBMCs of patients enrolled in the vaccination arm indicated a limited and transient modulation in the frequencies of Tregs in PBMCs collected after low-dose CTX administration and a strong Treg boost in those PBMCs collected after low-dose IL-2 administration. However, a fraction of the IL-2-boosted Tregs was functionally modulated to a Th-1-like phenotype in the vaccinated patients. Moreover, low-dose IL-2 promoted the concomitant expansion of conventional activated CD4(+) T cells. Despite the amplification of Tregs, IL-2 administration maintained or further increased the number of antigen-specific CD8(+) T cells that were induced by vaccination as demonstrated by the ex vivo human leukocyte antigen-multimer staining and IFN-γ ELISpot assays. Our study suggests that the use of CTX as a Treg modulator should be revised in terms of the administration schedule and of patients who may benefit from this drug treatment. Despite the Treg expansion that was observed in this study, low-dose IL-2 is not detrimental to the functional activities of vaccine-primed CD8(+) T cell effectors when used in the inflammatory environment of vaccination.


Assuntos
Linfócitos T CD4-Positivos/citologia , Ciclofosfamida/uso terapêutico , Antígenos de Histocompatibilidade Classe I/imunologia , Interleucina-2/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Antígenos de Neoplasias/imunologia , Antineoplásicos Alquilantes/uso terapêutico , Linfócitos T CD8-Positivos/citologia , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Imunossupressores/uso terapêutico , Imunoterapia/métodos , Interferon gama/metabolismo , Leucócitos Mononucleares/citologia , Masculino , Melanoma/metabolismo , Pessoa de Meia-Idade , Fenótipo , Neoplasias Cutâneas/metabolismo , Linfócitos T/citologia , Fatores de Tempo
5.
Lancet Oncol ; 13(9): 879-86, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22894884

RESUMO

BACKGROUND: Ipilimumab improves survival of patients with metastatic melanoma, many of whom develop brain metastases. Chemotherapy-induced release of tumour antigens might amplify ipilimumab's antitumour activity. We aimed to investigate the efficacy and safety of ipilimumab plus fotemustine in patients with metastatic melanoma with or without asymptomatic brain metastases. METHODS: In our open-label, single-arm phase 2 trial, we enrolled patients 18 years or older with measurable, locally advanced, unresectable stage III or stage IV melanoma between July 6, 2010, and April 14, 2011. Eligible patients had a life expectancy of 16 weeks or more and an Eastern Cooperative Oncology Group performance status of 1 or less, and could have received a maximum of one previous line of chemotherapy. Participants received induction treatment of 10 mg/kg intravenous ipilimumab every 3 weeks to a total of four doses, and 100 mg/m(2) intravenous fotemustine weekly for 3 weeks and then every 3 weeks from week 9 to week 24. Patients with a confirmed clinical response were eligible for maintenance treatment from week 24, with ipilimumab every 12 weeks and fotemustine every 3 weeks. The primary endpoint was the proportion of patients with immune-related disease control as established with immune-related response criteria. Analyses were done per protocol. This trial is registered with EudraCT, number 2010-019356-50, and with ClinicalTrials.gov, number NCT01654692. FINDINGS: 86 patients were eligible for treatment, of whom 20 had asymptomatic brain metastases at baseline. 40 patients in the study population achieved disease control (46·5%, 95% CI 35·7-57·6), as did ten with brain metastases (50·0%, 27·2-72·8). 47 patients (55%) had grade 3 or 4 treatment-related adverse events, of which the most common was myelotoxicity (thrombocytopenia in 21 [24%] patients and neutropenia in 16 [19%]). The most common grade 3 or 4 immune-related adverse events were hepatic: 21 patients (24%) had grade 3 or 4 increases in concentrations of alanine aminotransferase or aspartate aminotransferase. INTERPRETATION: The combination of ipilimumab plus fotemustine has clinical activity in patients with metastatic melanoma, including those with brain metastases. FUNDING: Bristol-Myers Squibb.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/secundário , Melanoma/tratamento farmacológico , Melanoma/secundário , Compostos de Nitrosoureia/administração & dosagem , Compostos Organofosforados/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Intervalo Livre de Doença , Feminino , Doenças Hematológicas/induzido quimicamente , Humanos , Ipilimumab , Masculino , Melanoma/diagnóstico , Melanoma/patologia , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia
6.
Eur J Cancer ; 188: 90-97, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37229836

RESUMO

BACKGROUND: Immune checkpoint inhibitors (ICIs) improve oncological outcomes in patients with microsatellite instability-high (MSI) or mismatch repair-deficient (dMMR) advanced solid tumours. Nevertheless, based on limited published data, the outcome of patients with MSI/dMMR pancreatic ductal adenocarcinoma (PDAC) seems poorer when compared to other malignancies. This multi-institutional analysis sought to assess the efficacy and tolerability of ICIs in a large real-world cohort of patients with MSI/dMMR PDAC. METHODS: We retrospectively collected data from patients with MSI/dMMR advanced PDAC treated with ICIs in 16 centers. Progression-free survival and overall survival were calculated from the start of treatment, and we report objective response and disease control rates according to RECIST V1.1. RESULTS: Thirty-one MSI/dMMR advanced PDAC patients were identified. Twenty-five patients received single-agent anti-PD-1 antibodies, three patients received the combination of nivolumab and ipilimumab and three patients received immunotherapy in combination with chemotherapy. Among 31 evaluable patients, 15 (48.4%) had an objective response (three complete responses and 12 partial responses), and six (19.4%) had stable disease. With a median follow-up of 18 months, the median progression-free survival (PFS) was 26.7 months and the median overall survival (OS) was not reached. Disease control rates (DCRs) among patients with only one line of prior therapy (N = 17) was 76.5%. Grade 3-4 treatment-related adverse events were not observed. CONCLUSION: This retrospective analysis suggests that ICIs are effective and well tolerated in patients with MSI/dMMR advanced PDAC. Hence, our work supports the use of PD-1 inhibition in this group of patients with high unmet medical need.


Assuntos
Adenocarcinoma , Antineoplásicos Imunológicos , Neoplasias Pancreáticas , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Antineoplásicos Imunológicos/efeitos adversos , Estudos Retrospectivos , Reparo de Erro de Pareamento de DNA , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Repetições de Microssatélites , Instabilidade de Microssatélites , Neoplasias Pancreáticas
7.
Cancer Immunol Immunother ; 61(8): 1169-82, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22207316

RESUMO

Tumor-infiltrating lymphocytes (TILs) have been successfully used for adoptive cell transfer (ACT) immunotherapy; however, due to their scarce availability, this therapy is possible for a limited fraction of cutaneous melanoma patients. We assessed whether an effective protocol for ex vivo T-cell expansion from peripheral blood mononuclear cells (PBMCs), suitable for ACT of both cutaneous and ocular melanoma patients, could be identified. PBMCs from both cutaneous and ocular melanoma patients were stimulated in vitro with autologous, irradiated melanoma cells (mixed lymphocyte tumor cell culture; MLTCs) in the presence of IL-2 and IL-15 followed by the rapid expansion protocol (REP). The functional activity of these T lymphocytes was characterized and compared with that of TILs. In addition, the immune infiltration in vivo of ocular melanoma lesions was analyzed. An efficient in vitro MLTC expansion of melanoma reactive T cells was achieved from all PBMC's samples obtained in 7 cutaneous and ocular metastatic melanoma patients. Large numbers of melanoma-specific T cells could be obtained when the REP protocol was applied to these MLTCs. Most MLTCs were enriched in non-terminally differentiated T(EM) cells homogeneously expressing co-stimulatory molecules (e.g., NKG2D, CD28, CD134, CD137). A similar pattern of anti-tumor activity, in association with a more variable expression of co-stimulatory molecules, was detected on short-term in vitro cultured TILs isolated from the same patients. In these ocular melanoma patients, we observed an immune infiltrate with suppressive characteristics and a low rate of ex vivo growing TILs (28.5% of our cases). Our MLTC protocol overcomes this limitation, allowing the isolation of T lymphocytes with effector functions even in these patients. Thus, anti-tumor circulating PBMC-derived T cells could be efficiently isolated from melanoma patients by our novel ex vivo enrichment protocol. This protocol appears suitable for ACT studies of cutaneous and ocular melanoma patients.


Assuntos
Técnicas de Cultura de Células/métodos , Neoplasias Oculares/imunologia , Imunoterapia Adotiva/métodos , Linfócitos do Interstício Tumoral/imunologia , Melanoma/imunologia , Neoplasias Cutâneas/imunologia , Linfócitos T/imunologia , Neoplasias Oculares/terapia , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Imunofenotipagem , Melanoma/terapia , Neoplasias Cutâneas/terapia
8.
J Vasc Interv Radiol ; 23(7): 937-41, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22720894

RESUMO

Five patients with uveal melanoma metastatic to the liver (two to five lesions per patient) were prospectively enrolled and treated with transarterial chemoembolization with drug-eluting beads preloaded with irinotecan as a first-line therapy. An overall response rate of 80% was obtained per Response Evaluation Criteria In Solid Tumors. All patients were alive after mean follow-up durations of 10.6 months and 16.3 months, respectively, after the first treatment and the diagnosis of liver metastasis. The apparent diffusion coefficient values obtained by diffusion-weighted magnetic resonance imaging were significantly lower in lesions that showed a response. These findings are very promising and can constitute the background for further studies involving larger cohorts of patients.


Assuntos
Camptotecina/análogos & derivados , Imagem de Difusão por Ressonância Magnética/métodos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Melanoma/secundário , Melanoma/terapia , Neoplasias Uveais/terapia , Idoso , Antineoplásicos/administração & dosagem , Camptotecina/administração & dosagem , Quimioembolização Terapêutica/métodos , Quimioterapia Adjuvante/métodos , Preparações de Ação Retardada/administração & dosagem , Feminino , Humanos , Irinotecano , Neoplasias Hepáticas/patologia , Angiografia por Ressonância Magnética/métodos , Masculino , Melanoma/patologia , Microesferas , Pessoa de Meia-Idade , Prognóstico , Resultado do Tratamento , Neoplasias Uveais/patologia
9.
Clin Res Hepatol Gastroenterol ; 46(9): 101983, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35732266

RESUMO

Colorectal cancer management has been dramatically impacted by molecular profiling these last years. Among these molecular subgroups, patients with microsatellite instability (MSI) are of particular interest, owing to the prognostic and predictive value of this tumor biomarker. This review article explains the molecular abnormalities underlying MSI phenotype and the consequences of such molecular abnormalities on carcinogenesis, genetic instability and immune infiltration. It details the diagnostic methods for identifying MSI colorectal cancer patients and describes how the prognostic and theranostic values of this marker are impacting treatment decision-making for these patients in 2022.


Assuntos
Neoplasias Colorretais , Instabilidade de Microssatélites , Humanos , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais/terapia , Prognóstico , Biomarcadores Tumorais/genética
10.
Eur J Cancer ; 168: 34-40, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35436675

RESUMO

BACKGROUND: Encorafenib plus cetuximab is efficient in anti-EGFR-naïve patients with BRAFV600E mutated (BRAFm) metastatic colorectal cancer (mCRC). No data are available concerning the efficacy of BRAF inhibitors associated with anti-EGFRs (B + E) in patients previously treated with an anti-EGFR agent. METHODS: We retrospectively collected a series of patients with BRAFm mCRC treated with B + E after previous anti-EGFR treatment, in 14 centers. Progression-free survival (PFS) and overall survival (OS) were calculated from the start of treatment, and we reported objective response and disease control rates (ORR, DCR; RECIST V1.1). RESULTS: Twenty-five BRAFm mCRC patients were enrolled. Prior to B + E treatment, 4/10/11 patients were treated with 1/2/> 2 previous treatment lines. Ten patients received previous panitumumab, 14 cetuximab, 1 both. Immediate progression with previous anti-EGFR was reported for 7 patients. Anti-BRAF was encorafenib for 21 patients, dabrafenib for 4 patients, with cetuximab for 24 patients and panitumumab for 1 patient. ORR was 40% (10 patients) and DCR was 80% (20 patients). Median PFS and OS were 4.8 months (95% CI, 4.01-7.95) and 10.1 months (95% CI, 7.75-NR). DCR amongst patients with previous primary resistance to anti-EGFR (N = 7) was 100%. Two patients discontinued B + E due to drug-related adverse event. CONCLUSIONS: Though in a limited retrospective series of patients, these results show the efficacy of the combination of anti-BRAF and anti-EGFRs in BRAFm mCRC patients previously treated with an anti-EGFR. The use of this combination should thus not be ruled out in this population with limited therapeutic options.


Assuntos
Carbamatos , Cetuximab , Neoplasias Colorretais , Sulfonamidas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carbamatos/uso terapêutico , Cetuximab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Humanos , Mutação , Panitumumabe , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Retrospectivos , Sulfonamidas/uso terapêutico
12.
J Immunother Cancer ; 9(2)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33589521

RESUMO

BACKGROUND: Myeloid-derived suppressor cells (MDSC), a cornerstone of cancer-related immunosuppression, influence response to therapy and disease outcomes in melanoma patients. Nevertheless, their quantification is far from being integrated into routine clinical practice mostly because of the complex and still evolving phenotypic signatures applied to define the cell subsets. Here, we used a multistep downsizing process to verify whether a core of few markers could be sufficient to capture the prognostic potential of myeloid cells in peripheral blood mononuclear cells (PBMC) of metastatic melanoma patients. METHODS: In baseline frozen PBMC from a total of 143 stage IIIc to IV melanoma patients, we first assessed the relevant or redundant expression of myeloid and MDSC-related markers by flow cytometry (screening set, n=23 patients). Subsequently, we applied the identified panel to the development set samples (n=59 patients undergoing first/second-line therapy) to obtain prognostic variables associated with overall survival (OS) and progression-free survival (PFS) by machine learning adaptive index modeling. Finally, the identified score was confirmed in a validation set (n=61) and compared with standard clinical prognostic factors to assess its additive value in patient prognostication. RESULTS: This selection process led to the identification of what we defined myeloid index score (MIS), which is composed by four cell subsets (CD14+, CD14+HLA-DRneg, CD14+PD-L1+ and CD15+ cells), whose frequencies above cut-offs stratified melanoma patients according to progressively worse prognosis. Patients with a MIS=0, showing no over-threshold value of MIS subsets, had the best clinical outcome, with a median survival of >33.6 months, while in patients with MIS 1→3, OS deteriorated from 10.9 to 6.8 and 6.0 months as the MIS increased (p<0.0001, c-index=0.745). MIS clustered patients into risk groups also according to PFS (p<0.0001). The inverse correlation between MIS and survival was confirmed in the validation set, was independent of the type of therapy and was not interfered by clinical prognostic factors. MIS HR was remarkably superior to that of lactate dehydrogenase, tumor burden and neutrophil-to-lymphocyte ratio. CONCLUSION: The MIS >0 identifies melanoma patients with a more aggressive disease, thus acting as a simple blood biomarker that can help tailoring therapeutic choices in real-life oncology.


Assuntos
Biomarcadores Tumorais/sangue , L-Lactato Desidrogenase/sangue , Melanoma/sangue , Células Supressoras Mieloides/metabolismo , Estudos de Casos e Controles , Humanos , Contagem de Linfócitos , Aprendizado de Máquina , Metástase Neoplásica , Neutrófilos/metabolismo , Prognóstico , Análise de Sobrevida
13.
Cancers (Basel) ; 12(11)2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33233603

RESUMO

Advances in the genomic, molecular and immunological make-up of melanoma allowed the development of novel targeted therapy and of immunotherapy, leading to changes in the paradigm of therapeutic interventions and improvement of patients' overall survival. Nevertheless, the mechanisms regulating either the responsiveness or the resistance of melanoma patients to therapies are still mostly unknown. The development of either the combinations or of the sequential treatment of different agents has been investigated but without a strongly molecularly motivated rationale. The need for robust biomarkers to predict patients' responsiveness to defined therapies and for their stratification is still unmet. Progress in immunological assays and genomic techniques as long as improvement in designing and performing studies monitoring the expression of these markers along with the evolution of the disease allowed to identify candidate biomarkers. However, none of them achieved a definitive role in predicting patients' clinical outcomes. Along this line, the cross-talk of melanoma cells with tumor microenvironment plays an important role in the evolution of the disease and needs to be considered in light of the role of predictive biomarkers. The overview of the relationship between the molecular basis of melanoma and targeted therapies is provided in this review, highlighting the benefit for clinical responses and the limitations. Moreover, the role of different candidate biomarkers is described together with the technical approaches for their identification. The provided evidence shows that progress has been achieved in understanding the molecular basis of melanoma and in designing advanced therapeutic strategies. Nevertheless, the molecular determinants of melanoma and their role as biomarkers predicting patients' responsiveness to therapies warrant further investigation with the vision of developing more effective precision medicine.

14.
Cells ; 9(3)2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32168869

RESUMO

Cholangiocarcinoma (CCA) represents a disease entity that comprises a heterogeneous group of biliary malignant neoplasms, with variable clinical presentation and severity. It may be classified according to its anatomical location and distinguished in intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA), each subtype implying distinct epidemiology, biology, prognosis, and strategy for clinical management. Its incidence has increased globally over the past few decades, and its mortality rate remains high due to both its biological aggressiveness and resistance to medical therapy. Surgery is the only potentially curative treatment and is the standard approach for resectable CCA; however, more than half of the patients have locally advanced or metastatic disease at presentation. For patients with unresectable CCA, the available systemic therapies are of limited effectiveness. However, the advances of the comprehension of the complex molecular landscape of CCA and its tumor microenvironment could provide new keys to better understand the pathogenesis, the mechanisms of resistance and ultimately to identify promising new therapeutic targets. Recently, clinical trials targeting isocitrate dehydrogenase (IDH)-1 mutations and fibroblast growth factor receptor (FGFR)-2 fusions, as well as immunotherapy showed promising results. All these new and emerging therapeutic options are herein discussed.


Assuntos
Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma , Terapia de Alvo Molecular , Microambiente Tumoral/efeitos dos fármacos , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/mortalidade , Colangiocarcinoma/patologia , Humanos , Imunoterapia/métodos , Terapia de Alvo Molecular/métodos , Microambiente Tumoral/genética
15.
Cancer Res ; 66(18): 9290-8, 2006 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16982774

RESUMO

Human tumors constitutively release endosome-derived microvesicles, transporting a broad array of biologically active molecules with potential modulatory effects on different immune cells. Here, we report the first evidence that tumor-released microvesicles alter myeloid cell function by impairing monocyte differentiation into dendritic cells and promoting the generation of a myeloid immunosuppressive cell subset. CD14+ monocytes isolated from healthy donors and differentiated with interleukin (IL)-4 and granulocyte macrophage colony-stimulating factor in the presence of tumor-derived microvesicles turned into HLA-DR(-/low) cells, retaining CD14 expression and failing to up-regulate costimulatory molecules, such as CD80 and CD86. These phenotypic changes were paralleled by a significant release of different cytokines, including IL-6, tumor necrosis factor-alpha, and transforming growth factor-beta (TGF-beta), and a dose-dependent suppressive activity on activated T-cell-proliferation and cytolytic functions, which could be reversed by anti-TGF-beta-neutralizing antibodies. Microvesicles isolated from plasma of advanced melanoma patients, but not from healthy donors, mediated comparable effects on CD14+ monocytes, skewing their differentiation toward CD14+HLA-DR-/low cells with TGF-beta-mediated suppressive activity on T-cell-functions. Interestingly, a subset of TGF-beta-secreting CD14+HLA-DR- cells mediating suppressive activity on T lymphocytes was found to be significantly expanded in peripheral blood of melanoma patients compared with healthy donors. These data suggest the development in cancer patients of an immunosuppressive circuit by which tumors promote the generation of suppressive myeloid cells through the release of circulating microvesicles and without the need for cell-to-cell contact. Therapeutic interventions on the crucial steps of this pathway may contribute to restore tumor/immune system interactions favoring T-cell-mediated control of tumor growth in cancer patients.


Assuntos
Neoplasias Colorretais/imunologia , Células Dendríticas/imunologia , Melanoma/imunologia , Vesículas Secretórias/imunologia , Linfócitos T/imunologia , Fator de Crescimento Transformador beta/imunologia , Apoptose/imunologia , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Endossomos/imunologia , Antígenos HLA-DR/imunologia , Humanos , Leucócitos Mononucleares/imunologia , Receptores de Lipopolissacarídeos/imunologia , Melanoma/patologia , Células Mieloides/imunologia , Fator de Crescimento Transformador beta/metabolismo
16.
Cancer Res ; 66(9): 4943-51, 2006 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-16651452

RESUMO

The use of IFN-alpha in clinical oncology has generally been based on the rationale of exploiting its antiproliferative and antiangiogenic activities. However, IFN-alpha also exhibits enhancing effects on T-cell and dendritic cell functions, which may suggest a novel use as a vaccine adjuvant. We have carried out a pilot phase I-II trial to determine the effects of IFN-alpha, administered as an adjuvant of Melan-A/MART-1:26-35(27L) and gp100:209-217(210M) peptides, on immune responses in stage IV melanoma patients. In five of the seven evaluable patients, a consistent enhancement of CD8(+) T cells recognizing modified and native MART-1 and gp100 peptides and MART-1(+)gp100(+) melanoma cells was observed. Moreover, vaccination induced an increase in CD8(+) T-cell binding to HLA tetramers containing the relevant peptides and an increased frequency of CD45RA(+)CCR7(-) (terminally differentiated effectors) and CD45RA(-)CCR7(-) (effector memory) cells. In all patients, treatment augmented significantly the percentage of CD14(+) monocytes and particularly of the CD14(+)CD16(+) cell fraction. An increased expression of CD40 and CD86 costimulatory molecules in monocytes was also observed. Notably, postvaccination monocytes from two of the three patients showing stable disease or long disease-free survival showed an enhanced antigen-presenting cell function and capability to secrete IP10/CXCL10 when tested in mixed leukocyte reaction assays, associated to a boost of antigen and melanoma-specific CD8(+) T cells. Although further clinical studies are needed to show the adjuvant activity of IFN-alpha, the present data represent an important starting point for considering a new clinical use of IFN-alpha and new immunologic end points, potentially predictive of clinical response.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/uso terapêutico , Células Dendríticas/imunologia , Interferon-alfa/uso terapêutico , Melanoma/terapia , Glicoproteínas de Membrana/imunologia , Proteínas de Neoplasias/imunologia , Adjuvantes Imunológicos/uso terapêutico , Apresentação de Antígeno , Antígenos de Neoplasias , Vacinas Anticâncer/imunologia , Células Dendríticas/citologia , Antígenos HLA-A/imunologia , Antígeno HLA-A2 , Humanos , Imunofenotipagem , Ativação Linfocitária , Antígeno MART-1 , Melanoma/imunologia , Melanoma/patologia , Monócitos/citologia , Monócitos/imunologia , Estadiamento de Neoplasias , Projetos Piloto , Antígeno gp100 de Melanoma
17.
Biomedicines ; 6(3)2018 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-30004433

RESUMO

The recent advances in immunotherapy and the availability of novel drugs to target the tumor microenvironment have dramatically changed the paradigm of cancer treatment. Nevertheless, a significant proportion of cancer patients are unresponsive or develop resistance to these treatments. With the aim to increase the clinical efficacy of immunotherapy, combinations of agents and standard therapies with complementary actions have been developed mostly on an empirical base, since their mechanisms of actions are not yet fully dissected. The characterization of immune responsiveness and its monitoring along with the treatment of cancer patients with immunotherapy can provide insights into the mechanisms of action of these therapeutic regimens and contribute to the optimization of patients' stratification and of combination strategies and to the prediction of treatment-related toxicities. Thus far, none of the immunomonitoring strategies has been validated for routine clinical practice. Moreover, it is becoming clear that the genomic and molecular make-up of tumors and of the infiltrating immune system represent important determinants of the clinical responses to immunotherapy. This review provides an overview of different approaches for the immune profiling of cancer patients and discusses their advantages and limitations. Recent advances in genomic-based assays and in the identification of host genomic relationships with immune responses represent promising approaches to identify molecular determinants and biomarkers to improve the clinical efficacy of cancer immunotherapy.

18.
Expert Opin Biol Ther ; 18(7): 765-784, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29874943

RESUMO

INTRODUCTION: Cancer vaccines represent one of the oldest immunotherapy strategies. A variety of tumor-associated antigens have been exploited to investigate their immunogenicity as well as multiple strategies for vaccine administration. These efforts have led to the development of several clinical trials in tumors with different histological origins to test the clinical efficacy of cancer vaccines. However, suboptimal clinical results have been reported mainly due to the lack of optimized strategies to induce strong and sustained systemic tumor antigen-specific immune responses. AREAS COVERED: We provide an overview of different types of cancer vaccines that have been developed and used in the context of clinical studies. Moreover, we review different preclinical and clinical strategies pursued to enhance the immunogenicity, stability, and targeting at tumor site of cancer vaccines. EXPERT OPINION: Additional and appropriate preclinical studies are warranted to optimize the immunogenicity and delivery of cancer vaccines. The appropriate choice of target antigens is challenging; however, the exploitation of neoantigens generated from somatic mutations of tumor cells represents a promising approach to target highly immunogenic tumor-specific antigens. Remarkably, the investigation of the combination of cancer vaccines with immunomodulating agents able to skew the tumor microenvironment from immunosuppressive to immunostimulating will dramatically improve their clinical efficacy.


Assuntos
Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Imunogenicidade da Vacina/fisiologia , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia , Animais , Antígenos de Neoplasias/imunologia , Humanos , Imunoterapia/tendências , Resultado do Tratamento , Microambiente Tumoral/imunologia
19.
Breast ; 42: 68-73, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30189381

RESUMO

OBJECTIVES: Cancer Testis Antigens are immunogenic tumor-specific proteins. We investigated NY-ESO-1, MAGE-A3 and PRAME, in addition to WT1 expression in different Breast Cancer (BC) subtypes. We then evaluated the expression rate of NY-ESO-1 in early Triple Negative breast cancer (TNBC), and investigated whether its expression would be maintained or lost in the metastatic setting to explore possible immunotherapy indication. MATERIALS AND METHODS: Three subgroups of BC patients were selected by the expression of ER, PgR and Her2. Tissue microarray was performed on a total of 92 Invasive BC. Sections were stained for NY-ESO-1, MAGE-A3, PRAME and WT1. The second cohort was composed by 26 metastatic TNBC patients from whom both the primary and secondary lesion tissues were available. Sections were stained for NY-ESO-1. RESULTS: NY-ESO-1 was the only differentially expressed antigen and was absent in ER+ and ER-PgR + tumors, as for an exclusive expression of either NY-ESO-1 or at least one hormonal receptor (HR+). NY-ESO-1 was particularly represented in TNBC. No correlation has been found between MAGE-A3 and PRAME expression and subtype WT1 had low expression, except in the Her2+ group. In the second cohort, NY-ESO-1 was expressed in 12 and 24% of primary and metastatic lesions respectively. CONCLUSIONS: This study defines a distinction between HR+ and HR-tumors through NY-ESO-1 expression. TNBC subgroup has the highest frequency of NY-ESO-1+ cases, and it could be the candidate population for the development of anti-NY-ESO-1 vaccine, both in the adjuvant or metastatic setting, and for the selection of cases suitable for immunotherapy.


Assuntos
Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Antígenos Específicos de Melanoma/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas WT1/metabolismo , Adulto , Neoplasias da Mama/terapia , Estudos de Coortes , Feminino , Humanos , Técnicas Imunoenzimáticas , Pessoa de Meia-Idade , Estadiamento de Neoplasias
20.
Cancer Res ; 65(9): 3942-9, 2005 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-15867395

RESUMO

Heat shock proteins (HSPs) are involved in the activation of both adaptive and innate immune systems. Here, we report that vaccination with autologous tumor-derived HSP96 of colorectal cancer patients, radically resected for liver metastases, induced a significant boost of natural killer (NK) activity detected as cytokine secretion and cytotoxicity in the presence of NK-sensitive targets. Increased NK activity was associated with a raise in CD3-CD56+ NK and/or CD3+CD56+ NK-like T cells, displaying enhanced expression of NKG2D and/or NKp46 receptors. Up-regulated expression of CD83 and CD40 and increased interleukin-12 release on stimulation were observed in CD14+ cells from post-HSP96 peripheral blood mononuclear cells, suggesting an indirect pathway of NK stimulation by HSP96-activated monocytes. Additionally, CD3-CD56+ and CD3+CD56+ lymphocytes were found to undergo functional and phenotypic activation on in vitro exposure to HSP96 even in the absence of monocytes, supporting a potential direct activity of HSP96 on these cell subsets. This evidence was confirmed by the specific binding of FITC-conjugated HSP96 to a subset of both CD3-CD56+ and CD3+CD56+ cells in peripheral blood mononuclear cells from colorectal cancer patients. Altogether, these findings identify the activation of the NK compartment as an additional immunologic effect of autologous tumor-derived HSP96 administration in cancer patients.


Assuntos
Vacinas Anticâncer/imunologia , Neoplasias Colorretais/imunologia , Proteínas de Choque Térmico/imunologia , Células Matadoras Naturais/imunologia , Linfócitos T/imunologia , Vacinas Anticâncer/uso terapêutico , Neoplasias Colorretais/sangue , Neoplasias Colorretais/terapia , Intervalo Livre de Doença , Proteínas de Choque Térmico/uso terapêutico , Humanos , Imunoterapia Ativa/métodos , Leucócitos Mononucleares/imunologia , Ativação Linfocitária
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