First-in-human, phase 1 study of PF-06753512, a vaccine-based immunotherapy regimen (VBIR), in non-metastatic hormone-sensitive biochemical recurrence and metastatic castration-resistant prostate cancer (mCRPC).

Background: This phase 1 study evaluated PF-06753512, a vaccine-based immunotherapy regimen (PrCa VBIR), in two clinical states of prostate cancer (PC), metastatic castration-resistant PC (mCRPC) and biochemical recurrence (BCR).

Methods: For dose escalation, patients with mCRPC received intramuscular PrCa VBIR (adenovirus vector and plasmid DNA expressing prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA), and prostate stem cell antigen (PSCA)) with or without immune checkpoint inhibitors (ICIs, tremelimumab 40 or 80 mg with or without sasanlimab 130 or 300 mg, both subcutaneous). For dose expansion, patients with mCRPC received recommended phase 2 dose (RP2D) of PrCa VBIR plus tremelimumab 80 mg and sasanlimab 300 mg; patients with BCR received PrCa VBIR plus tremelimumab 80 mg (Cohort 1B-BCR) or tremelimumab 80 mg plus sasanlimab 130 mg (Cohort 5B-BCR) without androgen deprivation therapy (ADT).

PK/PD model-informed dose selection for oncology phase I expansion: Case study based on PF-06939999, a PRMT5 inhibitor.

The optimal dose for targeted oncology therapeutics is often not the maximum tolerated dose. Pharmacokinetic/pharmacodynamic (PK/PD) modeling can be an effective tool to integrate clinical data to help identify the optimal dose. This case study shows the utility of population PK/PD modeling in selecting the recommended dose for expansion (RDE) for the first-in-patient (FIP) study of PF-06939999, a small-molecule inhibitor of protein arginine methyltransferase 5.

Functional Evaluation and Genetic Evolution of Human T-Cell Responses After Vaccination With a Conditionally Replication-Defective Cytomegalovirus Vaccine.

Background: Cytomegalovirus (CMV) can cause congenital infection and is the leading cause of nongenetic newborn disabilities. V160, a conditionally replication-defective virus, is an investigational vaccine under evaluation for prevention of congenital CMV. The vaccine was well tolerated and induced both humoral and cellular immunity in CMV-seronegative trial participants.

Comprehensive investigation of T and B cell receptor repertoires in an MC38 tumor model following murine anti‑PD‑1 administration.

The MC38 (derived from carcinogen‑induced colon adenocarcinoma) tumor model is sensitive to anti‑programmed cell death‑1 (anti-PD‑1) treatment. However, there is no comprehensive description of the T and B cell receptor (TCR, BCR) repertoires of the MC38 tumor model following anti‑PD‑1 treatment, an improved understanding of which is highly important in the development of anti‑PD‑1 immunotherapy. The present study analyzed the TCR and BCR repertoires of three types of tissue, including tumor, spleen and tumor draining lymph node (DLN) from 20 MC38 syngeneic mice receiving murine anti‑PD‑1 (mDX400) treatment or mouse immunoglobulin G1 (mIgG1) control treatment.

Peripheral immune-based biomarkers in cancer immunotherapy: can we realize their predictive potential?

The immunologic landscape of the host and tumor play key roles in determining how patients will benefit from immunotherapy, and a better understanding of these factors could help inform how well a tumor responds to treatment. Recent advances in immunotherapy and in our understanding of the immune system have revolutionized the treatment landscape for many advanced cancers. Notably, the use of immune checkpoint inhibitors has demonstrated durable responses in various malignancies.

Identification of Variable and Joining Germline Genes and Alleles for Rhesus Macaque from B Cell Receptor Repertoires.

The rhesus macaque is a valuable preclinical animal model to estimate vaccine effectiveness and is also important for understanding Ab maturation and B cell repertoire evolution responding to vaccination. However, incomplete mapping of rhesus Ig germline genes hinders the research efforts. To address this deficiency, we sequenced the BCR repertoires of 75 Indian rhesus macaques.

Corrigendum: A Comprehensive Analysis of the T and B Lymphocytes Repertoire Shaped by HIV Vaccines.

[This corrects the article DOI: 10.3389/fimmu.2018.

A Comprehensive Analysis of the T and B Lymphocytes Repertoire Shaped by HIV Vaccines.

The exploitation of various human immunodeficiency virus type-1 (HIV-1) vaccines has posed great challenges for the researchers in precisely evaluating the vaccine-induced immune responses, however, the understanding of vaccination response suffers from the lack of unbiased characterization of the immune landscape. The rapid development of high throughput sequencing (HTS) makes it possible to scrutinize the extremely complicated immunological responses during vaccination. In the current study, three vaccines, namely N36, N51, and 5-Helix based on the HIV-1 gp41 pre-hairpin fusion intermediate were applied in rhesus macaques.

Active evolution of memory B-cells specific to viral gH/gL/pUL128/130/131 pentameric complex in healthy subjects with silent human cytomegalovirus infection.

Human cytomegalovirus (HCMV) can cause life-threatening infection in immunosuppressed patients, and infection that may lead to birth defects. No vaccine is currently available. HCMV infection in healthy subjects is generally asymptomatic, and virus persists as latent infection for life.

Genome Sequences of Diverse Human Cytomegalovirus Strains with Utility in Drug Screening and Vaccine Evaluation.

Cytomegalovirus displays genetic heterogeneity, which has implications for antiviral and vaccine development. Many studies have focused on laboratory isolates that have been extensively adapted for growth on fibroblasts. Here, we report whole-genome sequences for 10 human cytomegalovirus (HCMV) strains that readily grow on ARPE-19 human retinal pigment epithelial cells.

Neutralization of Diverse Human Cytomegalovirus Strains Conferred by Antibodies Targeting Viral gH/gL/pUL128-131 Pentameric Complex.

Human cytomegalovirus (HCMV) is the leading cause of congenital viral infection, and developing a prophylactic vaccine is of high priority to public health. We recently reported a replication-defective human cytomegalovirus with restored pentameric complex glycoprotein H (gH)/gL/pUL128-131 for prevention of congenital HCMV infection. While the quantity of vaccine-induced antibody responses can be measured in a viral neutralization assay, assessing the quality of such responses, including the ability of vaccine-induced antibodies to cross-neutralize the field strains of HCMV, remains a challenge.

Inhibition of RORγT Skews TCRα Gene Rearrangement and Limits T Cell Repertoire Diversity.

Recent studies have elucidated the molecular mechanism of RORγT transcriptional regulation of Th17 differentiation and function. RORγT was initially identified as a transcription factor required for thymopoiesis by maintaining survival of CD4CD8 (DP) thymocytes. While RORγ antagonists are currently being developed to treat autoimmunity, it remains unclear how RORγT inhibition may impact thymocyte development.

IMPre: An Accurate and Efficient Software for Prediction of T- and B-Cell Receptor Germline Genes and Alleles from Rearranged Repertoire Data.

Large-scale study of the properties of T-cell receptor (TCR) and B-cell receptor (BCR) repertoires through next-generation sequencing is providing excellent insights into the understanding of adaptive immune responses. Variable(Diversity)Joining [V(D)J] germline genes and alleles must be characterized in detail to facilitate repertoire analyses. However, most species do not have well-characterized TCR/BCR germline genes because of their high homology.

Molecular and genetic inflammation networks in major human diseases.

It has been well-recognized that inflammation alongside tissue repair and damage maintaining tissue homeostasis determines the initiation and progression of complex diseases. Albeit with the accomplishment of having captured the most critical inflammation-involved molecules, genetic susceptibilities, epigenetic factors, and environmental factors, our schemata on the role of inflammation in complex diseases remain largely patchy, in part due to the success of reductionism in terms of research methodology per se. Omics data alongside the advances in data integration technologies have enabled reconstruction of molecular and genetic inflammation networks which shed light on the underlying pathophysiology of complex diseases or clinical conditions.

Pre-vaccination inflammation and B-cell signalling predict age-related hyporesponse to hepatitis B vaccination.

Aging is associated with hyporesponse to vaccination, whose mechanisms remain unclear. In this study hepatitis B virus (HBV)-naive older adults received three vaccines, including one against HBV. Here we show, using transcriptional and cytometric profiling of whole blood collected before vaccination, that heightened expression of genes that augment B-cell responses and higher memory B-cell frequencies correlate with stronger responses to HBV vaccine.

An effective analytic method for detecting tissue-specific genes in RNA-seq experiments.

Aim: To develop an analytic method for identifying tissue-specific (TS) genes from RNA-seq data.

Materials & Methods: Based on a negative binomial distribution, we develop a statistical method containing consecutive procedures incorporating data variability from replicates in each tissue.

Results: Simulations show that our approach can effectively identify at least 94% of the truly TS genes if the sample size is 3 and at least 84% of the TS genes detected by our method are truly TS genes.

Transcriptomic profiling of peripheral blood CD4⁺ T-cells in asthmatics with and without depression.

Background: Cumulative studies have shown that asthma is associated with depression but the underlying mechanisms are poorly understood. This study aimed to determine whether asthma with depression is characterized by unique pathophysiological pathways by analyzing the global gene expression patterns of CD4(+) T-cells from asthmatics with or without depression.

Materials And Methods: Four groups of subjects (non-depressive asthmatics, depressive asthmatics, depression patients, and healthy controls) consisting of 6 participants in each group were studied.

Genes related to emphysema are enriched for ubiquitination pathways.

Background: Increased small airway resistance and decreased lung elasticity contribute to the airflow limitation in chronic obstructive pulmonary disease (COPD). The lesion that corresponds to loss of lung elasticity is emphysema; the small airway obstruction is due to inflammatory narrowing and obliteration. Despite their convergence in altered physiology, different mechanisms contribute to these processes.

Genomic and systems approaches to translational biomarker discovery in immunological diseases.

The high failure rate of new therapeutic mechanisms tested in clinical development has spurred an upsurge in research dedicated to discovering biomarker readouts that can improve decision-making. Increasingly, systems biology and genomic technologies, such as transcriptional profiling, are being leveraged to aid in the discovery of biomarker readouts. For inflammatory and immunological diseases, such as rheumatoid arthritis (RA) and asthma, progress has been made in developing biomarkers to monitor disease activity, prediction of response to therapy, and pharmacodynamic (PD) measurements.

Strategic applications of gene expression: from drug discovery/development to bedside.

Gene expression is useful for identifying the molecular signature of a disease and for correlating a pharmacodynamic marker with the dose-dependent cellular responses to exposure of a drug. Gene expression offers utility to guide drug discovery by illustrating engagement of the desired cellular pathways/networks, as well as avoidance of acting on the toxicological pathways. Successful employment of gene-expression signatures in the later stages of drug development depends on their linkage to clinically meaningful phenotypic characteristics and requires a biologically meaningful mechanism combined with a stringent statistical rigor.

11β-HSD1 inhibition reduces atherosclerosis in mice by altering proinflammatory gene expression in the vasculature.

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is implicated in the etiology of metabolic syndrome. We previously showed that pharmacological inhibition of 11β-HSD1 ameliorated multiple facets of metabolic syndrome and attenuated atherosclerosis in ApoE-/- mice. However, the molecular mechanism underlying the atheroprotective effect was not clear.

Scientific investigations into febrile reactions observed in the paediatric population following vaccination with a 2010 Southern Hemisphere Trivalent Influenza Vaccine.

During the 2010 Southern Hemisphere (SH) influenza season, there was an unexpected increase in the number of febrile reactions reported in the paediatric population in Australia shortly after vaccination with the CSL 2010 trivalent influenza vaccine (TIV) compared to previous seasons. A series of scientific investigations were initiated to identify the root cause of these adverse events, including in vitro cytokine/chemokine assays following stimulation of adult and paediatric whole blood, as well as mammalian cell lines and primary cells, profiling of molecular signatures using microarrays, and in vivo studies in rabbits, ferrets, new born rats and rhesus non-human primates (NHPs). Various TIVs (approved commercial vaccines as well as re-engineered TIVs) and their individual monovalent pool harvest (MPH) components were examined in these assays and in animal models.

Systems biology approach for new target and biomarker identification.

The pharmaceutical industry is spending increasingly large amounts of money on the discovery and development of novel medicines, but this investment is not adequately paying off in an increased rate of newly approved drugs by the FDA. The post-genomic era has provided a wealth of novel approaches for generating large, high-dimensional genetic and transcriptomic data sets from large cohorts of preclinical species as well as normal and diseased individuals. This systems biology approach to understanding disease-related biology is revolutionizing our understanding of the cellular pathways and gene networks underlying the onset of disease, and the mechanisms of pharmacological treatments that ameliorate disease phenotypes.