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1.
Mol Ther ; 28(10): 2252-2270, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-32615068

RESUMO

Adoptive T cell therapy (ACT) in combination with lymphodepleting chemotherapy is an effective strategy to induce the eradication of tumors, providing long-term regression in cancer patients. Despite that lymphodepleting regimens condition the host for optimal engraftment and expansion of adoptively transferred T cells, lymphodepletion concomitantly promotes immunosuppression during the course of endogenous immune recovery. In this study, we have identified that lymphodepleting chemotherapy initiates the mobilization of hematopoietic progenitor cells that differentiate to immunosuppressive myeloid cells, leading to a dramatic increase of peripheral myeloid-derived suppressor cells (MDSCs). In melanoma and lung cancer patients, MDSCs rapidly expanded in the periphery within 1 week after completion of a lymphodepleting regimen and infusion of autologous tumor-infiltrating lymphocytes (TILs). This expansion was associated with disease progression, poor survival, and reduced TIL persistence in melanoma patients. We demonstrated that the interleukin 6 (IL-6)-driven differentiation of mobilized hematopoietic progenitor cells promoted the survival and immunosuppressive capacity of post-lymphodepletion MDSCs. Furthermore, the genetic abrogation or therapeutic inhibition of IL-6 in mouse models enhanced host survival and reduced tumor growth in mice that received ACT. Thus, the expansion of MDSCs in response to lymphodepleting chemotherapy may contribute to ACT failure, and targeting myeloid-mediated immunosuppression may support anti-tumor immune responses.


Assuntos
Antineoplásicos/uso terapêutico , Imunoterapia Adotiva , Depleção Linfocítica , Mielopoese , Neoplasias/imunologia , Neoplasias/terapia , Linfócitos T/imunologia , Animais , Antineoplásicos/farmacologia , Modelos Animais de Doenças , Progressão da Doença , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Depleção Linfocítica/métodos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Neoplasias/diagnóstico , Neoplasias/mortalidade , Linfócitos T/metabolismo , Resultado do Tratamento
2.
Br J Cancer ; 120(8): 791-796, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30880334

RESUMO

BACKGROUND: Bypass activation of Src family kinases can confer resistance to EGFR tyrosine kinase inhibitors (TKIs) based on preclinical models. We prospectively assessed the safety and clinical activity of dasatinib and afatinib in combination for patients with resistant EGFR-mutant lung cancer. METHODS: An open-label, dose-escalation phase 1/2 trial (NCT01999985) with 2-stage expansion was conducted with 25 lung cancer patients. Dose expansion required activating EGFR mutations and progression following prior EGFR TKI. RESULTS: Patients were 72% Caucasian and received median of 2 prior lines of therapy. Maximum-tolerated dose was 30 mg afatinib with 100 mg dasatinib. New or increased pleural effusions were observed in 56% of patients. No radiologic responses were observed, although several EGFR-mutant TKI-resistant patients (26%) had prolonged stable disease over 6 months. The combination reduced the EGFR mutation and T790M variant allele frequency in cell-free DNA (p < .05). Nonetheless, the threshold for futility was met, based on 6-month progression-free survival. For EGFR TKI-resistant patients, median progression-free survival was 3.7 months (95% confidence interval (CI), 2.3-5.0) and overall survival was 14.7 months (95% CI, 8.5-20.9). CONCLUSIONS: The combination had a manageable toxicity profile and in vivo T790M modulation, but no objective clinical responses were observed.


Assuntos
Afatinib/administração & dosagem , Dasatinibe/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Afatinib/efeitos adversos , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ácidos Nucleicos Livres/efeitos dos fármacos , Dasatinibe/efeitos adversos , Progressão da Doença , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Receptores ErbB/genética , Feminino , Frequência do Gene , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/administração & dosagem , Quinases da Família src/antagonistas & inibidores
3.
Oncologist ; 24(6): 829-835, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30842242

RESUMO

BACKGROUND: Juvenile-onset recurrent respiratory papillomatosis (JO-RRP) is a human papilloma virus-mediated progressive benign neoplasm that affects children and young adults. Primary management consists of regular surgical debulking to maintain airway patency and vocal function. Like condyloma acuminata, JO-RRP is associated with immune dysregulation, and T cells isolated from papillomas express an anergic phenotype. Therefore, we hypothesized that programmed death protein 1 axis inhibition could stabilize tumor growth. MATERIALS AND METHODS: We treated two patients with refractory JO-RRP using nivolumab, with the primary objective of assessing clinical activity. We explored baseline papilloma features using immunohistochemistry and comprehensive genomic profiling. RESULTS: Both patients experienced symptomatic improvement, and interval laryngoscopies revealed a reduction in papillomatosis burden. One patient has not required subsequent surgical debridement for almost 2 years. On pathologic examination of pretreatment papillomas from both cases, infiltrating T cells were evident in the papilloma stroma, and papilloma programmed death ligand 1 expression was absent. Papilloma mutational load ranged between three and six mutations per megabase for each case. From on-treatment biopsy tissue, a higher amount of intraepithelial T cells and programmed death ligand 1 expression were detected in the papilloma. CONCLUSION: Nivolumab appears to have promising activity in JO-RRP, and further clinical investigation with more patients in clinical trials is warranted. IMPLICATIONS FOR PRACTICE: To the authors' knowledge, this article is the first report describing clinical activity with a programed cell death-1 (PD-1) inhibitor to treat a rare but detrimental type of respiratory tract epithelial neoplasm that afflicts young adults. Two patients were treated, and tumor features, such as mutational load, were examined with the intent to stimulate future hypotheses for translational research. The safety and activity of PD-1 inhibitors in this population still need to be corroborated in clinical trials and should not yet be adopted into clinical practice.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Nivolumabe/uso terapêutico , Infecções por Papillomavirus/terapia , Infecções Respiratórias/terapia , Adulto , Antineoplásicos Imunológicos/farmacologia , Brônquios/diagnóstico por imagem , Brônquios/patologia , Brônquios/cirurgia , Brônquios/virologia , Broncoscopia , Quimioterapia Adjuvante/métodos , Procedimentos Cirúrgicos de Citorredução , Desbridamento , Feminino , Humanos , Laringoscopia , Masculino , Nivolumabe/farmacologia , Papillomaviridae/imunologia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/patologia , Infecções Respiratórias/virologia , Tomografia Computadorizada por Raios X , Traqueia/diagnóstico por imagem , Traqueia/patologia , Traqueia/cirurgia , Traqueia/virologia , Resultado do Tratamento
4.
Cancer Immunol Immunother ; 68(3): 517-527, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30591959

RESUMO

Small cell lung cancer TP53 mutations lead to expression of tumor antigens that elicits specific cytotoxic T-cell immune responses. In this phase II study, dendritic cells transfected with wild-type TP53 (vaccine) were administered to patients with extensive-stage small cell lung cancer after chemotherapy. Patients were randomized 1:1:1 to arm A (observation), arm B (vaccine alone), or arm C (vaccine plus all-trans-retinoic acid). Vaccine was administered every 2 weeks (3 times), and all patients were to receive paclitaxel at progression. Our primary endpoint was overall response rate (ORR) to paclitaxel. The study was not designed to detect overall response rate differences between arms. Of 69 patients enrolled (performance status 0/1, median age 62 years), 55 were treated in stage 1 (18 in arm A, 20 in arm B, and 17 in arm C) and 14 in stage 2 (arm C only), per 2-stage Simon Minimax design. The vaccine was safe, with mostly grade 1/2 toxicities, although 1 arm-B patient experienced grade 3 fatigue and 8 arm-C patients experienced grade 3 toxicities. Positive immune responses were obtained in 20% of arm B (95% confidence interval [CI], 5.3-48.6) and 43.3% of arm C (95% CI 23.9-65.1). The ORRs to the second-line chemotherapy (including paclitaxel) were 15.4% (95% CI 2.7-46.3), 16.7% (95% CI 2.9-49.1), and 23.8% (95% CI 9.1-47.5) for arms A, B, and C, with no survival differences between arms. Although our vaccine failed to improve ORRs to the second-line chemotherapy, its safety profile and therapeutic immune potential remain. Combinations with the other immunotherapeutic agents are reasonable options.


Assuntos
Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Neoplasias Pulmonares/terapia , Recidiva Local de Neoplasia/terapia , Carcinoma de Pequenas Células do Pulmão/terapia , Proteína Supressora de Tumor p53/genética , Vacinação , Adulto , Idoso , Vacinas Anticâncer/efeitos adversos , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Paclitaxel/uso terapêutico , Terapia de Salvação , Carcinoma de Pequenas Células do Pulmão/mortalidade , Transfecção
5.
Psychooncology ; 28(6): 1234-1242, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30932275

RESUMO

OBJECTIVE: Loneliness, or the discrepancy between perceived and desired level of social connectedness, is an understudied but important psychosocial factor in cancer patients. The current study investigated the relationship between loneliness, depressive symptoms, quality of life, and social cognitive variables (eg, stigma, social constraint, and cancer-related negative social expectations), and explored loneliness as a mediator of the relationship between social cognitive variables and depressive symptoms and quality of life in lung cancer patients beginning treatment. METHODS: Patients within 3 months of beginning treatment for lung cancer completed measures of loneliness, depressive symptoms, quality of life, and social cognitive variables. Correlational, chi-square, and hierarchical regression analyses evaluated relationships among variables. Bias-corrected bootstrapping methods estimated the indirect effect and 95% confidence interval for mediation models. RESULTS: Participants (n = 105, M = 65.5 years, 55% female) endorsed low to moderate levels of loneliness. Greater loneliness was associated with greater depressive symptoms and worse quality of life (P's < .001), and loneliness explained unique variance in depressive symptoms (F = 10.18, P < .001, ΔR2  = .06, Total R2  = .35) and quality of life (F = 19.55, P < .001, ΔR2  = .05, Total R2  = .52) after controlling for significant covariates. Greater stigma, social constraint, and cancer-related negative social expectations were associated with greater loneliness and depressive symptoms and worse quality of life (P's < .001). Loneliness partially mediated the relationship of social cognitive variables with depressive symptoms and quality of life. CONCLUSIONS: Beyond its direct impact on clinically relevant outcomes, the experience of loneliness may be a mechanism by which social cognitive factors influence depressive symptoms and quality of life in lung cancer patients.


Assuntos
Depressão/psicologia , Solidão/psicologia , Neoplasias Pulmonares/psicologia , Qualidade de Vida/psicologia , Percepção Social , Estigma Social , Idoso , Feminino , Humanos , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade
6.
Cancer Immunol Immunother ; 67(12): 1853-1862, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30209589

RESUMO

The GM.CD40L vaccine, which recruits and activates dendritic cells, migrates to lymph nodes, activating T cells and leading to systemic tumor cell killing. When combined with the CCL21 chemokine, which recruits T cells and enhances T-cell responses, additive effects have been demonstrated in non-small cell lung cancer mouse models. Here, we compared GM.CD40L versus GM.CD40L plus CCL21 (GM.CD40L.CCL21) in lung adenocarcinoma patients with ≥ 1 line of treatment. In this phase I/II randomized trial (NCT01433172), patients received intradermal vaccines every 14 days (3 doses) and then monthly (3 doses). A two-stage minimax design was used. During phase I, no dose-limiting toxicities were shown in three patients who received GM.CD40L.CCL21. During phase II, of evaluable patients, 5/33 patients (15.2%) randomized for GM.DCD40L (p = .023) and 3/32 patients (9.4%) randomized for GM.DCD40L.CCL21 (p = .20) showed 6-month progression-free survival. Median overall survival was 9.3 versus 9.5 months with GM.DCD40L versus GM.DCD40L.CCL21 (95% CI 0.70-2.25; p = .44). For GM.CD40L versus GM.CD40L.CCL21, the most common treatment-related adverse events (TRAEs) were grade 1/2 injection site reaction (51.4% versus 61.1%) and grade 1/2 fatigue (35.1% versus 47.2%). Grade 1 immune-mediated TRAEs were isolated to skin. No patients showed evidence of pseudo-progression or immune-related TRAEs of grade 1 or greater of pneumonitis, endocrinopathy, or colitis, and none discontinued treatment due to toxicity. Although we found no significant associations between vaccine immunogenicity and outcomes, in limited biopsies, one patient treated with GMCD40L.CCL21 displayed abundant tumor-infiltrating lymphocytes. This possible effectiveness warrants further investigation of GM.CD40L in combination approaches.


Assuntos
Adenocarcinoma/terapia , Ligante de CD40/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiocina CCL21/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Imunoterapia , Adenocarcinoma/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/imunologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida
7.
J Neurooncol ; 133(2): 331-338, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28466250

RESUMO

Anti-PD-1/PD-L1 therapies have demonstrated activity in patients with advanced stage non-small cell lung cancer (NSCLC). However, little is known about the safety and feasibility of patients receiving anti-PD-1/PD-L1 therapy and stereotactic radiation for the treatment of brain metastases. Data were analyzed retrospectively from NSCLC patients treated with stereotactic radiation either before, during or after anti-PD-1/PD-L1 therapy with nivolumab (anti-PD-1) or durvalumab (anti-PD-L1). Seventeen patients treated with stereotactic radiosurgery (SRS) or fractionated stereotactic radiation therapy (FSRT) to 49 brain metastases over 21 sessions were identified. Radiation was administered prior to, during and after anti-PD-1/PD-L1 therapy in 22 lesions (45%), 13 lesions (27%), and 14 lesions (29%), respectively. The 6 months Kaplan-Meier (KM) distant brain control rate was 48% following stereotactic radiation. Six and 12 month KM rates of OS from the date of stereotactic radiation and the date of cranial metastases diagnosis were 48/41% and 81/51%, respectively. The 6 month rate of distant brain control following stereotactic radiation for patients treated with stereotactic radiation during or prior to anti-PD-1/PD-L1 therapy was 57% compared to 0% among patients who received anti-PD-1/PD-L1 therapy before stereotactic radiation (p = 0.05). A Karnofsky Performance Status (KPS) of <90 was found to be predictive of worse OS following radiation treatment on both univariate and multivariate analyses (MVA, p = 0.01). In our series, stereotactic radiation to NSCLC brain metastases was well tolerated in patients who received anti-PD-1/PD-L1 therapy. Prospective evaluation to determine how these two modalities can be used synergistically to improve distant brain control and OS is warranted.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Irradiação Craniana/métodos , Receptor de Morte Celular Programada 1/imunologia , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Terapia Combinada , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Resultado do Tratamento
8.
Semin Respir Crit Care Med ; 34(6): 810-21, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24258571

RESUMO

Several recent immunotherapy agents have exhibited exceptional activity, and their eventual approval for use in lung cancer appears plausible. The immune checkpoint proteins, such as the B7 superfamily, are becoming increasingly relevant targets for therapeutic inhibition. Tumor vaccines hold the potential to deliver durable responses that are specific for tumor antigen, with favorable adverse effect profiles. Several vaccine trials are accruing more patients than any previous lung cancer trials and are designed to select a specific population based on a predefined, scientifically justified biomarker. These emerging immune treatments may hold great potential for the systemic treatment of lung cancers.


Assuntos
Antígenos B7/imunologia , Imunoterapia/métodos , Neoplasias Pulmonares/terapia , Animais , Antígenos de Neoplasias/imunologia , Biomarcadores Tumorais/metabolismo , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Ensaios Clínicos como Assunto , Humanos , Imunoterapia/efeitos adversos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Seleção de Pacientes
9.
Lung Cancer ; 183: 107313, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37499521

RESUMO

BACKGROUND: Activating mutations in EGFR or KRAS are highly prevalent in NSCLC, share activation of the MAPK pathway and may be amenable to combination therapy to prevent negative feedback activation. METHODS: In this phase 1/1B trial, we tested the combination of binimetinib and erlotinib in patients with advanced NSCLC with at least 1 prior line of treatment (unless with activating EGFR mutation which could be treatment-naïve). A subsequent phase 1B expansion accrued patients with either EGFR- or KRAS-mutation using the recommended phase 2 dose (RP2D) from Phase 1. The primary objective was to evaluate the safety of binimetinib plus erlotinib and establish the RP2D. RESULTS: 43 patients enrolled (dose-escalation = 23; expansion = 20). 17 harbored EGFR mutation and 22 had KRAS mutation. The RP2D was erlotinib 100 mg daily and binimetinib 15 mg BID × 5 days/week. Common AEs across all doses included diarrhea (69.8%), rash (44.2%), fatigue (32.6%), and nausea (32.6%), and were primarily grade 1/2. Among KRAS mutant patients, 1 (5%) had confirmed partial response and 8 (36%) achieved stable disease as best overall response. Among EGFR mutant patients, 9 were TKI-naïve with 8 (89%) having partial response, and 8 were TKI-pretreated with no partial responses and 1 (13%) stable disease as best overall response. CONCLUSIONS: Binimetinib plus erlotinib demonstrated a manageable safety profile and modest efficacy including one confirmed objective response in a KRAS mutant patient. While clinical utility of this specific combination was limited, these results support development of combinations using novel small molecule inhibitors of RAS, selective EGFR- and other MAPK pathway inhibitors, many of which have improved therapeutic indices. CLINICAL TRIAL REGISTRATION: NCT01859026.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas p21(ras)/genética
11.
Cell Metab ; 32(3): 420-436.e12, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32768387

RESUMO

Dysregulated metabolism is a key driver of maladaptive tumor-reactive T lymphocytes within the tumor microenvironment. Actionable targets that rescue the effector activity of antitumor T cells remain elusive. Here, we report that the Sirtuin-2 (Sirt2) NAD+-dependent deacetylase inhibits T cell metabolism and impairs T cell effector functions. Remarkably, upregulation of Sirt2 in human tumor-infiltrating lymphocytes (TILs) negatively correlates with response to TIL therapy in advanced non-small-cell lung cancer. Mechanistically, Sirt2 suppresses T cell metabolism by targeting key enzymes involved in glycolysis, tricarboxylic acid-cycle, fatty acid oxidation, and glutaminolysis. Accordingly, Sirt2-deficient murine T cells exhibit increased glycolysis and oxidative phosphorylation, resulting in enhanced proliferation and effector functions and subsequently exhibiting superior antitumor activity. Importantly, pharmacologic inhibition of Sirt2 endows human TILs with these superior metabolic fitness and effector functions. Our findings unveil Sirt2 as an unexpected actionable target for reprogramming T cell metabolism to augment a broad spectrum of cancer immunotherapies.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Sirtuína 2/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Animais , Antineoplásicos/química , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Células Cultivadas , Inibidores Enzimáticos/química , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Sirtuína 2/deficiência , Sirtuína 2/metabolismo , Linfócitos T/metabolismo
12.
Oncotarget ; 10(8): 810-824, 2019 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-30783512

RESUMO

Transforming growth factor beta (TGFß) plays a key role in regulating epithelial-to-mesenchymal transition (EMT). A gene expression signature (TGFß-EMT) associated with TGFß-induced EMT activities was developed using human Non-Small Cell Lung Carcinoma (NSCLC) cells treated with TGFß-1 and subjected to Affymetrix microarray analysis. The final 105-probeset TGFß-EMT signature covers 77 genes, and a NanoString assay utilized a subset of 60 of these genes (TGFß-EMTN signature). We found that the TGFß-EMT and TGFß-EMTN gene signatures predicted overall survival (OS) and metastasis-free survival (MFS). The TGFß-EMT signature was validated as prognostic of 5-year MFS in 3 cohorts: a 133 NSCLC tumor dataset (P = 0.0002), a NanoString assays of RNA isolated from formalin-fixed paraffin-embedded samples from these same tumors (P = 0.0015), and a previously published NSCLC MFS dataset (P = 0.0015). The separation between high and low metastasis signature scores was higher at 3 years (ΔMFS TGFß-EMT = -28.6%; ΔMFS TGFß-EMTN = -25.2%) than at 5 years (ΔMFS TGFß-EMT = -18.6%; ΔMFS TGFß-EMTN = -11.8%). In addition, the TGFß-EMT signature correlated with whether the cancer had already metastasized or not at time of surgery in a colon cancer cohort. The results show that the TGFß-EMT signature successfully discriminated lung cancer cell lines capable of undergoing EMT in response to TGFß-1 and predicts MFS in lung adenocarcinomas. Thus, the TGFß-EMT signature has the potential to be developed as a clinically relevant predictive biomarker, for example to identify those patients with resected early stage lung cancer who may benefit from adjuvant therapy.

13.
JNCI Cancer Spectr ; 2(3): pky021, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30057972

RESUMO

Clinical trials in the past decade have established the antitumor effects of immune checkpoint inhibition as a revolutionary treatment for cancer. Namely, blocking antibodies to cytotoxic T-lymphocyte antigen 4 and programmed death 1 or its ligand have reached routine clinical use. Manipulation of the immune system is not without side effects, and autoimmune toxicities often known as immune-related adverse events (IRAEs) are observed. Endocrine IRAEs, such as hypophysitis, thyroid dysfunction, and insulin-dependent diabetes mellitus, can present with unique profiles that are not seen with the use of traditional chemotherapeutics. In this Review, we discuss the current hypotheses regarding the mechanism of these endocrinopathies and their clinical presentations. Further, we suggest guidelines and algorithms for patient management and future clinical trials to optimize the detection and treatment of immune checkpoint-related endocrinopathies.

14.
J Immunother Cancer ; 5(1): 54, 2017 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-28716137

RESUMO

BACKGROUND: The combination of CTLA-4 and PD-L1 inhibitors has a manageable adverse effect profile, although rare immune-related adverse events (irAE) can occur. CASE PRESENTATION: We describe an autoimmune polymyositis following a partial response to combination tremelimumab and durvalumab for the treatment of recurrent lung adenocarcinoma. Radiography revealed significant reduction in all metastases; however, the patient developed progressive neuromuscular hypoventilation due to lymphocytic destruction of the diaphragmatic musculature. Serologic testing revealed a low level of de novo circulating antibodies against striated muscle fiber. Immunohistochemistry revealed type II muscle fiber atrophy with a mixed CD8+ and CD4+ lymphocyte infiltrate, indicative of inflammatory myopathy. CONCLUSIONS: This case supports the hypothesis that muscle tissue is a target for lymphocytic infiltration in immune checkpoint inhibitor-associated polymyositis. Further insights into the autoimmune mechanism of PM will hopefully contribute to the prevention and treatment of this phenomenon.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Hipoventilação/induzido quimicamente , Polimiosite/induzido quimicamente , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Evolução Fatal , Feminino , Humanos , Infiltração Leucêmica/induzido quimicamente , Infiltração Leucêmica/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Músculos Respiratórios/imunologia
15.
Onco Targets Ther ; 10: 4239-4250, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28919776

RESUMO

BACKGROUND: Omaveloxolone is a semisynthetic oleanane triterpenoid that potently activates Nrf2 with subsequent antioxidant function. We conducted a first-in-human Phase I clinical trial (NCT02029729) with the primary objectives to determine the appropriate dose for Phase II studies, characterize pharmacokinetic and pharmacodynamic parameters, and assess antitumor activity. METHODS: Omaveloxolone was administered orally once daily continuously in a 28-day cycle for patients with stage 4 relapsed/refractory melanoma or non-small cell lung cancer. An accelerated titration design was employed until a grade 2-related adverse event (AE) occurred. A standard 3+3 dose escalation was employed. Single-dose and steady-state plasma pharmacokinetics of the drug were characterized. Downstream Nrf2 activation was assessed in peripheral blood mononuclear cells by quantification of target gene mRNA expression. RESULTS: Omaveloxolone was tested at four dose levels up to 15 mg given orally once daily. No dose-limiting toxicities were detected, and the maximum tolerated dose was not determined. All drug-related AEs were either grade 1 or 2 in severity, and none required clinical action. The most common drug-related AEs were elevated alkaline phosphatase (18%) and anemia (18%). No drug interruptions or reductions were required. Omaveloxolone was rapidly absorbed and exhibited proportional increases in exposure across dose levels. With some exceptions, an overall trend toward time-dependent and dose-dependent activation of Nrf2 antioxidant genes was observed. No confirmed radiologic responses were seen, although one lung cancer subject did have stable disease exceeding 1 year. CONCLUSIONS: Omaveloxolone has favorable tolerability at biologically active doses, although this trial had a small sample size which limits definitive conclusions. These findings support further investigation of omaveloxolone in cancer.

16.
Oncotarget ; 7(50): 82254-82265, 2016 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-27756884

RESUMO

Clinicians routinely prescribe adjuvant chemotherapy (ACT) for resected non-small cell lung cancer patients. However, ACT only improves five-year disease-free survival in stage I-III non-small cell lung cancer by 5-15%, with most patients deriving no benefit. Herein, deregulation of the E2F pathway was explored as a biomarker in lung adenocarcinoma patients. An E2F pathway scoring system, based on 74 E2F-regulated genes, was trained for RNA from two platforms: fresh-frozen (FF) or formalin-fixed paraffin-embedded (FFPE) tissues. The E2F score was tested as a prognostic biomarker in five FF-based cohorts and two FFPE-based cohorts. The E2F score was tested as a predictive biomarker in two randomized clinical trials; JBR10 and the NATCH (Neo-Adjuvant Taxol-Carboplatin Hope) trial. The E2F score was prognostic in untreated patients in all seven datasets examined (p < 0.05). Stage-specific analysis of combined cohorts demonstrated that the E2F score was prognostic in stage I patients (p = 0.0495 to <0.001; hazard ratio, HR, =2.04- 2.22) with a similar trend in other stages. The E2F score was strongly predictive in stage II patients from the two combined randomized clinical trials with a significant differential treatment effect (p = 0.015). Specifically, ACT improved survival in stage II patients with high E2F (p = 0.01; HR= 0.21). The 5-year survival increased from 18% to 81%. In contrast, in patients with low E2F, 5-year survival was 57% in untreated patients and 41% in ACT-treated patients with a HR of 1.55 (p = 0.47). In summary, the E2F score provides valuable prognostic information for Stage I and predictive information for Stage II lung adenocarcinoma patients and should be further explored as a decision support tool for their treatment.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Fatores de Transcrição E2F/genética , Neoplasias Pulmonares/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Terapia Neoadjuvante , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Medicina de Precisão , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Fatores de Tempo , Transcriptoma , Resultado do Tratamento
17.
Oncoimmunology ; 2(3): e23428, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23802083

RESUMO

Indoleamine 2,3-dioxygenase (IDO) has recently been proposed to account for tumor-induced immunosuppression by influencing the conversion of tryptophan (Trp) into kynurenine (Kyn). The objective of our study was to correlate IDO activity with disease outcome in non-small cell lung cancer (NSCLC) patients treated with multimodal combination therapy. In a single-arm Phase II trial involving induction gemcitabine and carboplatin followed by concurrent paclitaxel, carboplatin and 74 Gy thoracic radiation in stage III NSCLC patients, plasma was drawn at baseline, post-induction, and post-concurrent therapy. The mean plasma Kyn/Trp ratio was used as a surrogate indicator of IDO activity. The 33 participants were distributed as follows: 15 females, 18 males; median age = 62; median overall survival (OS) = 22.4 (95% CI 19.3-25.1) months; median progression-free survival (PFS) = 11.5 (95% CI 6.7-16.3) months. The mean Kyn/Trp ratio at baseline (4.5 ± 2.8) was higher than that of healthy controls (2.9 ± 1.9, p = 0.03) and increased after induction therapy (5.2 ± 3.2, p = 0.08) and chemoradiation (5.8 ± 3.9, p = 0.01). The post-treatment Kyn/Trp ratio and radiologic responses were not significantly associated at any time point. No significant correlation was found between baseline Kyn/Trp ratios and OS (HR = 1.1, 95% CI 0.45-2.5) or PFS (HR = 0.74, 95% CI 0.30-1.82). A post-induction chemotherapy increase in IDO activity portended worse OS (HR = 0.43, 95% CI 0.19-0.95, p = 0.037) and PFS (HR = 0.47, 95% CI 0.22-1.0, p = 0.055). This observed increase in IDO transcription may be a means for tumors to evade immunosurveillance.

18.
J Immunother ; 36(8): 442-50, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23994887

RESUMO

We created a vaccine in which irradiated allogeneic lung adenocarcinoma cells are combined with a bystander K562 cell line transfected with hCD40L and hGM-CSF. By recruiting and activating dendritic cells, we hypothesized that the vaccine would induce tumor regression in metastatic lung adenocarcinoma. Intradermal vaccine was given q14 days×3, followed by monthly ×3. Cyclophosphamide (300 mg/m IV) was administered before the first and fourth vaccines to deplete regulatory T cells. All-trans retinoic acid was given (150/mg/m/d) after the first and fourth vaccines to enhance dendritic cell differentiation. Twenty-four participants were accrued at a single institution from October 2006 to June 2008, with a median age 64 years and median of 4 previous lines of systemic therapy. A total of 101 vaccines were administered. Common toxicities were headache (54%) and site reaction (38%). No radiologic responses were observed. Median overall survival was 7.9 months and median progression-free survival was 1.7 months. Of 14 patients evaluable for immunological study, 5 had peptide-induced CD8 T-cell activation after vaccination. Overall, vaccine administration was feasible in an extensively pretreated population of metastatic lung cancer. Despite a suggestion of clinical activity in the subset with immune response, the trial did not meet the primary endpoint of inducing radiologic tumor regression.


Assuntos
Adenocarcinoma/terapia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer , Células Dendríticas/imunologia , Neoplasias Pulmonares/terapia , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Idoso , Apresentação de Antígeno , Antígenos de Neoplasias/imunologia , Efeito Espectador , Ligante de CD40/genética , Ligante de CD40/metabolismo , Diferenciação Celular/efeitos dos fármacos , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Células K562 , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva , Análise de Sobrevida , Transgenes/genética , Resultado do Tratamento , Tretinoína/administração & dosagem
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