RESUMO
Background In pancreatic ductal adenocarcinoma (PDAC), the chemokine (C-C motif) ligand 2 (CCL2)/chemokine (C-C motif) receptor 2 (CCR2) axis plays a key role in immunosuppressive properties of the tumor microenvironment, patient prognosis, and chemoresistance. This phase Ib study assessed the effects of the orally administered CCR2 inhibitor PF-04136309 in combination with nab-paclitaxel and gemcitabine in patients with previously untreated metastatic PDAC. Methods Patients received PF-04136309 twice daily (BID) continuously plus nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) administered on days 1, 8, and 15 of each 28-day cycle. The primary objectives were to evaluate safety and tolerability, characterize dose-limiting toxicities (DLTs), and determine the recommended phase II dose (RP2D) of PF-04136309. Results In all, 21 patients received PF-04136309 at a starting dose of 500 mg or 750 mg BID. The RP2D was identified to be 500 mg BID. Of 17 patients treated at the 500 mg BID starting dose, three (17.6%) experienced a total of four DLTs, including grade 3 dysesthesia, diarrhea, and hypokalemia and one event of grade 4 hypoxia. Relative to the small number of patients (n = 21), a high incidence (24%) of pulmonary toxicity was observed in this study. The objective response rate for 21 patients was 23.8% (95% confidence interval: 8.2-47.2%). Levels of CD14 + CCR2+ inflammatory monocytes (IM) decreased in the peripheral blood, but did not accumulate in the bone marrow. Conclusions PF-04136309 in combination with nab-paclitaxel plus gemcitabine had a safety profile that raises concern for synergistic pulmonary toxicity and did not show an efficacy signal above nab-paclitaxel and gemcitabine. ClinicalTrials.gov identifier: NCT02732938.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Quimiocina CCL2/antagonistas & inibidores , Neoplasias Pancreáticas/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/uso terapêutico , Adenocarcinoma/metabolismo , Idoso , Albuminas/uso terapêutico , Carcinoma Ductal Pancreático/metabolismo , Estudos de Coortes , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/metabolismo , Prognóstico , Pirrolidinas/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Gencitabina , Neoplasias PancreáticasRESUMO
AIM: This open-label study investigated the effect of belatacept on cytokine levels and on the pharmacokinetics of caffeine, losartan, omeprazole, dextromethorphan and midazolam, as CYP probe substrates after oral administration of the Inje cocktail in healthy volunteers. METHODS: Twenty-two evaluable subjects received the Inje cocktail on Days 1, 4, 7 and 11 and belatacept infusion on Day 4. RESULTS: Since belatacept caused no major alterations to cytokine levels, there were no major effects on CYP-substrate pharmacokinetics, except for a slight (16-30%) increase in omeprazole exposure, which was probably due to omeprazole-mediated, time-dependent CYP inhibition. Belatacept did not cause major alterations in the pharmacokinetics, as measured by the geometric mean ratios and associated 90% confidence interval for area under the plasma concentration -time curve from time zero to infinity on Day 7 comparing administration with and without belatacept for caffeine (1.002 [0.914, 1.098]), dextromethorphan (1.031 [0.885, 1.200]), losartan (1.016 [0.938, 1.101)], midazolam (0.968 [0.892, 1.049]) or their respective metabolites. CONCLUSIONS: Therefore, no dose adjustments of CYP substrates are indicated with belatacept coadministration.
Assuntos
Abatacepte/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Citocinas/metabolismo , Imunossupressores/farmacologia , Adulto , Área Sob a Curva , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Interações Medicamentosas , Feminino , Humanos , Masculino , Farmacocinética , Fatores de Tempo , Adulto JovemRESUMO
PURPOSE: Stimulation of effector T cells is an appealing immunotherapeutic approach in oncology. OX40 (CD134) is a costimulatory receptor expressed on activated CD4+ and CD8+ T cells. Induction of OX40 following antigen recognition results in enhanced T-cell activation, proliferation, and survival, and OX40 targeting shows therapeutic efficacy in preclinical studies. We report the monotherapy dose-escalation portion of a multicenter, phase I trial (NCT02315066) of ivuxolimab (PF-04518600), a fully human immunoglobulin G2 agonistic monoclonal antibody specific for human OX40. PATIENTS AND METHODS: Adult patients (N = 52) with selected locally advanced or metastatic cancers received ivuxolimab 0.01 to 10 mg/kg. Primary endpoints were safety and tolerability. Secondary/exploratory endpoints included preliminary assessment of antitumor activity and biomarker analyses. RESULTS: The most common all-causality adverse events were fatigue (46.2%), nausea (28.8%), and decreased appetite (25.0%). Of 31 treatment-related adverse events, 30 (96.8%) were grade ≤2. No dose-limiting toxicities occurred. Ivuxolimab exposure increased in a dose-proportionate manner from 0.3 to 10 mg/kg. Full peripheral blood target engagement occurred at ≥0.3 mg/kg. Three (5.8%) patients achieved a partial response, and disease control was achieved in 56% of patients. Increased CD4+ central memory T-cell proliferation and activation, and clonal expansion of CD4+ and CD8+ T cells in peripheral blood were observed at 0.1 to 3.0 mg/kg. Increased immune cell infiltrate and OX40 expression were evident in on-treatment tumor biopsies. CONCLUSIONS: Ivuxolimab was generally well tolerated with on-target immune activation at clinically relevant doses, showed preliminary antitumor activity, and may serve as a partner for combination studies.
Assuntos
Antineoplásicos , Neoplasias , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/uso terapêutico , Linfócitos T CD8-Positivos , Humanos , Náusea , Neoplasias/tratamento farmacológicoRESUMO
IL-7 receptor-α (IL-7Rα) blockade has been shown to reverse autoimmune diabetes in the non-obese diabetic mouse by promoting inhibition of effector T cells and consequently altering the balance of regulatory T (Treg) and effector memory (TEM) cells. PF-06342674 is a humanized monoclonal antibody that binds to and inhibits the function of IL-7Rα. In the current phase 1b study, subjects with type 1 diabetes (T1D) received subcutaneous doses of either placebo or PF-06342674 (1, 3, 8 mg/kg/q2w or 6 mg/kg/q1w) for 10 weeks and were followed up to 18 weeks. Nonlinear mixed effects models were developed to characterize the pharmacokinetics (PK), target engagement biomarkers, and immunomodulatory activity. PF-06342674 was estimated to have 20-fold more potent inhibitory effect on TEM cells relative to Treg cells resulting in a non-monotonic dose-response relationship for the Treg:TEM ratio, reaching maximum at ~ 3 mg/kg/q2w dose. Target-mediated elimination led to nonlinear PK with accelerated clearance at lower doses due to high affinity binding and rapid clearance of the drug-target complex. Doses ≥ 3 mg/kg q2w result in sustained PF-06342674 concentrations higher than the concentration of cellular IL-7 receptor and, in turn, maintain near maximal receptor occupancy over the dosing interval. The results provide important insight into the mechanism of IL-7Rα blockade and immunomodulatory activity of PF-06342674 and establish a rational framework for dose selection for subsequent clinical trials of PF-06342674. Furthermore, this analysis serves as an example of mechanistic modeling to support dose selection of a drug candidate in the early phases of development.
Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/farmacocinética , Células Secretoras de Insulina/efeitos dos fármacos , Modelos Biológicos , Receptores de Interleucina-17/antagonistas & inibidores , Linfócitos T Reguladores/efeitos dos fármacos , Anticorpos Monoclonais Humanizados/administração & dosagem , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/imunologia , Relação Dose-Resposta a Droga , Humanos , Hipoglicemiantes/administração & dosagem , Injeções Subcutâneas , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/patologia , Dinâmica não Linear , Receptores de Interleucina-17/imunologia , Linfócitos T Reguladores/imunologia , Resultado do TratamentoRESUMO
BACKGROUND: The cytokine IL-7 is critical for T cell development and function. We performed a Phase Ib study in patients with type 1 diabetes (T1D) to evaluate how blockade of IL-7 would affect immune cells and relevant clinical responses. METHODS: Thirty-seven subjects with T1D received s.c. RN168, a monoclonal antibody that blocks the IL -7 receptor α (IL7Rα) in a dose-escalating study. RESULTS: Between 90% and 100% IL-7R occupancy and near-complete inhibition of pSTAT5 was observed at doses of RN168 1 mg/kg every other week (Q2wk) and greater. There was a significant decline in CD4+ and CD8+ effector and central memory T cells and CD4+ naive cells, but there were fewer effects on CD8+ naive T cells. The ratios of Tregs to CD4+ or CD8+ effector and central memory T cells versus baseline were increased. RNA sequencing analysis showed downmodulation of genes associated with activation, survival, and differentiation of T cells. Expression of the antiapoptotic protein Bcl-2 was reduced. The majority of treatment-emergent adverse events (TEAEs) were mild and not treatment related. Four subjects became anti-EBV IgG+ after RN168, and 2 had symptoms of active infection. The immunologic response to tetanus toxoid was preserved at doses of 1 and 3 mg/kg Q2wk but reduced at higher doses. CONCLUSIONS: This trial shows that, at dosages of 1-3 mg/kg, RN168 selectively inhibits the survival and activity of memory T cells while preserving naive T cells and Tregs. These immunologic effects may serve to eliminate pathologic T cells in autoimmune diseases. TRIAL REGISTRATION: NCT02038764. FUNDING: Pfizer Inc.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Diabetes Mellitus Tipo 1/tratamento farmacológico , Memória Imunológica/efeitos dos fármacos , Subunidade alfa de Receptor de Interleucina-7/antagonistas & inibidores , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/uso terapêutico , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/imunologia , Relação Dose-Resposta a Droga , Relação Dose-Resposta Imunológica , Feminino , Humanos , Interleucina-7/imunologia , Interleucina-7/metabolismo , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Masculino , Pessoa de Meia-Idade , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Resultado do TratamentoRESUMO
BACKGROUND: There are no effective treatments or validated clinical response markers in systemic sclerosis (SSc). We assessed imaging biomarkers and performed gene expression profiling in a single-arm open-label clinical trial of tyrosine kinase inhibitor dasatinib in patients with SSc-associated interstitial lung disease (SSc-ILD). METHODS: Primary objectives were safety and pharmacokinetics. Secondary outcomes included clinical assessments, quantitative high-resolution computed tomography (HRCT) of the chest, serum biomarker assays and skin biopsy-based gene expression subset assignments. Clinical response was defined as decrease of >5 or >20% from baseline in the modified Rodnan Skin Score (MRSS). Pulmonary function was assessed at baseline and day 169. RESULTS: Dasatinib was well-tolerated in 31 patients receiving drug for a median of nine months. No significant changes in clinical assessments or serum biomarkers were seen at six months. By quantitative HRCT, 65% of patients showed no progression of lung fibrosis, and 39% showed no progression of total ILD. Among 12 subjects with available baseline and post-treatment skin biopsies, three were improvers and nine were non-improvers. Improvers mapped to the fibroproliferative or normal-like subsets, while seven out of nine non-improvers were in the inflammatory subset (p = 0.0455). Improvers showed stability in forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), while both measures showed a decline in non-improvers (p = 0.1289 and p = 0.0195, respectively). Inflammatory gene expression subset was associated with higher baseline HRCT score (p = 0.0556). Non-improvers showed significant increase in lung fibrosis (p = 0.0313). CONCLUSIONS: In patients with SSc-ILD dasatinib treatment was associated with acceptable safety profile but no significant clinical efficacy. Patients in the inflammatory gene expression subset showed increase in skin fibrosis, decreasing pulmonary function and worsening lung fibrosis during the study. These findings suggest that target tissue-specific gene expression analyses can help match patients and therapeutic interventions in heterogeneous diseases such as SSc, and quantitative HRCT is useful for assessing clinical outcomes. TRIAL REGISTRATION: Clinicaltrials.gov NCT00764309.
Assuntos
Dasatinibe/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Doenças Pulmonares Intersticiais , Escleroderma Sistêmico , Pele , Tomografia Computadorizada por Raios X , Adulto , Idoso , Biomarcadores/metabolismo , Feminino , Humanos , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/metabolismo , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico por imagem , Escleroderma Sistêmico/dietoterapia , Escleroderma Sistêmico/metabolismo , Pele/diagnóstico por imagem , Pele/metabolismoRESUMO
The CD25-binding antibody daclizumab high-yield process (DAC HYP) is an interleukin (IL)-2 signal modulating antibody that shares primary amino acid sequence and CD25 binding affinity with Zenapax®, a distinct form of daclizumab, which was approved for the prevention of acute organ rejection in patients receiving renal transplants as part of an immunosuppressive regimen that includes cyclosporine and corticosteroids. Comparison of the physicochemical properties of the two antibody forms revealed the glycosylation profile of DAC HYP differs from Zenapax in both glycan distribution and the types of oligosaccharides, most notably high-mannose, galactosylated and galactose-α-1,3-galactose (α-Gal) oligosaccharides, resulting in a DAC HYP antibody material that is structurally distinct from Zenapax. Although neither antibody elicited complement-dependent cytotoxicity in vitro, DAC HYP antibody had significantly reduced levels of antibody-dependent cell-mediated cytotoxicity (ADCC). The ADCC activity required natural killer (NK) cells, but not monocytes, suggesting the effects were mediated through binding to Fc-gamma RIII (CD16). Incubation of each antibody with peripheral blood mononuclear cells also caused the down-modulation of CD16 expression on NK cells and the CD16 down-modulation was greater for Zenapax in comparison to that observed for DAC HYP. The substantive glycosylation differences between the two antibody forms and corresponding greater Fc-mediated effector activities by Zenapax, including cell killing activity, manifest as a difference in the biological function and pharmacology between DAC HYP and Zenapax.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Imunoglobulina G/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Daclizumabe , Glicosilação , Humanos , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Leucócitos Mononucleares/imunologiaRESUMO
Chemokines are a family of small, secreted chemoattractant cytokines that regulate distribution and function of leukocytes during immune responses. While most chemokines are members of the CC or CXC subgroups, XCL1, also known as lymphotactin, is the sole member of the C subgroup. XCL1 is produced by activated CD8(+) T cells, NK cells, gammadelta T cells, and mast cells. XCL1 differs from other chemokines in that it contains only a single disulfide bond and a mucin-like domain at its carboxy terminus that is glycosylated. Understanding the biologic functions of chemokines has largely depended upon expression of these recombinant molecules in E. coli. To examine the effects of glycosylation on the biologic activity of XCL1, we designed constructs for expression of human XCL1 in insect S2 cells. Comparison of this material with that expressed in E. coli reveals that glycosylation significantly increases the biologic activity of XCL1.
Assuntos
Quimiocinas C/metabolismo , Quimiocinas C/fisiologia , Quimiotaxia de Leucócito/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/fisiologia , Inibição de Migração Celular , Células Cultivadas , Quimiocinas C/genética , Drosophila melanogaster , Escherichia coli , Glicosilação , Humanos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , TransfecçãoRESUMO
Belatacept blocks CD28-mediated T-cell costimulation and prevents renal transplant rejection. Understanding T-cell subset sensitivity to belatacept may identify cellular markers for immunosuppression failure to better guide treatment selection. Here, we evaluate the belatacept sensitivity of allo-antigen-specific CD154-expressing-T-cells, whose T-cytotoxic memory (TcM) subset predicts rejection with high sensitivity after non-renal transplantation. The belatacept concentration associated with half-maximal reduction (EC50) of CD154 expression was calculated for 36 T-cell subsets defined by combinations of T-helper (Th), Tc, T-memory and CD28 receptors, following allostimulation of peripheral blood leukocytes from 20 normal healthy subjects. Subsets were ranked by median EC50, and by whether subset EC50 was correlated with and therefore could be represented by the frequency of other subsets. No single subset frequency emerged as the significant correlate of EC50 for a given subset. Most (n = 25) T-cell subsets were sensitive to belatacept. Less sensitive subsets demonstrated a memory phenotype and absence of CD28 receptor. Potential drug-resistance markers for future validation include the low frequency highly differentiated, Th-memory-CD28-negative T-cells with the highest median EC50, and the least differentiated, high-frequency Tc subset, with the most CD28-negative T-cells, the third highest median EC50, and significant correlations with frequencies of the highest number of CD28-negative and memory subsets.