Neoantigen-specific cytotoxic Tr1 CD4 T cells suppress cancer immunotherapy.

CD4 T cells can either enhance or inhibit tumour immunity. Although regulatory T cells have long been known to impede antitumour responses, other CD4 T cells have recently been implicated in inhibiting this response. Yet, the nature and function of the latter remain unclear.

Improvement of Tumor Neoantigen Detection by High-Field Asymmetric Waveform Ion Mobility Mass Spectrometry.

Cancer neoantigens have been shown to elicit cancer-specific T-cell responses and have garnered much attention for their roles in both spontaneous and therapeutically induced antitumor responses. Mass spectrometry (MS) profiling of tumor immunopeptidomes has been used, in part, to identify MHC-bound mutant neoantigen ligands. However, under standard conditions, MS-based detection of such rare but clinically relevant neoantigens is relatively insensitive, requiring 300 million cells or more.

VISTA checkpoint inhibition by pH-selective antibody SNS-101 with optimized safety and pharmacokinetic profiles enhances PD-1 response.

VISTA, an inhibitory myeloid-T-cell checkpoint, holds promise as a target for cancer immunotherapy. However, its effective targeting has been impeded by issues such as rapid clearance and cytokine release syndrome observed with previous VISTA antibodies. Here we demonstrate that SNS-101, a newly developed pH-selective VISTA antibody, addresses these challenges.

Unexpected suppression of tumorigenesis by c-MYC via TFAP4-dependent restriction of stemness in B lymphocytes.

The proliferative burst of B lymphocytes is essential for antigen receptor repertoire diversification during the development and selective expansion of antigen-specific clones during immune responses. High proliferative activity inevitably promotes oncogenesis, the risk of which is further elevated in B lymphocytes by endogenous gene rearrangement and somatic mutations. However, B-cell-derived cancers are rare, perhaps owing to putative intrinsic tumor-suppressive mechanisms.

Characteristics of residence time distribution in a continuous high shear mixer granulation using scraper rotation.

Characteristics of residence time distribution (RTD) in a continuous high shear mixer granulation were investigated to promote the development of a continuous manufacturing process in the pharmaceutical industry. A continuous granulator with an impeller and a scraper was utilized. The tracer behavior in the continuous wet granulation was verified in impulse-response experiments with acetaminophen.

Mechanical characteristics of orally disintegrating films: Comparison of folding endurance and tensile properties.

The tensile test is the most widely used method for testing the mechanical characteristics of orally disintegrating films (ODFs). The other available test is the folding endurance (FE) test, which is more suitable for clarifying the actual strength during the manufacturing and dosing. However, the FE test is performed manually, and the FE number it generates has not been adequately analyzed as an index.

The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies.

Immune checkpoint blockade has provided a paradigm shift in cancer therapy, but the success of this approach is very variable; therefore, biomarkers predictive of clinical efficacy are urgently required. Here, we show that the frequency of PD-1CD8 T cells relative to that of PD-1 regulatory T (T) cells in the tumor microenvironment can predict the clinical efficacy of programmed cell death protein 1 (PD-1) blockade therapies and is superior to other predictors, including PD ligand 1 (PD-L1) expression or tumor mutational burden. PD-1 expression by CD8 T cells and T cells negatively impacts effector and immunosuppressive functions, respectively.

TREM2 Modulation Remodels the Tumor Myeloid Landscape Enhancing Anti-PD-1 Immunotherapy.

Checkpoint immunotherapy unleashes T cell control of tumors, but is undermined by immunosuppressive myeloid cells. TREM2 is a myeloid receptor that transmits intracellular signals that sustain microglial responses during Alzheimer's disease. TREM2 is also expressed by tumor-infiltrating macrophages.

Control of residence time of pharmaceutical powder in a continuous mixer with impeller and scraper.

The control of residence time in a powder mixing process was investigated toward the development of a continuous pharmaceutical manufacturing system. A powder mixer equipped with an impeller and a scraper, which was designed for a continuous granulation machine, was used. The mixing homogeneity and dynamic behavior of the powder in the mixer were investigated by using a tracer, acetaminophen, in impulse- and step-response experiments.

Blockade of EGFR improves responsiveness to PD-1 blockade in -mutated non-small cell lung cancer.

The clinical efficacy of anti-PD-1 (programmed cell death-1) monoclonal antibody (mAb) against cancers with oncogenic driver gene mutations, which often harbor a low tumor mutation burden, is variable, suggesting different contributions of each driver mutation to immune responses. Here, we investigated the immunological phenotypes in the tumor microenvironment (TME) of epidermal growth factor receptor ()-mutated lung adenocarcinomas, for which anti-PD-1 mAb is largely ineffective. Whereas -mutated lung adenocarcinomas had a noninflamed TME, CD4 effector regulatory T cells, which are generally present in the inflamed TME, showed high infiltration.

Tyrosine kinase inhibitor imatinib augments tumor immunity by depleting effector regulatory T cells.

This report addresses whether small molecules can deplete FoxP3-expressing regulatory T (T reg) cells, thereby augmenting antitumor immunity. Imatinib, a tyrosine kinase inhibitor of oncogenic BCR-ABL protein expressed by chronic myelogenous leukemia (CML) cells, possesses off-targets including LCK expressed in T cells. We showed that imatinib-treated CML patients in complete molecular remission (CMR) exhibited selective depletion of effector T reg (eT reg) cells and significant increase in effector/memory CD8+ T cells while non-CMR patients did not.

Design of a new disintegration test system for the evaluation of orally disintegrating films.

In the design of the orally disintegrating films (ODFs), it is important to determine the disintegration time (DT) precisely and properly. These films' DTs are usually assessed by a disintegration test defined in the pharmacopoeias, but under the conditions of such tests, a much larger volume of water is used and a stronger up-down movement is applied compared to the conditions of the human oral cavity. Here we developed and tested our new disintegration test system for ODFs.

Characterization of mannitol granules and powder: A comparative study using two flowability testers.

In the manufacture of tablets, especially in direct tableting processes, the flowability of excipient powders and formulated powders is one of the most important characteristics. In the past two decades, orally disintegrating tablets (ODTs) have been prepared as popular solid dosage forms for elderly patients. Many types of mannitol granules have been developed and marketed as new pharmaceutical excipients for ODTs, owing to the solubility and palatability of mannitol.

Formulation design of granules prepared by wet granulation method using a multi-functional single-punch tablet press to avoid tableting failures.

We previously determined "Tableting properties" by using a multi-functional single-punch tablet press (GTP-1). We plotted "Compactability" on the x-axis against "Manufacturability" on the y-axis to allow visual evaluation of "Tableting properties". Here, we examined whether this evaluation method can be used in the formulation design of tablets prepared by wet granulation.

Clinical response to PD-1 blockade correlates with a sub-fraction of peripheral central memory CD4+ T cells in patients with malignant melanoma.

Cancer immunotherapy that blocks immune checkpoint molecules, such as PD-1/PD-L1, unleashes dysfunctional antitumor T-cell responses and has durable clinical benefits in various types of cancers. Yet its clinical efficacy is limited to a small proportion of patients, highlighting the need for identifying biomarkers that can predict the clinical response by exploring antitumor responses crucial for tumor regression. Here, we explored comprehensive immune-cell responses associated with clinical benefits using PBMCs from patients with malignant melanoma treated with anti-PD-1 monoclonal antibody.

Prediction of effects of punch shapes on tableting failure by using a multi-functional single-punch tablet press.

We previously determined "Tableting properties" by using a multi-functional single-punch tablet press (GTP-1). We proposed plotting "Compactability" on the x-axis against "Manufacturability" on the y-axis to allow visual evaluation of "Tableting properties". Various types of tableting failure occur in commercial drug production and are influenced by the amount of lubricant used and the shape of the punch.

An advanced technique using an electronic taste-sensing system to evaluate the bitterness of orally disintegrating films and the evaluation of model films.

Taste detection systems using electronic sensors are needed in the field of pharmaceutical design. The aim of this study was to propose an advanced technique using a taste-sensing system to evaluate the bitterness of an orally disintegrating film (ODF) samples. In this system, a solid film sample is kept in the test medium with stirring, and the sensor output is recorded.

Characterization of tableting properties measured with a multi-functional compaction instrument for several pharmaceutical excipients and actual tablet formulations.

Before designing tablet formulations, it is important to understand the "Tableting Properties" of excipients and API (active pharmaceutical ingredient) powders. Those properties refer to "Compressibility", "Compactability" and "Manufacturability", which are difficult to evaluate quantitatively. In this study, we aimed to evaluate the "Tableting Properties" by using a benchtop single-punch tablet press, developed recently to measure these parameters using a single device.

Roles of regulatory T cells in cancer immunity.

CD4(+) regulatory T cells (Tregs) expressing the transcription factor FoxP3 are highly immune suppressive and play central roles in the maintenance of self-tolerance and immune homeostasis, yet in malignant tumors they promote tumor progression by suppressing effective antitumor immunity. Indeed, higher infiltration by Tregs is observed in tumor tissues, and their depletion augments antitumor immune responses in animal models. Additionally, increased numbers of Tregs and, in particular, decreased ratios of CD8(+) T cells to Tregs among tumor-infiltrating lymphocytes are correlated with poor prognosis in various types of human cancers.

Dapsone hypersensitivity syndrome-related lung injury without eosinophilia in the bronchoalveolar lavage fluid.

A 73-year-old man was admitted in respiratory failure that had subacutely progressed after five weeks of dapsone treatment for a skin rash. He also presented with fever, systemic erythroderma and liver dysfunction. Chest computed tomography showed diffuse reticular shadows with ground-glass opacity and bilateral mediastinal lymphadenopathy.

Favorable response to trastuzumab plus irinotecan combination therapy in two patients with HER2-positive relapsed small-cell lung cancer.

Small-cell lung cancer (SCLC) easily recurs with multidrug resistance phenotype. However, standard therapeutic strategies for relapsed-SCLC remain unestablished. Human epidermal growth factor receptor 2 (HER2) expression correlates with poor prognosis in extensive disease-SCLC.

Development of microscopic polyangiitis-related pulmonary fibrosis in a patient with autoimmune pulmonary alveolar proteinosis.

Background: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare lung disease caused by the autoantibody against granulocyte-macrophage colony stimulating factor (GM-CSF). The clinical course of aPAP is variable; in severe cases, patients develop lethal respiratory failure due to pulmonary fibrosis. However, the pathogenesis of pulmonary fibrosis in aPAP has never been delineated.

Ambulatory pulse oximetry monitoring in Japanese COPD outpatients not receiving oxygen therapy.

Background: It remains unknown whether desaturation profiles during daily living are associated with prognosis in patients with chronic obstructive pulmonary disease (COPD). Point measurements of resting oxygen saturation by pulse oximetry (SpO2) and partial pressure of arterial oxygen (PaO2) are not sufficient for assessment of desaturation during activities of daily living. A small number of studies continuously monitored oxygen saturation throughout the day during activities of daily living in stable COPD patients.

Phase II trial of pemetrexed continuation--maintenance after carboplatin-based induction in untreated non-squamous non-small cell lung cancer.

Aim: We conducted a phase II study to evaluate the efficacy and safety of pemetrexed continuation-maintenance after carboplatin-based induction for advanced non-squamous non-small cell lung cancer (NSCLC).

Patients And Methods: Thirty-four patients with advanced or recurrent non-squamous NSCLC received carboplatin (area under the concentration-time curve 6 mg/ml×min) plus pemetrexed (500 mg/m(2)) on day 1 tri-weekly. After four cycles of induction, patients without disease progression received pemetrexed maintenance until disease progression or unacceptable toxicity.