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1.
Clin Cancer Res ; 2024 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-39405343

RESUMEN

PURPOSE: This multicenter phase Ib study investigated trastuzumab deruxtecan (T-DXd) plus nivolumab in patients with HER2-expressing metastatic breast cancer (mBC) and metastatic urothelial cancer (mUC). PATIENTS AND METHODS: Part 1 determined the recommended dose for expansion (RDE) of T-DXd plus nivolumab. Part 2 evaluated efficacy and safety; the primary endpoint was confirmed objective response rate (cORR) by independent central review. RESULTS: Seven patients with mBC were enrolled in part 1 and received T-DXd 3.2 mg/kg (4 patients) or 5.4 mg/kg (3 patients) plus nivolumab. The RDE for T-DXd was 5.4 mg/kg plus nivolumab 360 mg intravenously/3 weeks. In part 2, 32 patients with HER2-positive mBC (cohort 1; inclusive of 3 administered 5.4 mg/kg in part 1), 16 with HER2-low mBC (cohort 2), 30 with HER2-high mUC (cohort 3), and 4 with HER2-low mUC (cohort 4) were enrolled. At data cutoff (July 22, 2021), the cORR (95% CI) for cohorts 1-4 was 65.6% (46.8%-81.4%), 50.0% (24.7%-75.3%), 36.7% (19.9%-56.1%), and not assessed due to small sample size, respectively. Median treatment duration (range) with T-DXd in cohorts 1-4 was 8.9 (1-23), 6.9 (1-21), 3.9 (1-21) months, and not assessed; most common treatment-emergent adverse event was nausea (55.2%, 62.5%, 73.3%, 75.0%). Adjudicated drug-related ILD/pneumonitis rates (cohorts 1-3) were 20.7%, 0%, and 20.0% (1 grade 5 each, cohorts 1 and 3). CONCLUSION: T-DXd plus nivolumab demonstrated promising antitumor activity in HER2-expressing mBC or mUC and safety consistent with the known profile of T­DXd. ILD/pneumonitis is an important risk and requires careful monitoring and prompt intervention.

3.
Nat Cancer ; 3(9): 1039-1051, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35715501

RESUMEN

Patients with cancer frequently receive immune-checkpoint inhibitors (ICIs), which may modulate immune responses to COVID-19 vaccines. Recently, cytokine release syndrome (CRS) was observed in a patient with cancer who received BTN162b2 vaccination under ICI treatment. Here, we analyzed adverse events and serum cytokines in patients with 23 different tumors undergoing (n = 64) or not undergoing (n = 26) COVID-19 vaccination under ICI therapy in a prospectively planned German single-center cohort study (n = 220). We did not observe clinically relevant CRS (≥grade 2) after vaccination (95% CI 0-5.6%; Common Terminology of Adverse Events v.5.0) in this small cohort. Within 4 weeks after vaccination, serious adverse events occurred in eight patients (12.5% 95% CI 5.6-23%): six patients were hospitalized due to events common under cancer therapy including immune related adverse events and two patients died due to conditions present before vaccination. Despite absence of CRS symptoms, a set of pairwise-correlated CRS-associated cytokines, including CXCL8 and interleukin-6 was >1.5-fold upregulated in 40% (95% CI 23.9-57.9%) of patients after vaccination. Hence, elevated cytokine levels are common and not sufficient to establish CRS diagnosis.


Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Neoplasias , Vacunas contra la COVID-19/efectos adversos , Estudios de Cohortes , Síndrome de Liberación de Citoquinas , Citocinas , Humanos , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia/efectos adversos , Interleucina-6 , Neoplasias/tratamiento farmacológico , Vacunación
4.
J Immunother Cancer ; 9(10)2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34607895

RESUMEN

BACKGROUND: Immunotherapy in microsatellite stable colorectal or pancreatic cancer has not shown promising results. It has been hypothesized that targeting immunosuppressive molecules like SDF1-alpha/CXCL12 could contribute to immunotherapy and animal models showed promising results on T cell activation and migration in combination with immune checkpoint inhibition. METHODS: Here, we describe the successful application of anti-CXCL12 (NOX-A12) in patients with advanced stage pretreated metastatic colorectal and pancreatic cancer (OPERA trial). The treatment consisted of 2 weeks of anti-CXCL12 monotherapy with NOX-A12 followed by combination therapy with pembrolizumab (n=20 patients) until progression or intolerable toxicity had occurred. RESULTS: The treatment was safe and well tolerated with 83.8% grade I/II, 15.5% grade III and 0.7% grade V adverse events. Of note, for a majority of patients, time on trial treatment was prolonged compared with their last standard treatment preceding trial participation. Systematic serial biopsies revealed distinct patterns of modulation. Tissue and clinical responses were associated with Th1-like tissue reactivity upon CXCL12 inhibition. A downregulation of a cytokine cassette of interleukin (IL)-2/IL-16/CXCL-10 was associated with tumor resistance and furthermore linked to a rare, CXCL12-associated CD14+CD15+promonocytic population. T cells showed aggregation and directed movement towards the tumor cells in responding tissues. Serum analyses detected homogeneous immunomodulatory patterns in all patients, regardless of tissue responses. CONCLUSIONS: We demonstrate that the combination of CXCL12 inhibition and checkpoint inhibition is safe and grants further exploration of synergistic combinatorial strategies.


Asunto(s)
Quimiocina CXCL12/antagonistas & inhibidores , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inmunoterapia/métodos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas
5.
Curr Probl Cancer ; 43(5): 487-494, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-30827742

RESUMEN

Gastrointestinal cancers are very common cancers with colorectal being the fourth most common type, gastric the sixth, and esophageal the tenth. Although recent advances have been made in management including incorporation of antiangiogenic, anti-EGFR, and anti-HER2 directed therapies, overall their prognosis remains poor. Anti-PD-1 therapy with nivolumab and pembrolizumab are licensed for advanced chemorefractory gastroesophageal cancer and many other checkpoint inhibitor therapies are being assessed alone and in combination in these diseases. One of the challenges posed in assessing response to immunotherapy treatment is the phenomenon of pseudoprogression. This phenomenon, which is well described in patients with malignant melanoma is most frequently described as a size increase of contrast enhancing lesions or appearance of new lesions that stabilize or reduce in size with time. Most other solid tumors have a low incidence of pseudoprogression although cases have been reported for lung, head, and neck cancer and a range of gliomas. Herein we present 6 cases of patients with gastrointestinal cancers who were treated with anti-PD1 (programmed cell death) and anti-PD-L1 (programmed cell death ligand-1) antibodies, and experience pseudoprogression.


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Gastrointestinales/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Medios de Contraste/administración & dosificación , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Femenino , Neoplasias Gastrointestinales/diagnóstico por imagen , Neoplasias Gastrointestinales/inmunología , Neoplasias Gastrointestinales/patología , Humanos , Masculino , Melanoma/diagnóstico por imagen , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Melanoma/patología , Persona de Mediana Edad , Nivolumab/farmacología , Nivolumab/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias Cutáneas/diagnóstico por imagen , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Tomografía Computarizada por Rayos X , Resultado del Tratamiento
6.
Gut ; 67(8): 1484-1492, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-28790159

RESUMEN

OBJECTIVE: Regorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need for better patient selection. DESIGN: Patients with RAS mutant mCRC with biopsiable metastases were enrolled in this phase II trial. Dynamic contrast-enhanced (DCE) MRI was acquired pretreatment and at day 15 post-treatment. Median values of volume transfer constant (Ktrans), enhancing fraction (EF) and their product KEF (summarised median values of Ktrans× EF) were generated. Circulating tumour (ct) DNA was collected monthly until progressive disease and tested for clonal RAS mutations by digital-droplet PCR. Tumour vasculature (CD-31) was scored by immunohistochemistry on 70 sequential tissue biopsies. RESULTS: Twenty-seven patients with paired DCE-MRI scans were analysed. Median KEF decrease was 58.2%. Of the 23 patients with outcome data, >70% drop in KEF (6/23) was associated with higher disease control rate (p=0.048) measured by RECIST V. 1.1 at 2 months, improved progression-free survival (PFS) (HR 0.16 (95% CI 0.04 to 0.72), p=0.02), 4-month PFS (66.7% vs 23.5%) and overall survival (OS) (HR 0.08 (95% CI 0.01 to 0.63), p=0.02). KEF drop correlated with CD-31 reduction in sequential tissue biopsies (p=0.04). RAS mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS (HR 0.21 (95% CI 0.06 to 0.71), p=0.01) and OS (HR 0.28 (95% CI 0.07-1.04), p=0.06). CONCLUSIONS: Combining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Compuestos de Fenilurea/uso terapéutico , Piridinas/uso terapéutico , Adulto , Anciano , Biomarcadores/sangre , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/diagnóstico por imagen , Femenino , Humanos , Estimación de Kaplan-Meier , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento
7.
J Biol Chem ; 288(13): 9272-83, 2013 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-23386617

RESUMEN

RGC1 and RGC2 comprise a functional RalGAP complex (RGC) that suppresses RalA activity. The PI3-kinase/Akt signaling pathway activates RalA through phosphorylation-mediated inhibition of the RGC. Here we identify a novel phosphorylation-dependent interaction between 14-3-3 and the RGC. 14-3-3 binds to the complex through an Akt-phosphorylated residue, threonine 715, on RGC2. Interaction with 14-3-3 does not alter in vitro activity of the GTPase-activating protein complex. However, blocking the interaction between 14-3-3 and RGC2 in cells increases suppression of RalA activity by the RGC, suggesting that 14-3-3 inhibits the complex through a non-catalytic mechanism. Together, these data show that 14-3-3 negatively regulates the RGC downstream of the PI3-kinase/Akt signaling pathway.


Asunto(s)
Proteínas 14-3-3/metabolismo , Proteínas Activadoras de GTPasa/metabolismo , Regulación de la Expresión Génica , Proteínas del Tejido Nervioso/metabolismo , Proteínas de Unión al GTP ral/metabolismo , Células 3T3 , Adipocitos/citología , Secuencias de Aminoácidos , Androstadienos/farmacología , Animales , ADN/metabolismo , Inhibidores Enzimáticos/farmacología , Proteínas de Unión al GTP/metabolismo , Células HEK293 , Humanos , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Fosforilación , Unión Proteica , Transducción de Señal , Wortmanina
8.
Case Rep Oncol ; 6(3): 508-13, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24403895

RESUMEN

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal malignancy of the gastrointestinal tract. PET/CT is a common diagnostic tool and is also used for therapy monitoring. GISTs typically show strong (18)F-fluorodeoxyglucose (FDG) uptake. Here we present two cases of GIST with unusually low/negative FDG uptake. FDG negativity does not preclude the diagnosis of a GIST.

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