RESUMEN
PURPOSE: BAY1436032, an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), was active against multiple IDH1-R132X solid tumors in preclinical models. This first-in-human study was designed to determine the safety and pharmacokinetics of BAY1436032, and to evaluate its potential pharmacodynamics and antitumor effects. PATIENTS AND METHODS: The study comprised of dose escalation and dose expansion cohorts. BAY1436032 tablets were orally administered twice daily on a continuous basis in subjects with mIDH1 solid tumors. RESULTS: In dose escalation, 29 subjects with various tumor types were administered BAY1436032 across five doses (150-1,500 mg twice daily). BAY1432032 exhibited a relatively short half-life. Most evaluable subjects experienced target inhibition as indicated by a median maximal reduction of plasma R-2-hydroxyglutarate levels of 76%. BAY1436032 was well tolerated and an MTD was not identified. A dose of 1,500 mg twice daily was selected for dose expansion, where 52 subjects were treated in cohorts representing four different tumor types [lower grade glioma (LGG), glioblastoma, intrahepatic cholangiocarcinoma, and a basket cohort of other tumor types]. The best clinical outcomes were in subjects with LGG (n = 35), with an objective response rate of 11% (one complete response and three partial responses) and stable disease in 43%. As of August 2020, four of these subjects were in treatment for >2 years and still ongoing. Objective responses were observed only in LGG. CONCLUSIONS: BAY1436032 was well tolerated and showed evidence of target inhibition and durable objective responses in a small subset of subjects with LGG.
Asunto(s)
Compuestos de Anilina/uso terapéutico , Antineoplásicos/uso terapéutico , Bencimidazoles/uso terapéutico , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Isocitrato Deshidrogenasa/genética , Mutación , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/efectos adversos , Compuestos de Anilina/farmacocinética , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Bencimidazoles/farmacocinética , Biomarcadores de Tumor , Análisis Mutacional de ADN , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasias/diagnóstico , Neoplasias/mortalidadRESUMEN
The mutant IDH1 (mIDH1) inhibitor BAY1436032 demonstrated robust activity in preclinical AML models, supporting clinical evaluation. In the current dose-escalation study, BAY1436032 was orally administered to 27 mIDH1 AML subjects across 4 doses ranging from 300 to 1500 mg twice-daily. BAY1436032 exhibited a relatively short half-life and apparent non-linear pharmacokinetics after continuous dosing. Most subjects experienced only partial target inhibition as indicated by plasma R-2HG levels. BAY1436032 was safe and a maximum tolerated dose was not identified. The median treatment duration for all subjects was 3.0 months (0.49-8.5). The overall response rate was 15% (4/27; 1 CRp, 1 PR, 2 MLFS), with responding subjects experiencing a median treatment duration of 6.0 months (3.9-8.5) and robust R-2HG decreases. Thirty percent (8/27) achieved SD, with a median treatment duration of 5.5 months (3.1-7.0). Degree of R-2HG inhibition and clinical benefit did not correlate with dose. Although BAY1436032 was safe and modestly effective as monotherapy, the low overall response rate and incomplete target inhibition achieved at even the highest dose tested do not support further clinical development of this investigational agent in AML.
Asunto(s)
Compuestos de Anilina/uso terapéutico , Antineoplásicos/uso terapéutico , Bencimidazoles/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Terapia Molecular Dirigida , Mutación , Adulto , Anciano , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/efectos adversos , Compuestos de Anilina/farmacocinética , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Bencimidazoles/farmacocinética , Médula Ósea/patología , Análisis Mutacional de ADN , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Femenino , Humanos , Isocitrato Deshidrogenasa/metabolismo , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
This open-label, phase I first-in-human study (NCT01915576) of BAY 1125976, a highly specific and potent allosteric inhibitor of AKT1/2, aimed to evaluate the safety, pharmacokinetics, and maximum tolerated dose of BAY 1125976 in patients with advanced solid tumors. Oral dose escalation was investigated with a continuous once daily (QD) treatment (21 days/cycle) and a twice daily (BID) schedule. A dose expansion in 28 patients with hormone receptor-positive metastatic breast cancer, including nine patients harboring the AKT1E17K mutation, was performed at the recommended phase 2 dose (R2D) of 60 mg BID. Dose-limiting toxicities (Grades 3-4) were increased in transaminases, γ-glutamyltransferase (γ-GT), and alkaline phosphatase in four patients in both schedules and stomach pain in one patient. Of the 78 patients enrolled, one patient had a partial response, 30 had stable disease, and 38 had progressive disease. The clinical benefit rate was 27.9% among 43 patients treated at the R2D. AKT1E17K mutation status was not associated with tumor response. Genetic analyses revealed additional mutations that could promote tumor cell growth despite the inhibition of AKT1/2. BAY 1125976 was well tolerated and inhibited AKT1/2 signaling but did not lead to radiologic or clinical tumor responses. Thus, the refinement of a selection of biomarkers for AKT inhibitors is needed to improve their monotherapy activity.
RESUMEN
A mixture of different fumaric acid esters (FAE) is established for systemic therapy of psoriasis, a frequent inflammatory skin disease. The main active compound of FAE, however, has not been identified so far, and the mechanisms of activity are only partially understood. We analyzed the impact of FAE on in vitro immune function and aimed to gain knowledge about the mode of action. Dimethylfumarate (DMF) and diethylfumarate (DEF), but not fumaric acid, methylhydrogenfumarate and ethylhydrogenfumarate, exhibited potent depression of inflammatory cytokine secretion (e.g., tumor necrosis factoralpha, IL-12, and IFNgamma) in activated human peripheral blood mononuclear cells. Moreover, solely DMF and DEF inhibited alloreactive T-cell proliferation in mixed leukocyte reaction. Interestingly, these immunosuppressive effects were accompanied by the strong induction of the anti-inflammatory stress protein heme oxygenase 1 (HO-1). Supplementation with exogenous glutathione (GSH), which is known to bind DMF, prevented both HO-1 induction as well as the anti-inflammatory effects of DMF. Moreover, inhibition of HO-1 activity restored the diminished IL-12 and IFNgamma production after FAE treatment. These results suggest that DMF acts as active compound within the FAE mixture and at least partially mediates its immunomodulatory activity by the induction of the anti-inflammatory stress protein HO-1 ascribed to the functional depletion of reduced GSH.
Asunto(s)
Fumaratos/farmacología , Glutatión/antagonistas & inhibidores , Hemo-Oxigenasa 1/biosíntesis , Inmunosupresores/farmacología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Citocinas/antagonistas & inhibidores , Dimetilfumarato , Relación Dosis-Respuesta a Droga , Inducción Enzimática/efectos de los fármacos , Fumaratos/administración & dosificación , Glutatión/análogos & derivados , Glutatión/farmacología , Hemo-Oxigenasa 1/antagonistas & inhibidores , Hemo-Oxigenasa 1/genética , Humanos , Inmunosupresores/administración & dosificación , Mediadores de Inflamación/antagonistas & inhibidores , Interferón gamma/antagonistas & inhibidores , Interferón gamma/metabolismo , Interleucina-12/antagonistas & inhibidores , Interleucina-12/metabolismo , Linfocitos/citología , ARN Interferente Pequeño/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
PURPOSE: There is evidence that some tumor patients are able to generate tumor-associated antigen (TAA)-specific T-cell immunity spontaneously. However, little is understood about the existence and nature of self-reactive T-cells that recognize TAA in healthy donors (HD). METHODS: Human mucin (MUC-1), a highly glycosylated transmembrane protein, is a well characterized TAA expressed by epithelial tumors. We compared endogenous MUC-1-specific T-cell immunity of breast cancer patients (BCP) and healthy volunteers using two MUC-1-derived HLA-A*0201-restricted peptides (MUC-1(950-958), MUC-1(12-20)). Antigen-dependent interferon (IFN)-gamma and Granzyme B expression of T-cells were analysed by a reverse transcription-polymerase chain reaction (qRT-PCR)-based assay. RESULTS: A 32% of BCP and 43% of healthy volunteers revealed pre-existent CD8+ T-cells specific for MUC-1(950-958) but not for MUC-1(12-20). In patients, MUC-1-specific T-cells have been detected mainly in early stage disease prior adjuvant therapy. Those T-cells showed MUC-1-dependent IFN-gamma production after short-term stimulation but no clear Granzyme B expression. However, after repetitive in vitro stimulations using peptide-pulsed CD40-stimulated B-cell lines as autologous antigen presenting cells (APC) T-cell lines exhibited lytic capacity against HLA-A*0201+/MUC-1+ tumor cells. CONCLUSION: MUC-1(950-958) is a dominant tumor antigen against which CD8+ T-cells were found frequently in BCP as well as in HD. Until now, this was only known for MelanA/MART-1. In contrast to previous reports, MUC-1-specific immunity was not linked to gender or number of pregnancies in women. Whether MUC-1(950-958)-related immunity highlights a yet unknown cross-reactivity in HD remains unclear. The presence of MUC-1-specific T-cells in some BCP may reflect a balance between immune tolerance and immune defence during aetiopathology.
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Antígenos de Neoplasias/inmunología , Neoplasias de la Mama/inmunología , Carcinoma/inmunología , Mucinas/inmunología , Linfocitos T Citotóxicos/inmunología , Adulto , Anciano , Antígenos de Neoplasias/química , Antígenos Virales/inmunología , Linfocitos B/inmunología , Neoplasias de la Mama/sangre , Neoplasias de la Mama/patología , Carcinoma/sangre , Carcinoma/patología , Estudios de Casos y Controles , Epítopos de Linfocito T/inmunología , Femenino , Humanos , Inmunidad Celular , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Mucina-1 , Mucinas/química , Fragmentos de Péptidos/inmunología , Linfocitos T Citotóxicos/patología , Células Tumorales CultivadasRESUMEN
Adjuvant treatment is still only working in a small percentage of breast cancer patients. Therefore, new strategies need to be developed. Immunotherapies are a very promising approach because they could successfully attack tumor cells in the stage of dormancy. To assess the feasibility of using an allogeneic approach for vaccination of breast cancer patients, we selected a CD80-transfected breast cancer cell line based on its immunogenic properties. Using CD80+ KS breast cancer cells and human leukocyte antigen (HLA)-A*02-matched peripheral blood mononuclear cells (PBMCs) of breast cancer patients in allogeneic mixed lymphocyte-tumor cell cultures (MLTCs), it was possible to isolate HLA-A*02-restricted cytotoxic T cells (CTLs). Furthermore, a genetically modified KS variant expressing influenza A matrix protein serving as a surrogate tumor-associated antigen (TAA) was able to stimulate flu peptide-specific T cells alongside the induction of alloresponses in MLTCs. KS breast cancer cells were demonstrated to express already known TAAs such as CEA, MUC-1, MAGE-1, MAGE-2, and MAGE-3. To further improve antigenicity, HER-2/neu was added to this panel as a marker antigen known to elicit HLA-A*02-restricted CTLs in patients with breast cancer. Thus, the antigen-processing and antigen-presentation capacity of KS cells was further demonstrated by the stimulation of HER-2/neu-specific CD8+ T cells in PBMCs of breast cancer patients in vitro. These results gave a good rationale for a phase I/II trial, where the CD80+ HER-2/neu-overexpressing KS variant is actually used as a cellular vaccine in patients with metastatic breast cancer. As a proof of principle, we present data from two patients where a significant increase of interferon-gamma (IFN-gamma) release was detected when postvaccination PBMCs were stimulated by allogeneic vaccine cells as well as by HLA-A*02-restricted HER-2/neu epitopes. In whole cell vaccine trials, monitoring is particularly challenging because of strong alloresponses and limited knowledge of TAAs. In this study, a panel of HER-2/neu epitopes, together with the quantitative real time (qRT)-PCR method to analyze vaccine-induced cytokines secreted by T cells, proved to be highly sensitive and feasible to perform an "immunological staging" following vaccination.
Asunto(s)
Antígeno B7-1/metabolismo , Neoplasias de la Mama/inmunología , Antígenos HLA-A/inmunología , Receptor ErbB-2/metabolismo , Linfocitos T Citotóxicos/inmunología , Linfocitos T/inmunología , Antígenos de Neoplasias/metabolismo , Antígeno B7-1/inmunología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Antígeno Carcinoembrionario/metabolismo , Citocinas/metabolismo , Estudios de Factibilidad , Femenino , Antígeno HLA-A2 , Humanos , Técnicas In Vitro , Virus de la Influenza A/fisiología , Células K562 , Leucocitos Mononucleares/inmunología , Antígenos Específicos del Melanoma , Mucina-1/metabolismo , Proteínas de Neoplasias/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/inmunología , Linfocitos T/metabolismo , Linfocitos T/patología , Transfección , Vacunación , Proteínas de la Matriz Viral/metabolismoRESUMEN
PURPOSE: Breast cancers are known to frequently (over)express several well-characterized tumor-associated antigens (TAAs) such as carcinoembryonic antigen, MUC-1, Her-2/neu, and cancer/testis antigens such as NY-ESO-1, SSX-2, and members of the MAGE family. Whereas in melanoma patients, the detection of pre-existing T cell responses to tumor-associated differentiation antigens was a rationale to initiate several vaccination strategies, little is known thus far concerning tumor-specific immunity in breast cancer patients. The objectives of our study were (a) to modify and compare different immunodiagnostic T cell assays with regard to their suitability for clinical applications and (b) to determine endogenous TAA-specific T cell immunity of breast cancer patients at the time point of primary diagnosis. EXPERIMENTAL DESIGN: Using MUC-1- and Her-2/neu-derived HLA-A*0201-restricted peptides as model antigens, we analyzed antigen-dependent IFN-gamma release of T cells by enzyme-linked immunospot (ELISpot) assay, intracellular cytokine flow cytometry (CytoSpot), and quantitative real-time PCR. As an assay independent of T cell function, we performed tetramer staining. RESULTS: In our hands, the quantitative real-time PCR method is most sensitive and a feasible screening test to perform an "immunological staging" of cancer patients. By doing this, we detected in 7 of 13 (54%) of HLA-A*0201(+) breast cancer patients a pre-existent specific cellular immune response to at least one of the investigated TAAs (MUC-1, Her-2/neu, carcinoembryonic antigen, NY-ESO-1, and SSX-2). Four of 21 patients (19%) were found to have a significant Her-2/neu-specific T cell response as defined by a stimulation index >/==" BORDER="0"> 2 (range, 10-88). CONCLUSIONS: Although the clinical relevance of endogenous TAA-specific immunity remains unclear, our findings suggest that patients with primary breast cancer can mount a T cell immune response to their tumor that might be beneficially enhanced by TAA-dependent vaccination strategies in the adjuvant situation.
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Antígenos de Neoplasias/inmunología , Neoplasias de la Mama/inmunología , Linfocitos T/inmunología , Células Presentadoras de Antígenos , Antígenos de Neoplasias/genética , Antígeno Carcinoembrionario/genética , Antígeno Carcinoembrionario/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Regulación Neoplásica de la Expresión Génica , Antígenos HLA-A/inmunología , Antígeno HLA-A2 , Humanos , Inmunidad Celular , Interferón gamma/metabolismo , Leucocitos Mononucleares/inmunología , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Mucina-1/genética , Mucina-1/inmunología , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Estadificación de Neoplasias , Fragmentos de Péptidos/inmunología , Receptor ErbB-2/genética , Receptor ErbB-2/inmunología , Proteínas Represoras/genética , Proteínas Represoras/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
PURPOSE: The absence of tumor-associated antigens (TAA) which might elicit an immune response is one reason for the disappointing results of therapeutical vaccines in cancer patients. Moreover, impaired expression of MHC class-I and components involved in antigen processing, such as TAP-1, -2, LMP-2, -7, and MECL-1, may lead to tumor escape from immune recognition. Expression profiling of TAA is one approach towards the design of well-defined and individualized anti-tumor vaccines. METHODS: Quantitative polymerase chain reaction (qRT-PCR) is the method of choice to characterize immunologically relevant properties of individual tumors. However, the application of qRT-PCR as a surrogate parameter for the expression of TAAs depends upon the assumption that the level of an mRNA species correlates with the cellular level of the protein it encodes. Therefore, we additionally analyzed TAA expression by immunofluorescence and T cell recognition. RESULTS: In the present study we were unable to confirm that impaired TAP-1 or -2 (transporter associated with antigen processing) expression characterized at the mRNA level is an appropriate surrogate parameter for down-regulated MHC class-I expression in breast cancer. In addition, we analyzed the expression pattern of TAAs in breast and ovarian cancer cell lines. Besides the well-known over-expression of HER-2/neu, CEA, and MUC-1, multiple antigens of the MAGE-family were frequently co-expressed. We investigated whether detection of TAAs by qRT-PCR correlates with monoclonal antibody staining, and which method could predict T cell recognition. We demonstrated a correlation between tumor cell lysis by HLA-A*0201-restricted, MUC-1-specific CTL and threshold levels of MUC-1-specific mRNA. CONCLUSION: MUC-1 is an example that TAA profiling by RT-PCR and flow cytometry can fail to correlate with each other and are of limited value in the prediction of T cell recognition.