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1.
Allergy ; 78(5): 1269-1279, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36385701

RESUMEN

BACKGROUND: Chronic inducible urticaria (CIndU) is characterized by mast cell (MC)-mediated wheals in response to triggers: cold in cold urticaria (ColdU) and friction in symptomatic dermographism (SD). KIT receptor activation by stem cell factor (SCF) is essential for MC function. Barzolvolimab (CDX-0159) is a humanized antibody that inhibits KIT activation by SCF and was well tolerated in healthy volunteers with dose-dependent plasma tryptase suppression indicative of systemic mast cell ablation. METHODS: This is an open-label, trial in patients with antihistamine refractory ColdU or SD, receiving one IV dose of barzolvolimab (3 mg/kg), with a 12-week follow-up. Primary endpoint was safety/tolerability; pharmacodynamic (PD)/clinical endpoints included serum tryptase, plasma SCF, skin MC histology, provocation tests, urticaria control test (UCT), and dermatology life quality index (DLQI). RESULTS: Analysis populations were safety (n = 21) and pharmacodynamics/clinical activity (n = 20). Barzolvolimab was well tolerated; most adverse events were mild and resolved. Treatment resulted in significant depletion of skin MCs, decreased tryptase (

Asunto(s)
Mastocitos , Urticaria , Humanos , Enfermedad Crónica , Urticaria Crónica Inducible , Mastocitos/patología , Calidad de Vida , Triptasas , Urticaria/tratamiento farmacológico , Urticaria/diagnóstico , Proteínas Proto-Oncogénicas c-kit
2.
Allergy ; 77(8): 2393-2403, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35184297

RESUMEN

BACKGROUND: Mast cells (MC) are powerful inflammatory immune sentinel cells that drive numerous allergic, inflammatory, and pruritic disorders when activated. MC-targeted therapies are approved in several disorders, yet many patients have limited benefit suggesting the need for approaches that more broadly inhibit MC activity. MCs require the KIT receptor and its ligand stem cell factor (SCF) for differentiation, maturation, and survival. Here we describe CDX-0159, an anti-KIT monoclonal antibody that potently suppresses MCs in human healthy volunteers. METHODS: CDX-0159-mediated KIT inhibition was tested in vitro using KIT-expressing immortalized cells and primary human mast cells. CDX-0159 safety and pharmacokinetics were evaluated in a 13-week good laboratory practice (GLP)-compliant cynomolgus macaque study. A single ascending dose (0.3, 1, 3, and 9 mg/kg), double-blinded placebo-controlled phase 1a human healthy volunteer study (n = 32) was conducted to evaluate the safety, pharmacokinetics, and pharmacodynamics of CDX-0159. RESULTS: CDX-0159 inhibits SCF-dependent KIT activation in vitro. Fc modifications in CDX-0159 led to elimination of effector function and reduced serum clearance. In cynomolgus macaques, multiple high doses were safely administered without a significant impact on hematology, a potential concern for KIT inhibitors. A single dose of CDX-0159 in healthy human subjects was generally well tolerated and demonstrated long antibody exposure. Importantly, CDX-0159 led to dose-dependent, profound suppression of plasma tryptase, a MC-specific protease associated with tissue MC burden, indicative of systemic MC suppression or ablation. CONCLUSION: CDX-0159 administration leads to systemic mast cell ablation and may represent a safe and novel approach to treat mast cell-driven disorders.


Asunto(s)
Anticuerpos Monoclonales , Mastocitos , Proteínas Proto-Oncogénicas c-kit , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacología , Voluntarios Sanos , Humanos , Mastocitos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-kit/antagonistas & inhibidores , Factor de Células Madre
3.
Nature ; 535(7613): 556-60, 2016 07 28.
Artículo en Inglés | MEDLINE | ID: mdl-27338952

RESUMEN

Interruption of combination antiretroviral therapy in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117,a broad and potent neutralizing antibody against the CD4 binding site of the HIV-1 Env protein, during analytical treatment interruption in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Results show that two or four 30 mg kg(-1) 3BNC117 infusions,separated by 3 or 2 weeks, respectively, are generally well tolerated.Infusions are associated with a delay in viral rebound of 5-9 weeks after two infusions, and up to 19 weeks after four infusions, or an average of 6.7 and 9.9 weeks, respectively, compared with 2.6 weeks for historical controls (P < 0.00001). Rebound viruses arise predominantly from a single provirus. In most individuals,emerging viruses show increased resistance, indicating escape.However, 30% of participants remained suppressed until antibody concentrations waned below 20 µg ml(-1), and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9-19 weeks.We conclude that the administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during analytical treatment interruption in humans.


Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Anticuerpos Neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/crecimiento & desarrollo , VIH-1/inmunología , Adolescente , Adulto , Anciano , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Anticuerpos Monoclonales Humanizados , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Neutralizantes/uso terapéutico , Sitios de Unión/efectos de los fármacos , Sitios de Unión/inmunología , Anticuerpos ampliamente neutralizantes , Antígenos CD4/metabolismo , Reservorios de Enfermedades/virología , Esquema de Medicación , Femenino , Anticuerpos Anti-VIH/administración & dosificación , Anticuerpos Anti-VIH/uso terapéutico , Proteínas gp160 de Envoltorio del VIH/antagonistas & inhibidores , Proteínas gp160 de Envoltorio del VIH/química , Proteínas gp160 de Envoltorio del VIH/inmunología , Proteínas gp160 de Envoltorio del VIH/metabolismo , Infecciones por VIH/inmunología , VIH-1/efectos de los fármacos , Estudio Históricamente Controlado , Humanos , Masculino , Persona de Mediana Edad , Provirus/efectos de los fármacos , Provirus/crecimiento & desarrollo , Provirus/inmunología , Factores de Tiempo , Distribución Tisular , Carga Viral/efectos de los fármacos , Carga Viral/inmunología , Adulto Joven
4.
Nature ; 522(7557): 487-91, 2015 06 25.
Artículo en Inglés | MEDLINE | ID: mdl-25855300

RESUMEN

HIV-1 immunotherapy with a combination of first generation monoclonal antibodies was largely ineffective in pre-clinical and clinical settings and was therefore abandoned. However, recently developed single-cell-based antibody cloning methods have uncovered a new generation of far more potent broadly neutralizing antibodies to HIV-1 (refs 4, 5). These antibodies can prevent infection and suppress viraemia in humanized mice and nonhuman primates, but their potential for human HIV-1 immunotherapy has not been evaluated. Here we report the results of a first-in-man dose escalation phase 1 clinical trial of 3BNC117, a potent human CD4 binding site antibody, in uninfected and HIV-1-infected individuals. 3BNC117 infusion was well tolerated and demonstrated favourable pharmacokinetics. A single 30 mg kg(-1) infusion of 3BNC117 reduced the viral load in HIV-1-infected individuals by 0.8-2.5 log10 and viraemia remained significantly reduced for 28 days. Emergence of resistant viral strains was variable, with some individuals remaining sensitive to 3BNC117 for a period of 28 days. We conclude that, as a single agent, 3BNC117 is safe and effective in reducing HIV-1 viraemia, and that immunotherapy should be explored as a new modality for HIV-1 prevention, therapy and cure.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/terapia , VIH-1/inmunología , Carga Viral/inmunología , Viremia/terapia , Adulto , Secuencia de Aminoácidos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Neutralizantes/efectos adversos , Anticuerpos Neutralizantes/farmacología , Anticuerpos Neutralizantes/uso terapéutico , Sitios de Unión , Anticuerpos ampliamente neutralizantes , Antígenos CD4/metabolismo , Estudios de Casos y Controles , Evolución Molecular , Femenino , Anticuerpos Anti-VIH/administración & dosificación , Anticuerpos Anti-VIH/efectos adversos , Anticuerpos Anti-VIH/farmacología , Anticuerpos Anti-VIH/uso terapéutico , Proteína gp120 de Envoltorio del VIH/química , Proteína gp120 de Envoltorio del VIH/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/química , VIH-1/efectos de los fármacos , Humanos , Inmunización Pasiva/métodos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Factores de Tiempo , Carga Viral/efectos de los fármacos , Viremia/inmunología , Viremia/virología , Adulto Joven
5.
Invest New Drugs ; 38(6): 1807-1814, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32472319

RESUMEN

CDX-014 is an antibody-drug conjugate directed against TIM-1, a surface marker highly expressed in renal cell carcinoma (RCC) and ovarian carcinoma. This phase I, first-in-human trial was conducted to evaluate the safety and preliminary activity of CDX-014 in patients with advanced refractory RCC, following a dose-escalation and dose expansion design. CDX-014 was administered intravenously at doses ranging from 0.15 to 2.0 mg/kg every 2 or 3 weeks until progression or unacceptable toxicity. Sixteen patients received at least one dose of CDX-014. The maximum tolerated dose was not identified. Most frequent adverse grade 1 or 2 adverse events included nausea (38%), fatigue, alopecia, elevation of AST and decreased appetite (25% each). Adverse events of grade 3 or more included hyperglycemia (19%), urosepsis (6%), and one multi-organ failure (6%) responsible for one treatment-related death. Two patients discontinued therapy for adverse events including fatigue grade 2 and urosepsis grade 4. CDX-014 showed antitumor activity with one prolonged partial response and a clinical benefit rate (objective response or stable disease >6 months) of 31%. The two patients that exhibited the most marked tumor shrinkage had high TIM-1 expression on tumor tissue. Overall, CDX-014 exhibited a manageable toxicity profile and early signs of activity, supporting further evaluation of antibody-drug conjugates in patients with advanced RCC and potentially other TIM-1 expressing cancers. Trial registration https://clinicaltrials.gov/ct2/show/NCT02837991 NCT02837991; July 20, 2016.


Asunto(s)
Antineoplásicos/administración & dosificación , Carcinoma de Células Renales/tratamiento farmacológico , Receptor Celular 1 del Virus de la Hepatitis A/antagonistas & inhibidores , Inmunoconjugados/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Femenino , Receptor Celular 1 del Virus de la Hepatitis A/metabolismo , Humanos , Inmunoconjugados/efectos adversos , Inmunoconjugados/farmacocinética , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Carga Tumoral
6.
Cancer ; 125(7): 1113-1123, 2019 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-30690710

RESUMEN

BACKGROUND: Glembatumumab vedotin is an antibody-drug conjugate that produced preliminary clinical activity against advanced melanoma in a phase 1 dose-escalation trial. The objective of the current study was to investigate further the antitumor activity of glembatumumab vedotin at the recommended phase 2 dose in heavily pretreated patients with melanoma. METHODS: This single-arm, phase 2 study enrolled patients with stage IV melanoma who were refractory to checkpoint inhibition and to B-raf proto-oncogene, serine/threonine kinase (BRAF)/mitogen-activated protein kinase kinase (MEK) inhibition (in the presence of a BRAF valine mutation at codon 600). Patients received 1.9 mg/kg glembatumumab vedotin intravenously every 3 weeks until they developed disease progression or intolerance. The primary endpoint was objective response rate (ORR), which was determined according to Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints included progression-free survival (PFS), duration of response, overall survival (OS), safety, and clinical efficacy versus tumor glycoprotein NMB (gpNMB) expression. Tumor expression of gpNMB was assessed using immunohistochemistry. RESULTS: In total, 62 patients received treatment. The ORR was 11% and the median response duration was 6.0 months (95% confidence interval [CI], 4.1 months to not reached). The median PFS was 4.4 months (95% CI, 2.6-5.5 months), and the median OS was 9.0 months (95% CI, 6.1-11.7 months). For patients who developed rash during the first cycle versus those who did not, the ORR was 21% versus 7%, respectively, and there was an overall improvement in PFS (hazard ratio, 0.43; P = .013) and OS (hazard ratio, 0.43; P = .017). The most frequent adverse events were alopecia, neuropathy, rash, fatigue, and neutropenia. With one exception, all evaluable tumors were positive for gpNMB, and 46 of 59 tumors (76%) had 100% gpNMB-positive epithelial cells. CONCLUSIONS: Glembatumumab vedotin had modest activity and an acceptable safety profile in patients with advanced melanoma who were refractory to checkpoint inhibitors and MEK/BRAF inhibition. Treatment-related rash may be associated with response.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Inmunoconjugados/uso terapéutico , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Melanoma/metabolismo , Melanoma/patología , Glicoproteínas de Membrana/metabolismo , Persona de Mediana Edad , Estadificación de Neoplasias , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Proto-Oncogenes Mas , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Resultado del Tratamiento
8.
Pediatr Blood Cancer ; 63(1): 32-8, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26305408

RESUMEN

BACKGROUND: Cure rates for children and young adults with osteosarcoma have remained stagnant over the past three decades. Targeting glycoprotein non-metastatic b (GPNMB) with the antibody-drug conjugate glembatumumab vedotin has improved outcomes for patients with melanoma and breast cancer. The potential utility of targeting GPNMB in osteosarcoma was explored. METHODS: GPNMB protein expression was evaluated by immunohistochemistry in human osteosarcoma tumor samples and by enzyme-linked immunosorbent assay (ELISA) in osteosarcoma cell lines. mRNA expression was measured by quantitative PCR in primary osteosarcoma samples and cell lines. Surface GPNMB expression was evaluated by flow cytometry and correlated with in vitro and in vivo cytotoxicity of glembatumumab vedotin. RESULTS: Sixty seven human osteosarcoma samples were evaluated by immunohistochemistry, including 12 samples from initial biopsy, 38 samples from definitive surgery, and 17 from the time of disease recurrence. GPNMB was expressed in 92.5% (62/67) of osteosarcoma samples. All primary osteosarcoma samples expressed high levels of GPNMB mRNA. Glembatumumab induced cytotoxic effects in 74% (14/19) of osteosarcoma cell lines, and GPNMB protein levels correlated with glembatumumab in vitro cytotoxicity (r = -0.46, P = 0.04). All osteosarcoma cell lines demonstrated surface GPNMB expression. CONCLUSIONS: GPNMB is expressed in osteosarcoma and targeting GPNMB with the antibody-drug conjugate glembatumumab vedotin demonstrates osteosarcoma cytotoxic activity. Clinical trials are indicated to assess the efficacy of targeting GPNMB in patients with osteosarcoma.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Inmunoconjugados/uso terapéutico , Glicoproteínas de Membrana/efectos de los fármacos , Osteosarcoma/tratamiento farmacológico , Adolescente , Adulto , Anciano , Línea Celular , Niño , Preescolar , Pruebas Inmunológicas de Citotoxicidad , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Expresión Génica , Humanos , Inmunohistoquímica , Glicoproteínas de Membrana/análisis , Glicoproteínas de Membrana/genética , Persona de Mediana Edad , ARN Mensajero/análisis , Reacción en Cadena en Tiempo Real de la Polimerasa , Análisis de Matrices Tisulares
9.
Pediatr Blood Cancer ; 61(10): 1816-21, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24912408

RESUMEN

BACKGROUND: Glembatumumab vedotin is an antibody-auristatin conjugate that targets cells expressing the transmembrane glycoprotein NMB (GPNMB, also known as osteoactivin). It has entered clinical evaluation for adult cancers that express GPNMB, including melanoma and breast cancer. PROCEDURES: Glembatumumab vedotin was administered intravenously at a dose of 2.5 mg/kg using a weekly × 3 schedule, and its antitumor activity was evaluated against selected Pediatric Preclinical Testing Program (PPTP) solid tumor xenografts using standard PPTP response metrics. RESULTS: Among PPTP xenografts, GPNMB was primarily expressed on the osteosarcoma xenografts, all of which expressed GPNMB at the RNA level, although at varying levels. Protein expression assessed by immunohistochemistry (IHC) showed variation across the osteosarcoma xenografts with one model showing no tumor cell expression. Glembatumumab vedotin induced statistically significant differences (P < 0.05) in event-free survival (EFS) distribution compared to control in each of the six osteosarcoma models studied. Three of six osteosarcoma xenografts demonstrated a maintained complete response (MCR). Two other xenografts showed progressive disease with growth delay, while the final xenograft showed progressive disease with no growth delay. Two of the osteosarcoma xenografts with MCRs showed the highest GPNMB expression at the RNA level. Conversely, the xenograft with the lowest GPNMB mRNA expression had the poorest response to glembatumumab vedotin. Two rhabdomyosarcoma xenografts that did not express GPNMB showed limited responses to glembatumumab vedotin. CONCLUSIONS: Glembatumumab vedotin yielded high-level activity against three of six osteosarcoma xenografts, with evidence for response being related to GPNMB expression levels.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Antineoplásicos/farmacología , Inmunoconjugados/farmacología , Osteosarcoma/patología , Animales , Femenino , Humanos , Inmunohistoquímica , Ratones , Ratones SCID , Ensayos Antitumor por Modelo de Xenoinjerto
10.
J Immunother Cancer ; 10(8)2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35940825

RESUMEN

BACKGROUND: Phase 1/2 dose-escalation and expansion study evaluating varlilumab, a fully human agonist anti-CD27 mAb, with nivolumab in anti-PD-1/L1 naïve, refractory solid tumors. METHODS: Phase 1 evaluated the safety of varlilumab (0.1-10 mg/kg) with nivolumab (3 mg/kg) administered once every 2 weeks. Phase 2 evaluated varlilumab regimens (3 mg/kg once every 2 weeks, 3 mg/kg once every 12 weeks, and 0.3 mg/kg once every 4 weeks) with nivolumab 240 mg once every 2 weeks in tumor-specific cohorts. Primary objective was safety; key clinical endpoints included objective response rate (ORR) and overall survival rate at 12 months (OS12) (glioblastoma (GBM) only). Exploratory objectives included determination of effects on peripheral blood and intratumoral immune signatures. RESULTS: 175 patients were enrolled (36 in phase 1 and 139 in phase 2). Phase 1 dose-escalation proceeded to the highest varlilumab dose level without determining a maximum tolerated dose. In phase 2, ORR were ovarian 12.5%, squamous cell carcinoma of the head and neck 12.5%, colorectal cancer 5%, and renal cell carcinoma 0%; GBM OS12 was 40.9%. Increased tumor PD-L1 and intratumoral T cell infiltration were observed in ovarian cancer patients, with increases of ≥5% associated with better progression-free survival. The most common treatment related adverse events were fatigue (18%), pruritus (16%), and rash (15%). CONCLUSION: Varlilumab and nivolumab were well tolerated, without significant toxicity beyond that expected for each agent alone. Clinical activity was observed in patients that are typically refractory to anti-PD-1 therapy, however, overall was not greater than expected for nivolumab monotherapy. Treatment was associated with proinflammatory changes in the tumor microenvironment, particularly in ovarian cancer where the changes were associated with better clinical outcomes. TRIAL REGISTRATION NUMBER: NCT02335918.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Neoplasias Ováricas , Anticuerpos Monoclonales Humanizados , Carcinoma de Células Renales/tratamiento farmacológico , Femenino , Humanos , Neoplasias Renales/tratamiento farmacológico , Nivolumab/efectos adversos , Neoplasias Ováricas/tratamiento farmacológico , Microambiente Tumoral
11.
NPJ Breast Cancer ; 7(1): 57, 2021 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-34016993

RESUMEN

The METRIC study (NCT#0199733) explored a novel antibody-drug conjugate, glembatumumab vedotin (GV), targeting gpNMB that is overexpressed in ~40% of patients with triple-negative breast cancer (TNBC) and associated with poor prognosis. The study was a randomized, open-label, phase 2b study that evaluated progression-free survival (PFS) of GV compared with capecitabine in gpNMB-overexpressing TNBC. Patients who had previously received anthracycline and taxane-based therapy were randomized 2:1 to receive, GV (1.88 mg/kg IV q21 days) or capecitabine (2500 mg/m2 PO daily d1-14 q21 days). The primary endpoint was RECIST 1.1 PFS per independent, blinded central review. In all, 327 patients were randomized to GV (213 treated) or capecitabine (92 treated). Median PFS was 2.9 months for GV vs. 2.8 months for capecitabine. The most common grade ≥3 toxicities for GV were neutropenia, rash, and leukopenia, and for capecitabine were fatigue, diarrhea, and palmar-plantar erythrodysesthesia. The study did not meet the primary endpoint of improved PFS over capecitabine or demonstrate a relative risk/benefit improvement over capecitabine.

12.
Blood Adv ; 4(9): 1917-1926, 2020 05 12.
Artículo en Inglés | MEDLINE | ID: mdl-32380537

RESUMEN

CD27, a costimulatory molecule on T cells, induces intracellular signals mediating cellular activation, proliferation, effector function, and cell survival on binding to its ligand, CD70. Varlilumab, a novel, first-in-class, agonist immunoglobulin G1 anti-CD27 antibody, mediates antitumor immunity and direct killing of CD27+ tumor cells in animal models. This first-in-human, dose-escalation, and expansion study evaluated varlilumab in patients with hematologic malignancies. Primary objectives were to assess safety and the maximum tolerated and optimal biologic doses of varlilumab. Secondary objectives were to evaluate pharmacokinetics, pharmacodynamics, immunogenicity, and antitumor activity. In a 3 + 3 dose-escalation design, 30 patients with B-cell (n = 25) or T-cell (n = 5) malignancies received varlilumab (0.1, 0.3, 1, 3, or 10 mg/kg IV) as a single dose with a 28-day observation period, followed by weekly dosing (4 doses per cycle, up to 5 cycles, depending on tumor response). In an expansion cohort, 4 additional patients with Hodgkin lymphoma received varlilumab at 0.3 mg/kg every 3 weeks (4 doses per cycle, up to 5 cycles). No dose-limiting toxicities were observed. Treatment-related adverse events, generally grade 1 to 2, included fatigue, decreased appetite, anemia, diarrhea, and headache. Exposure was linear and dose-proportional across dose groups and resulted in increases in proinflammatory cytokines and soluble CD27. One patient with stage IV Hodgkin lymphoma experienced a complete response and remained in remission at >33 months with no further anticancer therapy. These data support further investigation of varlilumab for hematologic malignancies, particularly in combination approaches targeting nonredundant immune regulating pathways. This trial was registered at www.clinicaltrials.gov as #NCT01460134.


Asunto(s)
Neoplasias Hematológicas , Enfermedad de Hodgkin , Animales , Anticuerpos Monoclonales Humanizados , Fatiga , Neoplasias Hematológicas/tratamiento farmacológico , Humanos
13.
Nat Cancer ; 1(12): 1204-1217, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-35121932

RESUMEN

Generating responses to tumor antigens poses a challenge for immunotherapy. This phase II trial (NCT02129075) tested fms-like tyrosine kinase 3 (Flt3) ligand pre-treatment enhancement of responses to dendritic cell (DC)-targeting vaccines. We evaluated a regimen of Flt3L (CDX-301) to increase DCs and other antigen-presenting cells, poly-ICLC (TLR3 agonist that activates DCs) and a vaccine comprising anti-DEC-205-NY-ESO-1, a fusion antibody targeting CD205, linked to NY-ESO-1. High-risk melanoma patients were randomized to vaccine, with and without CDX-301. The end point was immune response to NY-ESO-1. Flt3L increased peripheral monocytes and conventional DCs (cDCs), including cross-presenting cDC1 and cDC2 and plasmacytoid DCs. Significant increases in humoral and T-cell responses and activation of DCs, natural killer cells and T cells were elicited. Transcriptional analyses revealed gene signatures associated with CDX-301 induction of an early, durable immune response. This study reveals in vivo effects of Flt3L on innate immune cells in the setting of vaccination, leading to an immunogenic vaccine regimen.


Asunto(s)
Vacunas contra el Cáncer , Melanoma , Células Dendríticas , Humanos , Inmunidad , Proteínas de la Membrana , Tirosina Quinasa 3 Similar a fms
14.
Clin Cancer Res ; 25(19): 5752-5758, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31308059

RESUMEN

PURPOSE: ErbB3 and its ligand neuregulin-1 (NRG1) are widely expressed in head and neck squamous cell carcinoma (HNSCC) and associated with tumor progression. A "window-of-opportunity" study (NCT02473731) was conducted to evaluate the pharmacodynamic effects of CDX-3379, an anti-ErbB3 mAb, in patients with HNSCC. PATIENTS AND METHODS: Twelve patients with newly diagnosed, operable HNSCC received two infusions of CDX-3379 (1,000 mg) at a 2-week interval prior to tumor resection. The primary study objective was to achieve ≥50% reduction in tumor ErbB3 signaling (phosphorylation of ErbB3; pErbB3) in ≥30% of patients. Other potential tumor biomarkers, pharmacokinetics, safety, and tumor measurements were also assessed. RESULTS: pErbB3 was detectable in all tumors prior to treatment and decreased for 10 of 12 (83%) patients following CDX-3379 dosing, with ≥50% reduction in 7 of 12 (58%; P = 0.04; 95% confidence interval, 27.7%-84.8%). Target trough CDX-3379 serum levels were achieved in all patients. CDX-3379 treatment-related toxicity was grade 1-2 and included diarrhea, fatigue, and acneiform dermatitis. Five of 12 (42%) patients had shrinkage in tumor burden, including a marked clinical response in a patient with human papillomavirus-negative oral cavity HNSCC. All patients with tumor shrinkage had tumors that expressed both NRG1 and ErbB3 and demonstrated reduced pErbB3 with CDX-3379 treatment. CONCLUSIONS: This study demonstrates that CDX-3379 can inhibit tumor ErbB3 phosphorylation in HNSCC. CDX-3379 was well tolerated and associated with measurable tumor regression. A phase II study (NCT03254927) has been initiated to evaluate CDX-3379 in combination with cetuximab for patients with advanced HNSCC.


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Receptor ErbB-3/antagonistas & inhibidores , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/farmacocinética , Biomarcadores de Tumor/metabolismo , Femenino , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Neurregulina-1/metabolismo , Receptor ErbB-3/inmunología , Receptor ErbB-3/metabolismo , Transducción de Señal , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología
15.
Eur J Cancer ; 121: 177-183, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31586757

RESUMEN

BACKGROUND: The prognosis is poor for children and adolescents with recurrent osteosarcoma (OS). Glycoprotein non-metastatic B (gpNMB) is a glycoprotein highly expressed in OS cells. We conducted a phase II study of glembatumumab vedotin (GV), a fully human IgG2 monoclonal antibody (CR011) against gpNMB conjugated to the microtubule inhibitor, monomethyl auristatin E. PATIENTS AND METHODS: Patients aged ≥12 years and <50 years with relapsed or refractory OS were eligible. GV 1.9 mg/kg/dose was administered on day 1 of each 21 day cycle. Pharmacokinetics were mandatory in patients aged <15 years. gpNMB expression was measured by immunohistochemistry. The primary end-point was disease control at 4 months and Response Evaluation Criteria in Solid Tumours response. A 2-stage design was used to determine efficacy. RESULTS: Twenty-two patients were enrolled, and all were evaluable for response. Antibody-drug conjugate levels were detectable in patients, although small numbers limit comparison to adult data. The toxicities observed were similar to the previous studies with GV. The most common grade III adverse event was rash. One death from end organ failure occurred possibly related to GV. Of the 22 patients, one patient had a partial response, and two had stable disease. There was no correlation between gpNMB expression and response to GV. CONCLUSIONS: GV was well tolerated in this population. Although there was some antitumour activity, the extent of disease control in stage I did not meet the level required to proceed to stage II. TRIAL REGISTRATION NUMBERS: NCT02487979.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Inmunoconjugados/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Adolescente , Adulto , Edad de Inicio , Anticuerpos Monoclonales/farmacocinética , Neoplasias Óseas/epidemiología , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Niño , Femenino , Humanos , Inmunoconjugados/farmacocinética , Masculino , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Osteosarcoma/epidemiología , Osteosarcoma/metabolismo , Osteosarcoma/patología , Pronóstico , Resultado del Tratamiento , Adulto Joven
16.
Int J Radiat Biol ; 84(5): 401-12, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18464069

RESUMEN

PURPOSE: Velafermin (recombinant human fibroblast growth factor-20, rhFGF-20) has been shown to reduce the severity and duration of mucositis in preclinical acute (single dose) radiation and chemotherapy/radiation models of oral mucositis. Our present study assessed the impact of velafermin on the severity and duration of oral mucositis that occurred as a consequence of fractionated radiation. EXPERIMENTAL DESIGN: Male Golden Syrian hamsters were exposed to eight doses of radiation (7.5 Gy/dose) to the cheek pouch on days 0, 1, 2, 3, 6, 7, 8 and 9 that resulted in severe mucositis. Velafermin (4 mg/kg intraperitoneally) was administered on days 3 and 9; days 2, 3, 8 and 9; days 3, 4, 9 and 10; or days 4, 5, 10 and 11. RESULTS: Although all velafermin-treated groups showed some reduction in the degree of mucositis relative to the vehicle control, the most significant reduction (p < 0.001) was observed in the groups treated on days 3 and 9 or on days 4, 5, 10 and 11. Further histological analysis of resected buccal mucosa revealed improvements in epithelial tissue degradation, connective tissue degradation and inflammation severity after velafermin treatment. Most notably, velafermin treatment reduced inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor (TNF) production possibly through nuclear factor-kappaB (NF-kappaB) mediation. The detection of increased NF-E2-related factor-2 (NRF-2) expression in the early onset stage of mucositis in the buccal mucosa suggested additional protective benefits from reactive oxygen species (ROS) generated as a consequence of fractionated radiation treatment. CONCLUSION: Thus, velafermin provided therapeutic benefit in a hamster model of oral mucositis induced by fractionated radiation therapy.


Asunto(s)
Factores de Crecimiento de Fibroblastos/química , Factores de Crecimiento de Fibroblastos/farmacología , Mucosa Bucal/patología , Traumatismos por Radiación/tratamiento farmacológico , Estomatitis/tratamiento farmacológico , Animales , Mejilla , Cricetinae , Epitelio/efectos de la radiación , Humanos , Inflamación/radioterapia , Interleucina-6/biosíntesis , Masculino , Factor 2 Relacionado con NF-E2/biosíntesis , FN-kappa B/biosíntesis , Factor de Necrosis Tumoral alfa/biosíntesis
17.
Oncotarget ; 8(61): 104303-104314, 2017 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-29262642

RESUMEN

High levels of expression of glycoprotein non-metastatic B (gpNMB) in triple negative breast cancer (TNBC) and its association with metastasis and recurrence make it an attractive target for therapy with the antibody drug conjugate, glembatumumab vedotin (CDX-011). This report describes the development of a companion PET-based diagnostic imaging agent using 89Zr-labeled glembatumumab ([89Zr]DFO-CR011) to potentially aid in the selection of patients most likely to respond to targeted treatment with CDX-011. [89Zr]DFO-CR011 was characterized for its pharmacologic properties in TNBC cell lines. Preclinical studies determined that [89Zr]DFO-CR011 binds specifically to gpNMB with high affinity (Kd = 25 ± 5 nM), immunoreactivity of 2.2-fold less than the native CR011, and its cellular uptake correlates with gpNMB expression (r = 0.95). In PET studies at the optimal imaging timepoint of 7 days p.i., the [89Zr]DFO-CR011 tumor uptake in gpNMB-expressing MDA-MB-468 xenografts had a mean SUV of 2.9, while significantly lower in gpNMB-negative MDA-MB-231 tumors with a mean SUV of 1.9. [89Zr]DFO-CR011 was also evaluated in patient-derived xenograft models of TNBC, where tumor uptake in vivo had a positive correlation with total gpNMB protein expression via ELISA (r = 0.79), despite the heterogeneity of gpNMB expression within the same group of PDX mice. Lastly, the radiation dosimetry calculated from biodistribution studies in MDA-MB-468 xenografts determined the effective dose for human use would be 0.54 mSv/MBq. Overall, these studies demonstrate that [89Zr]DFO-CR011 is a potential companion diagnostic imaging agent for CDX-011 which targets gpNMB, an emerging biomarker for TNBC.

18.
J Clin Oncol ; 35(18): 2028-2036, 2017 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-28463630

RESUMEN

Purpose CD27, a costimulatory molecule on T cells, induces intracellular signals that mediate cellular activation, proliferation, effector function, and cell survival upon binding to its ligand, CD70. Varlilumab is a novel, first-in-class, agonist CD27 antibody that stimulates the CD27 pathway, which results in T-cell activation and antitumor activity in tumor models. This first-in-human, dose-escalation and expansion study evaluated the safety, pharmacology, and activity of varlilumab in patients with advanced solid tumors. Methods In a 3 + 3 dose-escalation design (n = 25), patients received a single dose of varlilumab (0.1, 0.3, 1.0, 3.0, or 10 mg/kg intravenously) with a 28-day observation, followed by up to five multidose cycles (one dose per week for 4 weeks), depending on tumor response. Expansion cohorts were initiated at 3.0 mg/kg in patients with melanoma (n = 16) and renal cell carcinoma (RCC; n = 15). Primary objectives were to assess the safety and the maximum tolerated and optimal biologic doses of varlilumab. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics, and clinical antitumor activity of varlilumab. Results Exposure to varlilumab was linear and dose proportional across dose groups. Only one patient experienced a dose-limiting toxicity-grade 3 transient asymptomatic hyponatremia at the 1.0-mg/kg dose level. Treatment-related adverse events were generally grade 1 or 2 in severity. Evidence of biologic activity consistent with CD27 stimulation-chemokine induction, T-cell stimulation, regulatory T cell depletion-was observed at all dose levels. A patient with metastatic RCC experienced a partial response (78% shrinkage, progression-free survival > 2.3 years). Eight patients experienced stable disease > 3 months, including a patient with metastatic RCC with progression-free survival of > 3.9 years. Conclusion Dose escalation of varlilumab to 10 mg/kg was well tolerated without identification of a maximum tolerated dose. Varlilumab was biologically and clinically active.


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Neoplasias/tratamiento farmacológico , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/agonistas , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/secundario , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales Humanizados , Antineoplásicos/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/secundario , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/secundario , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Citocinas/sangre , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Masculino , Melanoma/tratamiento farmacológico , Melanoma/secundario , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/patología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Resultado del Tratamiento , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología
19.
Mol Cancer Ther ; 15(3): 379-91, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26832796

RESUMEN

Sensitivity to MDM2 inhibitors is widely different among responsive TP53 wild-type cell lines and tumors. Understanding the determinants of MDM2 inhibitor sensitivity is pertinent for their optimal clinical application. Wild-type p53-inducible phosphatase-1 (WIP1) encoded by PPM1D, is activated, gained/amplified in a range of TP53 wild-type malignancies, and is involved in p53 stress response homeostasis. We investigated cellular growth/proliferation of TP53 wild-type and matched mutant/null cell line pairs, differing in PPM1D genetic status, in response to Nutlin-3/RG7388 ± a highly selective WIP1 inhibitor, GSK2830371. We also assessed the effects of GSK2830371 on MDM2 inhibitor-induced p53(Ser15) phosphorylation, p53-mediated global transcriptional activity, and apoptosis. The investigated cell line pairs were relatively insensitive to single-agent GSK2830371. However, a non-growth-inhibitory dose of GSK2830371 markedly potentiated the response to MDM2 inhibitors in TP53 wild-type cell lines, most notably in those harboring PPM1D-activating mutations or copy number gain (up to 5.8-fold decrease in GI50). Potentiation also correlated with significant increase in MDM2 inhibitor-induced cell death endpoints that were preceded by a marked increase in a WIP1 negatively regulated substrate, phosphorylated p53(Ser15), known to increase p53 transcriptional activity. Microarray-based gene expression analysis showed that the combination treatment increases the subset of early RG7388-induced p53 transcriptional target genes. These findings demonstrate that potent and selective WIP1 inhibition potentiates the response to MDM2 inhibitors in TP53 wild-type cells, particularly those with PPM1D activation or gain, while highlighting the mechanistic importance of p53(Ser15) and its potential use as a biomarker for response to this combination regimen.


Asunto(s)
Aminopiridinas/farmacología , Antineoplásicos/farmacología , Dipéptidos/farmacología , Resistencia a Antineoplásicos , Proteína Fosfatasa 2C/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/metabolismo , Apoptosis/efectos de los fármacos , Apoptosis/genética , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Catálisis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Humanos , Imidazoles/farmacología , Mutación , Neoplasias/genética , Neoplasias/metabolismo , Piperazinas/farmacología , Proteína Fosfatasa 2C/genética , Proteína Fosfatasa 2C/metabolismo , Proteolisis/efectos de los fármacos , Pirrolidinas/farmacología , Transcripción Genética , Proteína p53 Supresora de Tumor/genética , Ubiquitina/metabolismo , para-Aminobenzoatos/farmacología
20.
Clin Cancer Res ; 22(24): 6088-6098, 2016 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-27515299

RESUMEN

PURPOSE: To determine if BRAF and/or MEK inhibitor-induced GPNMB expression renders melanomas sensitive to CDX-011, an antibody-drug conjugate targeting GPNMB. EXPERIMENTAL DESIGN: The Cancer Genome Atlas melanoma dataset was interrogated for a panel of MITF-regulated melanosomal differentiation antigens, including GPNMB. BRAF-mutant melanoma cell lines treated with BRAF or MEK inhibitors were assessed for GPNMB expression by RT-qPCR, immunoblot, and FACS analyses. Transient siRNA-mediated knockdown approaches were used to determine if MITF is requirement for treatment-induced GPNMB upregulation. GPNMB expression was analyzed in serial biopsies and serum samples from patients with melanoma taken before, during, and after disease progression on MAPK inhibitor treatment. Subcutaneous injections were performed to test the efficacy of MAPK inhibitors alone, CDX-011 alone, or their combination in suppressing melanoma growth. RESULTS: A MITF-dependent melanosomal differentiation signature is associated with poor prognosis in patients with this disease. MITF is increased following BRAF and MEK inhibitor treatment and induces the expression of melanosomal differentiation genes, including GPNMB. GPNMB is expressed at the cell surface in MAPK inhibitor-treated melanoma cells and is also elevated in on-treatment versus pretreatment biopsies from melanoma patients receiving MAPK pathway inhibitors. Combining BRAF and/or MEK inhibitors with CDX-011, an antibody-drug conjugate targeting GPNMB, is effective in causing melanoma regression in preclinical animal models and delays the recurrent melanoma growth observed with MEK or BRAF/MEK inhibitor treatment alone. CONCLUSIONS: The combination of MAPK pathway inhibitors with an antibody-drug conjugate targeting GPNMB is an effective therapeutic option for patients with melanoma. Clin Cancer Res; 22(24); 6088-98. ©2016 AACR.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Antineoplásicos/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Melanoma/tratamiento farmacológico , Glicoproteínas de Membrana/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Humanos , Inmunoconjugados/farmacología , Melanoma/genética , Ratones , Mutación , Proteínas Proto-Oncogénicas B-raf/metabolismo , Neoplasias Cutáneas/genética , Melanoma Cutáneo Maligno
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