RESUMO
BACKGROUND: In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy or in combination with pembrolizumab. PATIENTS AND METHODS: Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1. RESULTS: Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs-the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs-the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy. CONCLUSIONS: Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Anticorpos Monoclonais Humanizados/efeitos adversos , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/patologia , Critérios de Avaliação de Resposta em Tumores SólidosRESUMO
We undertook a prospective longitudinal study of thyroid function in 60 normal pregnant women and measured serum concentrations of T4, triiodothyronine (T3), T-uptake, thyroxine binding globulin (TBG), free thyroxine index (FTI), free T4, albumin and thyrotropin (TSH). From these data we established reference ranges for each of these analytes for each trimester and examined the inter-relationships between laboratory measurements of thyroid function tests. We observed significant increases in serum concentrations of thyrotropin and decreases in free T4, assays commonly used as first line investigations of thyroid activity during pregnancy. However, the 95th centile intervals for both analytes remained within the reference range for nonpregnant women.
Assuntos
Gravidez/sangue , Hormônios Tireóideos/sangue , Feminino , Humanos , Estudos Longitudinais , Estudos ProspectivosRESUMO
Chromosomal locations of members of the xenotropic-related env gene family in the mouse genome have been determined. Endonuclease restriction site polymorphisms detected by molecular hybridization were used to study the inheritance of mink cell-focus inducing and xenotropic env gene-related sequences in recombinant inbred strains of mice. Some of the endogenous env sequences appear to be closely linked to genes determining leukemia virus induction and to genes involved in the immune response, such as the heavy and light chains of the immunoglobulin molecules or allotypic determinants on B and T lymphocytes. The use of probes that detect restriction fragment length polymorphisms in a small family of dispersed sequences promises to yield a large number of markers that can be used together with recombinant inbred strains for efficient mapping of the mouse genome.
Assuntos
Transformação Celular Viral , Genes Virais , Camundongos/genética , Retroviridae/genética , Proteínas do Envelope Viral/genética , Animais , Mapeamento Cromossômico , Ligação Genética , Hibridização de Ácido Nucleico , Especificidade da EspécieRESUMO
We have measured the expression levels of a range of distinct ion channel genes in the apex/ventricle region and sino-atrial node (SAN) sub-regions of heart under conditions in which conventional Northern hybridization or ribonuclease protection methods were too insensitive or non-quantitative. The abundance of six potassium channel mRNAs was determined in relation to a single synthetic competitor RNA template which was co-reverse transcribed and PCR-amplified. By these methods we have shown that coronary artery ligation procedures which induce anoxia and ischaemic scarring in the apical region reduce amplifiable message abundance in a time-dependent, but non-specific manner. There was no evidence for any selective reduction of individual mRNA levels during this process. Despite a high reproducibility of titration endpoints, competitive RNA template amplification assays did not provide a simple marker for ischaemic damage, since it was not possible to control for tissue sample heterogeneity. We have also applied these competitive nucleic acid titration techniques to demonstrate expression of cAMP- and cGMP-gated ion channel sequences in small pieces of tissue derived from the SAN sub-region of rabbit heart. Although the ion channels encoded by these sequences are obligately coupled to intracellular signalling agonists commonly found in cardiac cells, they have not been described in functional terms within SAN or any other cardiac subregion. For rapid determination of cDNA molecular numbers, we have devised single-gene, DNA template controls to measure absolute abundance of a cAMP-gated cDNA derived from heart tissue. Competitive titration procedures therefore provide an important technique for probing gene induction and/or repression accompanying pharmacological or surgical interventions, or in progression of disease states. For rare cDNAs, they can estimate the representativeness of a given preparation prior to library construction, screening and retrieval of clones, while eliminating 'false positive' or 'false negative' signals.
Assuntos
Canais Iônicos/genética , Isquemia Miocárdica/genética , Miocárdio/química , RNA Mensageiro/análise , RNA Mensageiro/genética , Animais , Sequência de Bases , Northern Blotting , Primers do DNA , Amplificação de Genes , Ventrículos do Coração/química , Ventrículos do Coração/metabolismo , Ativação do Canal Iônico/fisiologia , Canais Iônicos/metabolismo , Canais Iônicos/fisiologia , Masculino , Dados de Sequência Molecular , Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , Reação em Cadeia da Polimerase , Canais de Potássio/genética , Canais de Potássio/metabolismo , Canais de Potássio/fisiologia , RNA Mensageiro/metabolismo , Coelhos , Ratos , Ratos Sprague-Dawley , Nó Sinoatrial/química , Nó Sinoatrial/metabolismo , Titulometria , Transcrição GênicaRESUMO
We have demonstrated the use of the Escherichia coli LexA repressor-operator system to down-regulate gene expression in mouse cells. The LexA gene was placed downstream of the RSVLTR promoter with polyadenylation and splice signals from SV40. This expression unit was introduced into mouse Ltk- cells by calcium phosphate transfection and stable transfectants selected which express LexA protein. We have used the bacterial chloramphenicol acetyltransferase gene (CAT) as our reporter gene. Transcription of this gene was driven by the HSV tk promoter, into which we have introduced one or two synthetic LexA operator sequences in various positions throughout the promoter. Necessary 3' signals were from the HSV tk gene. Repression by LexA was assessed by comparing the transient expression of tkCAT target constructs, containing LexA operator sequences in the promoter, in cells expressing LexA protein with that in control cells not expressing the repressor. We have observed up to 10-fold repression of CAT expression in LexA+ cells from promoters containing LexA operator sequences.