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1.
Gynecol Oncol ; 191: 74-79, 2024 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-39362046

RESUMO

BACKGROUND: Denileukin diftitox (ONTAK) is a diphtheria/IL-2R fusion protein able to deplete regulatory T cells in peripheral blood. Regulatory T cells in the local immune microenvironment have been shown to be associated with poor prognosis in ovarian cancer. This study examined whether denileukin diftitox (ONTAK) could be safely administered intraperitoneal in patients with advanced refractory ovarian cancer and assessed its effects on regulatory T cells and tumor associated cytokines in ascites and peripheral blood. PATIENTS AND METHODS: A phase I dose escalation study of intraperitoneal denileukin diftitox (ONTAK) enrolled 10 patients with advanced, refractory ovarian carcinoma at 3 doses (5 µg/kg, 15 µg/kg, and 25 µg/kg). Serial CA-125 measurements assessed clinical response. Regulatory T cells were quantified using RT-PCR and cytokine levels measured by Luminex. RESULTS: The maximum tolerated dose was 15 µg/kg with a dose limiting toxicity observed in 1 out of 6 patients in the expansion group. The majority of adverse events were transient grades 1-2. One patient treated at the 25 µg/kg dose experienced cytokine storm with prolonged hospitalization. 3 patients had decreases in CA-125 after treatment but none met criteria for partial response. Treatment with denileukin diftitox (ONTAK) decreased regulatory T cells in peripheral blood and ascites. Treated patients did not show any significant changes in IL-8, TGF-ß, sIL2Ra in ascites or peripheral blood. CONCLUSIONS: Denileukin diftitox (ONTAK) can be safely administered intraperitoneally to recurrent refractory ovarian cancer patients. Regulatory T cells were reduced in ascites and peripheral blood, but there were no significant changes in cytokine levels. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov # NCT00357448.

2.
Adv Exp Med Biol ; 1168: 117-129, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31713168

RESUMO

Personalized medicine in oncology utilizes evidence derived from genetic, immune, and proteomic profiling to inform therapeutic options as well as provide prognostic information for each unique individual and their tumor. Our ability to biologically and immunologically define each patient's tumor has been driven by the development of assays characterizing the genomic and proteomic profiles of tumors that in turn have led to the development of large biologic databases and computational tools for the analysis of these large data sets. In Immuno-oncology, the introduction of checkpoint inhibitors and their approval across multiple tumor types has led to the recognition that the majority of patients will not clinically respond to these therapies but will remain at risk for the development of significant immunologic side effects. This challenge highlights the need for the development and validation of both predictive biomarkers for response to such therapies as well as biomarkers prognostic of disease course. Despite extensive investigation into predictive biomarkers using these biologic databases and computational methods, only recently has progress been made in this area. This progress is the first step allowing us to identify patients likely to benefit from these therapies and moving our field closer to a truly personalized approach to the use of immune therapies in oncology.


Assuntos
Neoplasias , Medicina de Precisão , Biomarcadores Tumorais , Humanos , Oncologia/tendências , Neoplasias/imunologia , Neoplasias/terapia , Medicina de Precisão/tendências , Proteômica
3.
Breast Cancer Res ; 20(1): 90, 2018 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-30092835

RESUMO

BACKGROUND: Upregulation of human epidermal growth factor receptor 3 (HER3) is a major mechanism of acquired resistance to therapies targeting its heterodimerization partners epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), but also exposes HER3 as a target for immune attack. We generated an adenovirus encoding full length human HER3 (Ad-HER3) to serve as a cancer vaccine. Previously we reported the anti-tumor efficacy and function of the T cell response to this vaccine. We now provide a detailed assessment of the antitumor efficacy and functional mechanisms of the HER3 vaccine-induced antibodies (HER3-VIAs) in serum from mice immunized with Ad-HER3. METHODS: Serum containing HER3-VIA was tested in complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) assays and for its effect on HER3 internalization and degradation, downstream signaling of HER3 heterodimers and growth of metastatic HER2+ (BT474M1), HER2 therapy-resistant (rBT474), and triple negative (MDA-MB-468) breast cancers. RESULTS: HER3-VIAs mediated CDC and ADCC, HER3 internalization, interruption of HER3 heterodimer-driven tumor signaling pathways, and anti-proliferative effects against HER2+ tumor cells in vitro and significant antitumor effects against metastatic HER2+ BT474M1, treatment refractory HER2+ rBT474 and triple negative MDA-MB-468 in vivo. CONCLUSIONS: In addition to the T cell anti-tumor response induced by Ad-HER3, the HER3-VIAs provide additional functions to eliminate tumors in which HER3 signaling mediates aggressive behavior or acquired resistance to HER2-targeted therapy. These data support clinical studies of vaccination against HER3 prior to or concomitantly with other therapies to prevent outgrowth of therapy-resistant HER2+ and triple negative clones.


Assuntos
Anticorpos/imunologia , Antineoplásicos/farmacologia , Vacinas Anticâncer/imunologia , Receptor ErbB-3/imunologia , Neoplasias de Mama Triplo Negativas/terapia , Adenoviridae/genética , Animais , Citotoxicidade Celular Dependente de Anticorpos , Antineoplásicos/uso terapêutico , Mama/patologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/genética , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Mapeamento de Epitopos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Humanos , Imunização Passiva/métodos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Receptor ErbB-3/genética , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Breast Cancer Res ; 16(4): 407, 2014 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-25060555

RESUMO

INTRODUCTION: Despite improvements in adjuvant therapy, late systemic recurrences remain a lethal consequence of both early- and late-stage breast cancer. A delayed recurrence is thought to arise from a state of tumor dormancy, but the mechanisms that govern tumor dormancy remain poorly understood. METHODS: To address the features of breast tumors associated with late recurrence, but not confounded by variations in systemic treatment, we compiled breast tumor gene expression data from 4,767 patients and established a discovery cohort consisting of 743 lymph node-negative patients who did not receive systemic neoadjuvant or adjuvant therapy. We interrogated the gene expression profiles of the 743 tumors and identified gene expression patterns that were associated with early and late disease recurrence among these patients. We applied this classification to a subset of 46 patients for whom expression data from microdissected tumor epithelium and stroma was available, and identified a distinct gene signature in the stroma and also a corresponding tumor epithelium signature that predicted disease recurrence in the discovery cohort. This tumor epithelium signature was then validated as a predictor for late disease recurrence in the entire cohort of 4,767 patients. RESULTS: We identified a novel 51-gene signature from microdissected tumor epithelium associated with late disease recurrence in breast cancer independent of the molecular disease subtype. This signature correlated with gene expression alterations in the adjacent tumor stroma and describes a process of epithelial to mesenchymal transition (EMT) and tumor-stroma interactions. CONCLUSIONS: Our findings suggest that an EMT-related gene signature in the tumor epithelium is related to both stromal activation and escape from disease dormancy in breast cancer. The presence of a late recurrence gene signature in the primary tumor also suggests that intrinsic features of this tumor regulate the transition of disseminated tumor cells into a dormant phenotype with the ability to outgrowth as recurrent disease.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Transição Epitelial-Mesenquimal/genética , Células Estromais/metabolismo , Transcriptoma , Adulto , Idoso , Biomarcadores Tumorais , Neoplasias da Mama/mortalidade , Análise por Conglomerados , Conjuntos de Dados como Assunto , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Recidiva Local de Neoplasia , Razão de Chances , Prognóstico , Carga Tumoral , Microambiente Tumoral
5.
Breast Cancer Res ; 15(5): R85, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24044505

RESUMO

INTRODUCTION: The human epidermal growth factor receptor 2 (HER2) receptor tyrosine kinase (RTK) oncogene is an attractive therapeutic target for the treatment of HER2-addicted tumors. Although lapatinib, an FDA-approved small-molecule HER2 and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), represents a significant therapeutic advancement in the treatment of HER2+ breast cancers, responses to lapatinib have not been durable. Consequently, elucidation of mechanisms of acquired therapeutic resistance to HER-directed therapies is of critical importance. METHODS: Using a functional protein-pathway activation mapping strategy, along with targeted genomic knockdowns applied to a series of isogenic-matched pairs of lapatinib-sensitive and resistant cell lines, we now report an unexpected mechanism of acquired resistance to lapatinib and similar TKIs. RESULTS: The signaling analysis revealed that whereas HER2 was appropriately inhibited in lapatinib-resistant cells, EGFR tyrosine phosphorylation was incompletely inhibited. Using a targeted molecular knockdown approach to interrogate the causal molecular underpinnings of EGFR-persistent activation, we found that lapatinib-resistant cells were no longer oncogene addicted to HER2-HER3-PI3K signaling, as seen in the parental lapatinib-sensitive cell lines, but instead were dependent on a heregulin (HRG)-driven HER3-EGFR-PI3K-PDK1 signaling axis. Two FDA-approved EGFR TKIs could not overcome HRG-HER3-mediated activation of EGFR, or reverse lapatinib resistance. The ability to overcome EGFR-mediated acquired therapeutic resistance to lapatinib was demonstrated through molecular knockdown of EGFR and treatment with the irreversible pan-HER TKI neratinib, which blocked HRG-dependent phosphorylation of HER3 and EGFR, resulting in apoptosis of resistant cells. In addition, whereas HRG reversed lapatinib-mediated antitumor effects in parental HER2+ breast cancer cells, neratinib was comparatively resistant to the effects of HRG in parental cells. Finally, we showed that HRG expression is an independent negative predictor of clinical outcome in HER2+ breast cancers, providing potential clinical relevance to our findings. CONCLUSIONS: Molecular analysis of acquired therapeutic resistance to lapatinib identified a new resistance mechanism based on incomplete and "leaky" inhibition of EGFR by lapatinib. The selective pressure applied by incomplete inhibition of the EGFR drug target resulted in selection of ligand-driven feedback that sustained EGFR activation in the face of constant exposure to the drug. Inadequate target inhibition driven by a ligand-mediated autocrine feedback loop may represent a broader mechanism of therapeutic resistance to HER TKIs and suggests adopting a different strategy for selecting more effective TKIs to advance into the clinic.


Assuntos
Comunicação Autócrina , Neoplasias da Mama/metabolismo , Receptores ErbB/metabolismo , Neuregulina-1/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Transdução de Sinais , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Proteína Tirosina Quinase CSK , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Lapatinib , Neuregulina-1/genética , Fosfatidilinositol 3-Quinases , Fosfoproteínas Fosfatases/metabolismo , Fosforilação , Prognóstico , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Piruvato Desidrogenase Quinase de Transferência de Acetil , Quinazolinas/farmacologia , Receptor ErbB-3/genética , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Quinases da Família src/antagonistas & inibidores
6.
J Clin Oncol ; 41(2): 198-205, 2023 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-36332179

RESUMO

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Final overall survival (OS) in SOPHIA (ClinicalTrials.gov identifier: NCT02492711), a study of margetuximab versus trastuzumab, both with chemotherapy, in patients with previously treated human epidermal growth factor receptor 2-positive advanced breast cancer, is reported with updated safety. Overall, 536 patients in the intention-to-treat population were randomly assigned to margetuximab (15 mg/kg intravenously once every 3 weeks; n = 266) plus chemotherapy or trastuzumab (6 mg/kg intravenously once every 3 weeks after a loading dose of 8 mg/kg; n = 270) plus chemotherapy. Primary end points were progression-free survival, previously reported, and OS. Final OS analysis was triggered by 385 prespecified events. The median OS was 21.6 months (95% CI, 18.89 to 25.07) with margetuximab versus 21.9 months (95% CI, 18.69 to 24.18) with trastuzumab (hazard ratio [HR], 0.95; 95% CI, 0.77 to 1.17; P = .620). Preplanned, exploratory analysis of CD16A genotyping suggested a possible improvement in OS for margetuximab in CD16A-158FF patients versus trastuzumab (median OS, 23.6 v 19.2 months; HR, 0.72; 95% CI, 0.52 to 1.00) and a possible improvement in OS for trastuzumab in CD16A-158VV patients versus margetuximab (median OS, 31.1 v 22.0 months; HR, 1.77; 95% CI, 1.01 to 3.12). Margetuximab safety was comparable with trastuzumab. Final overall OS analysis did not demonstrate margetuximab advantage over trastuzumab. Margetuximab studies in patients with human epidermal growth factor receptor 2-positive breast cancer with different CD16A allelic variants are warranted.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Trastuzumab/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Receptor ErbB-2 , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
7.
Target Oncol ; 16(2): 121-152, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33512679

RESUMO

There are strong biologic and preclinical rationales for the development of therapeutic cancer vaccines; however, the clinical translation of this treatment strategy has been challenging. It is now understood that many previous clinical trials of cancer vaccines used target antigens or vaccine designs that inherently lacked sufficient immunogenicity to induce clinical responses. Despite the historical track record, breakthrough advances in cancer immunobiology and vaccine technologies have supported continued interest in therapeutic cancer vaccinations, with the hope that next-generation vaccine strategies will enable patients with cancer to develop long-lasting anti-tumor immunity. There has been substantial progress identifying antigens and vaccine vectors that lead to strong and broad T cell responses, tailoring vaccine designs to achieve optimal antigen presentation, and finding combination partners employing complementary mechanisms of action (e.g., checkpoint inhibitors) to overcome the diverse methods cancer cells use to evade and suppress the immune system. Results from randomized, phase 3 studies testing therapeutic cancer vaccines based on these advances are eagerly awaited. Here, we summarize the successes and failures in the clinical development of cancer vaccines, address how this historical experience and advances in science and technology have shaped efforts to improve vaccines, and offer a clinical perspective on the future role of vaccine therapies for cancer.


Assuntos
Vacinas Anticâncer/uso terapêutico , Neoplasias/tratamento farmacológico , Vacinas Anticâncer/farmacologia , Humanos
8.
J Immunother Cancer ; 9(9)2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34531249

RESUMO

BACKGROUND: Anti-programmed death 1 (PD1)/programmed cell death ligand 1 (PD-L1) therapies have shown modest activity as monotherapy in recurrent ovarian cancer. Platinum chemotherapies induce T-cell proliferation and enhance tumor recognition. We assessed activity and safety of pembrolizumab with carboplatin in recurrent platinum-resistant ovarian cancer. PATIENTS AND METHODS: This phase I/II, single-arm clinical trial studied concurrent carboplatin and pembrolizumab in recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer. Primary platinum refractory patients were excluded. Patients were treated after progression on subsequent non-platinum systemic therapy after becoming platinum resistant or refractory. Pembrolizumab 200 mg was given on day 1 and carboplatin area under the curve 2 on days 8 and 15 of a 3-week cycle until progression. Imaging was assessed by blinded independent review. PD-L1 expression was assessed by immunohistochemistry. Flow cytometry on peripheral blood mononuclear cells was performed for CD3, CD4, CD8, PD1, CTLA4 and Ki67. RESULTS: The most common treatment-related adverse events were lymphopenia (18%) and anemia (9%) with most being grade 1 or 2 (93%). Of 29 patients treated, 23 patients were evaluable for best objective response: 10.3% (95% CI 2.2 to 27.4) had partial response (PR), 51.7% (95% CI 32.5 to 70.6) had stable disease (SD). 56.5% of patients had decreases in target lesions from baseline. All PD-L1-positive patients achieved PR (3/7, 42.8%) or SD (4/7, 57.2%). Median progression-free survival was 4.63 months (95% CI 4.3 to 4.96). Median OS was 11.3 months (95% CI 6.094 to 16.506). Peripheral CD8+PD1+Ki67+ T cells expanded after 3 (p=0.0015) and 5 (p=0.0023) cycles. CTLA4+PD1+CD8+ T cells decreased through the course of treatment up to the 12th cycle (p=0.004). When stratified by ratio of peripheral CD8+PD1+Ki67+ T cells to tumor burden at baseline, patients with a ratio ≥0.0375 who had a significantly longer median OS of 18.37 months compared with those with a ratio <0.0375 who had a median OS of 8.72 months (p=0.0099). No survival advantage was seen with stratification by tumor burden alone (p=0.24) or by CD8+PD1+Ki67+ T cells alone (p=0.53). CONCLUSIONS: Pembrolizumab with carboplatin was well-tolerated and active in recurrent platinum-resistant ovarian cancer. A ratio of peripheral T-cell exhaustion to radiographic tumor burden may identify patients more likely to benefit from this chemoimmunotherapy. TRIAL REGISTRATION NUMBER: NCT03029598.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/uso terapêutico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carboplatina/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Prognóstico
9.
Commun Biol ; 3(1): 226, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385408

RESUMO

Photodynamic therapy (PDT) ablates malignancies by applying focused near-infrared (nIR) light onto a lesion of interest after systemic administration of a photosensitizer (PS); however, the accumulation of existing PS is not tumor-exclusive. We developed a tumor-localizing strategy for PDT, exploiting the high expression of heat shock protein 90 (Hsp90) in cancer cells to retain high concentrations of PS by tethering a small molecule Hsp90 inhibitor to a PS (verteporfin, VP) to create an Hsp90-targeted PS (HS201). HS201 accumulates to a greater extent than VP in breast cancer cells both in vitro and in vivo, resulting in increased treatment efficacy of HS201-PDT in various human breast cancer xenografts regardless of molecular and clinical subtypes. The therapeutic index achieved with Hsp90-targeted PDT would permit treatment not only of localized tumors, but also more diffusely infiltrating processes such as inflammatory breast cancer.


Assuntos
Antineoplásicos/administração & dosagem , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Fotoquimioterapia/estatística & dados numéricos , Fármacos Fotossensibilizantes/administração & dosagem , Verteporfina/administração & dosagem , Linhagem Celular Tumoral , Proteínas de Choque Térmico HSP90/administração & dosagem , Proteínas de Choque Térmico HSP90/efeitos da radiação , Humanos , Células MCF-7
11.
Cancer Chemother Pharmacol ; 81(2): 365-372, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29242966

RESUMO

PURPOSE: A prospective study was performed to compare the outcome for metastatic breast cancer (MBC) patients treated with docetaxel plus thiotepa (DT) or docetaxel plus capecitabine (DC), and to explore the value of CYP1A1*2C polymorphisms in predicting clinical efficacy of these chemotherapies. METHODS: MBC patients (n = 130) were randomized to treatment with DT (n = 65) or DC (n = 65). Response rate, disease control rate, progression-free and overall survival were monitored. Genotyping of CYP1A1*2C was performed in all patients. RESULTS: DT and DC produced similar overall disease control rates (76.9 vs 69.2%), median PFS (6.7 vs. 7.5 months) and OS (20.1 vs. 21.0 months) (P > 0.05 for all comparisons); however, DT exhibited a higher rate of control of localized liver metastases (78.6 vs 41.2%, P = 0.023). Among patients homozygous for wild-type CYP1A1*1 genotype (AA), DT treatment was associated with a significantly longer PFS (8.4 vs. 6.4 months, P = 0.019) and OS (33.4 vs. 15.8 months, P = 0.018). Conversely, among patients carrying the variant CYP1A1*2C genotype (AG/GG), DC treatment was associated with a significantly longer PFS (8.4 vs. 5.5 month, P = 0.005), and OS (28.5 vs. 19.6 months, P = 0.010). After adjusting for competing risk factors, CYP1A1*2C genotype was confirmed to be an independent predictor of PFS and OS for each chemotherapy combination. CONCLUSIONS: Overall, DT and DC result in similar clinical efficacy for MBC patients; however, efficacy for each therapy differs depending on CYP1A1*2C genotype.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Citocromo P-450 CYP1A1/genética , Marcadores Genéticos/genética , Polimorfismo Genético/genética , Adulto , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina/administração & dosagem , Docetaxel/administração & dosagem , Feminino , Humanos , Neoplasias Hepáticas/secundário , Pessoa de Meia-Idade , Metástase Neoplásica , Polimorfismo de Nucleotídeo Único/genética , Intervalo Livre de Progressão , Análise de Sobrevida , Tiotepa/administração & dosagem
12.
Clin Cancer Res ; 23(24): 7531-7542, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-28993342

RESUMO

Purpose: Hsp90, a chaperone to numerous molecular pathways in malignant cells, is elevated in aggressive breast cancers. We hypothesized that identifying breast cells with elevated Hsp90 activity in situ could result in early detection of aggressive breast cancers.Experimental Design: We exploited the uptake of an Hsp90 inhibitor by malignant cells to create an imaging probe (HS131) of Hsp90 activity by linking it to a near-infrared (nIR) dye. HS131 uptake into cells correlated with cell membrane expression of Hsp90 and was used to image molecular subtypes of murine and human breast cancers in vitro and in murine models.Results: HS131 imaging was both sensitive and specific in detecting the murine 4T1 breast cancer cell line, as well as subclones with differing metastatic potential. Highly metastatic subclones (4T07) had high HS131 uptake, but subclones with lower metastatic potential (67NR, 168FARN) had low HS131 uptake. We generated isogenic cell lines to demonstrate that overexpression of a variety of specific oncogenes resulted in high HS131 uptake and retention. Finally, we demonstrated that HS131 could be used to detect spontaneous tumors in MMTV-neu mice, as well as primary and metastatic human breast cancer xenografts. HS131 could image invasive lobular breast cancer, a histologic subtype of breast cancer which is often undetectable by mammography.Conclusions: An HSP90-targeting nIR probe is sensitive and specific in imaging all molecular subtypes of murine and human breast cancer, with higher uptake in aggressive and highly metastatic clones. Clinical studies with Hsp90-targeting nIR probes will be initiated shortly. Clin Cancer Res; 23(24); 7531-42. ©2017 AACR.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Peptídeos Cíclicos/administração & dosagem , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Proteínas de Choque Térmico HSP90/genética , Humanos , Ligantes , Camundongos , Peptídeos Cíclicos/química , Transdução de Sinais/efeitos dos fármacos , Espectroscopia de Luz Próxima ao Infravermelho , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Oncoimmunology ; 6(4): e1264563, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28507788

RESUMO

Purpose: Although local oncolytic viral therapy (OVT) may enhance tumor lysis, antigen release, and adaptive immune responses, systemic antitumor responses post-therapy are limited. Adoptive immunotherapy with autologous dendritic cells (DC) and cytokine-induced killer cells (DC-CIK) synergizes with systemic therapies. We hypothesized that OVT with Herpes Simplex Virus-granulocyte macrophage-colony-stimulating factor (HSV-GM-CSF) would induce adaptive T cell responses that could be expanded systemically with sequential DC-CIK therapy. Patients and Methods: We performed a pilot study of intratumoral HSV-GM-CSF OVT followed by autologous DC-CIK cell therapy. In addition to safety and clinical endpoints, we monitored adaptive T cell responses by quantifying T cell receptor (TCR) populations in pre-oncolytic therapy, post-oncolytic therapy, and after DC-CIK therapy. Results: Nine patients with advanced malignancy were treated with OVT (OrienX010), of whom seven experienced stable disease (SD). Five of the OVT treated patients underwent leukapheresis, generation, and delivery of DC-CIKs, and two had SD, whereas three progressed. T cell receptor sequencing of TCR ß sequences one month after OVT therapy demonstrates a dynamic TCR repertoire in response to OVT therapy in the majority of patients with the systematic expansion of multiple T cell clone populations following DC-CIK therapy. This treatment was well tolerated and long-term event free and overall survival was observed in six of the nine patients. Conclusions: Strategies inducing the local activation of tumor-specific immune responses can be combined with adoptive cellular therapies to expand the adaptive T cell responses systemically and further studies are warranted.

14.
Oncoimmunology ; 6(6): e1315495, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28680745

RESUMO

Expression of human epidermal growth factor family member 3 (HER3), a critical heterodimerization partner with EGFR and HER2, promotes more aggressive biology in breast and other epithelial malignancies. As such, inhibiting HER3 could have broad applicability to the treatment of EGFR- and HER2-driven tumors. Although lack of a functional kinase domain limits the use of receptor tyrosine kinase inhibitors, HER3 contains antigenic targets for T cells and antibodies. Using novel human HER3 transgenic mouse models of breast cancer, we demonstrate that immunization with recombinant adenoviral vectors encoding full length human HER3 (Ad-HER3-FL) induces HER3-specific T cells and antibodies, alters the T cell infiltrate in tumors, and influences responses to immune checkpoint inhibitions. Both preventative and therapeutic Ad-HER3-FL immunization delayed tumor growth but were associated with both intratumoral PD-1 expressing CD8+ T cells and regulatory CD4+ T cell infiltrates. Immune checkpoint inhibition with either anti-PD-1 or anti-PD-L1 antibodies increased intratumoral CD8+ T cell infiltration and eliminated tumor following preventive vaccination with Ad-HER3-FL vaccine. The combination of dual PD-1/PD-L1 and CTLA4 blockade slowed the growth of tumor in response to Ad-HER3-FL in the therapeutic model. We conclude that HER3-targeting vaccines activate HER3-specific T cells and induce anti-HER3 specific antibodies, which alters the intratumoral T cell infiltrate and responses to immune checkpoint inhibition.

15.
Clin Cancer Res ; 23(17): 5066-5073, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28611200

RESUMO

Purpose: Advanced pancreatic cancer has remained challenging to treat effectively. This study aimed to investigate the clinical effects and safety of immunotherapy with dendritic cells and cytokine-induced killer cells (DC-CIK) administered with the chemotherapy (CT) S-1 in this malignancy.Experimental Design: Consecutive patients (n = 47) with advanced pancreatic cancer were treated with either DC-CIK + S-1, DC-CIK alone, S-1 alone, or best supportive care.Results: DC-CIK plus S-1 produced significantly longer median OS and PFS (212 and 136 days) compared with DC-CIK (128 and 85 days), CT (141 and 92 days), or supportive care only (52 and 43 days; P < 0.001). After adjusting for competing risk factors, DC-CIK combined with S-1 and receipt of 2 or more cycles of DC-CIK treatment remained independent predictors of disease-free and overall survival (P < 0.05). Phenotypic analysis of PBMCs demonstrated that the CD3+, CD3+/CD4+, and CD8+/CD28+ T-cell subsets were elevated (P < 0.05), while the CD3+/CD8+, CD3+/CD16+/CD56+ and CD4+/CD25+ cell subsets were significantly decreased after DC-CIK cell therapy (P < 0.05). There were no grade 3 or 4 toxicities. In addition, the mutational frequency in cell-free tumor DNA (cfDNA) declined in 4 of 14 patients who received DC-CIK, and was associated with a more favorable survival.Conclusions: Treatment of advanced pancreatic cancer with combined DC-CIK infusions and S-1 was safe, resulted in favorable PFS and OS, and modulated the peripheral blood immune repertoire. Clin Cancer Res; 23(17); 5066-73. ©2017 AACR.


Assuntos
Células Matadoras Induzidas por Citocinas/imunologia , Células Dendríticas/imunologia , Imunoterapia Adotiva , Neoplasias Pancreáticas/tratamento farmacológico , Idoso , DNA Tumoral Circulante/sangue , Terapia Combinada , Intervalo Livre de Doença , Combinação de Medicamentos , Feminino , Humanos , Imunoterapia Adotiva/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Tegafur/administração & dosagem , Tegafur/efeitos adversos
16.
Clin Cancer Res ; 20(2): 278-80, 2014 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-24240115

RESUMO

Trastuzumab emtansine (T-DM1) represents a significant advancement in the treatment of HER2(+) breast cancers. Its clinical efficacy however will be limited by the development of therapeutic resistance. In this report, the HER3 ligand neuregulin is shown to mediate T-DM1 resistance, which was overcome by administration of pertuzumab, a steric inhibitor of HER2 dimerization.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neurregulinas/antagonistas & inibidores , Receptor ErbB-2/antagonistas & inibidores , Animais , Feminino , Humanos , Trastuzumab
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