Impact of isotype on the mechanism of action of agonist anti-OX40 antibodies in cancer: implications for therapeutic combinations.

Background: OX40 has been widely studied as a target for immunotherapy with agonist antibodies taken forward into clinical trials for cancer where they are yet to show substantial efficacy. Here, we investigated potential mechanisms of action of anti-mouse (m) OX40 and anti-human (h) OX40 antibodies, including a clinically relevant monoclonal antibody (mAb) (GSK3174998) and evaluated how isotype can alter those mechanisms with the aim to develop improved antibodies for use in rational combination treatments for cancer.

Methods: Anti-mOX40 and anti-hOX40 mAbs were evaluated in a number of in vivo models, including an OT-I adoptive transfer immunization model in hOX40 knock-in (KI) mice and syngeneic tumor models.

Precision Oncology Comes of Age: Designing Best-in-Class Small Molecules by Integrating Two Decades of Advances in Chemistry, Target Biology, and Data Science.

Unlabelled: Small-molecule drugs have enabled the practice of precision oncology for genetically defined patient populations since the first approval of imatinib in 2001. Scientific and technology advances over this 20-year period have driven the evolution of cancer biology, medicinal chemistry, and data science. Collectively, these advances provide tools to more consistently design best-in-class small-molecule drugs against known, previously undruggable, and novel cancer targets.

Activating Inducible T-cell Costimulator Yields Antitumor Activity Alone and in Combination with Anti-PD-1 Checkpoint Blockade.

Unlabelled: In recent years, there has been considerable interest in mAb-based induction of costimulatory receptor signaling as an approach to combat cancer. However, promising nonclinical data have yet to translate to a meaningful clinical benefit. Inducible T-cell costimulator (ICOS) is a costimulatory receptor important for immune responses.

Pain Processing in Cognitive Impairment and Its Association with Executive Function and Memory: Which Neurocognitive Factor Takes the Lead?

It is well established that individuals with cognitive impairment present with disturbed forms of pain processing of still unknown origin. As a neurocognitive factor, executive functions have become favored candidates for explanation. For further insights, we aimed at comparing executive functions and memory in their association with parameters indicating onset and escalation of pain perception.

Belantamab Mafodotin (GSK2857916) Drives Immunogenic Cell Death and Immune-mediated Antitumor Responses .

B-cell maturation antigen (BCMA) is an attractive therapeutic target highly expressed on differentiated plasma cells in multiple myeloma and other B-cell malignancies. GSK2857916 (belantamab mafodotin, BLENREP) is a BCMA-targeting antibody-drug conjugate approved for the treatment of relapsed/refractory multiple myeloma. We report that GSK2857916 induces immunogenic cell death in BCMA-expressing cancer cells and promotes dendritic cell activation and GSK2857916 treatment enhances intratumor immune cell infiltration and activation, delays tumor growth, and promotes durable complete regressions in immune-competent mice bearing EL4 lymphoma tumors expressing human BCMA (EL4-hBCMA).

Industrializing engineered autologous T cells as medicines for solid tumours.

Cell therapy is one of the fastest growing areas in the pharmaceutical industry, with considerable therapeutic potential. However, substantial challenges regarding the utility of these therapies will need to be addressed before they can become mainstream medicines with applicability similar to that of small molecules or monoclonal antibodies. Engineered T cells have achieved success in the treatment of blood cancers, with four chimeric antigen receptor (CAR)-T cell therapies now approved for the treatment of B cell malignancies based on their unprecedented efficacy in clinical trials.

Single-agent belantamab mafodotin for relapsed/refractory multiple myeloma: analysis of the lyophilised presentation cohort from the pivotal DREAMM-2 study.

DREAMM-2 (NCT03525678) is an ongoing global, open-label, phase 2 study of single-agent belantamab mafodotin (belamaf; GSK2857916), a B-cell maturation antigen-targeting antibody-drug conjugate, in a frozen-liquid presentation in patients with relapsed/refractory multiple myeloma (RRMM). Alongside the main study, following identical inclusion/exclusion criteria, a separate patient cohort was enrolled to receive belamaf in a lyophilised presentation (3.4 mg/kg, every 3 weeks) until disease progression/unacceptable toxicity.

Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study.

Background: Belantamab mafodotin (GSK2857916), an immunoconjugate targeting B-cell maturation antigen, showed single-agent activity in the phase 1 DREAMM-1 study in heavily pre-treated patients with relapsed or refractory multiple myeloma. We further investigated the safety and activity of belantamab mafodotin in the DREAMM-2 study.

Methods: DREAMM-2 is an open-label, two-arm, phase 2 study done at 58 multiple myeloma specialty centres in eight countries.

Co-creation of patient engagement quality guidance for medicines development: an international multistakeholder initiative.

Introduction: Meaningful patient engagement (PE) can enhance medicines' development. However, the current PE landscape is fragmentary and lacking comprehensive guidance.

Methods: We systematically searched for PE initiatives (SYNaPsE database/publications).

Anti-OX40 Antibody Directly Enhances The Function of Tumor-Reactive CD8 T Cells and Synergizes with PI3Kβ Inhibition in PTEN Loss Melanoma.

Purpose: OX40 agonist-based combinations are emerging as a novel avenue to improve the effectiveness of cancer immunotherapy. To better guide its clinical development, we characterized the role of the OX40 pathway in tumor-reactive immune cells. We also evaluated combining OX40 agonists with targeted therapy to combat resistance to cancer immunotherapy.

MeV photoelectron spectrometer for ultraintense laser interactions with atoms and molecules.

Traditional laser-matter spectroscopy techniques fail to accurately analyze photoelectrons and ions from ultrahigh intensity studies with terawatt and petawatt laser systems. We present a magnetic deflection, photoelectron spectrometer for ultrahigh intensity laser interactions with atoms and molecules in the single atom/molecule limit. Spectrometer fabrication and calibration, and noise background are presented as well as example photoelectron spectra for argon and chloromethane over an energy range from 20 keV to 2 MeV.

Author Correction: Design of amidobenzimidazole STING receptor agonists with systemic activity.

Change history: In this Letter, author Ana Puhl was inadvertently omitted; this error has been corrected online.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Targeting B-cell maturation antigen with GSK2857916 antibody-drug conjugate in relapsed or refractory multiple myeloma (BMA117159): a dose escalation and expansion phase 1 trial.

Background: B-cell maturation antigen (BCMA) is a cell-surface receptor of the tumour necrosis superfamily required for plasma cell survival. BMCA is universally detected on patient-derived myeloma cells and has emerged as a selective antigen to be targeted by novel treatments in multiple myeloma. We assessed the safety, tolerability, and preliminary clinical activity of GSK2857916, a novel anti-BCMA antibody conjugated to microtubule-disrupting agent monomethyl auristatin F, in patients with relapsed and refractory multiple myeloma.

Design of amidobenzimidazole STING receptor agonists with systemic activity.

Stimulator of interferon genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen-derived and self DNA. The development of compounds that modulate STING has recently been the focus of intense research for the treatment of cancer and infectious diseases and as vaccine adjuvants. To our knowledge, current efforts are focused on the development of modified cyclic dinucleotides that mimic the endogenous STING ligand cGAMP; these have progressed into clinical trials in patients with solid accessible tumours amenable to intratumoral delivery.

Tumor-immune profiling of murine syngeneic tumor models as a framework to guide mechanistic studies and predict therapy response in distinct tumor microenvironments.

Mouse syngeneic tumor models are widely used tools to demonstrate activity of novel anti-cancer immunotherapies. Despite their widespread use, a comprehensive view of their tumor-immune compositions and their relevance to human tumors has only begun to emerge. We propose each model possesses a unique tumor-immune infiltrate profile that can be probed with immunotherapies to inform on anti-tumor mechanisms and treatment strategies in human tumors with similar profiles.

The Partnership for Accelerating Cancer Therapies.

As a part of the Cancer Moonshot, the National Cancer Institute, part of the National Institutes of Health, the Foundation for National Institutes of Health, the US Food and Drug Administration, and 12 pharmaceutical companies have formed a 5-year, $220 million precompetitive public-private research collaboration called the Partnership for Accelerating Cancer Therapies. A systematic cross-sector effort to identify and develop robust, standardized biomarkers and related clinical data, Partnership for Accelerating Cancer Therapies will support the selection and testing of promising immunotherapies for the treatment of cancer, with the goal of bringing effective therapy to more patients.

Leveraging Big Data Towards Functionally-Based, Catchment Scale Restoration Prioritization.

The persistence of freshwater degradation has necessitated the growth of an expansive stream and wetland restoration industry, yet restoration prioritization at broad spatial extents is still limited and ad-hoc restoration prevails. The River Basin Restoration Prioritization tool has been developed to incorporate vetted, distributed data models into a catchment scale restoration prioritization framework. Catchment baseline condition and potential improvement with restoration activity is calculated for all National Hydrography Dataset stream reaches and catchments in North Carolina and compared to other catchments within the river subbasin to assess where restoration efforts may best be focused.

The promise and challenges of immune agonist antibody development in cancer.

Immune cell functions are regulated by co-inhibitory and co-stimulatory receptors. The first two generations of cancer immunotherapy agents consist primarily of antagonist antibodies that block negative immune checkpoints, such as programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte protein 4 (CTLA4). Looking ahead, there is substantial promise in targeting co-stimulatory receptors with agonist antibodies, and a growing number of these agents are making their way through various stages of development.

What do stakeholders expect from patient engagement: Are these expectations being met?

Background: Meaningful patient engagement (PE) in medicines development and during the life cycle of a product requires all stakeholders have a clear understanding of respective expectations.

Objective: A qualitative survey was undertaken to understand stakeholder expectations.

Design: The survey explored 4 themes from the perspective of each stakeholder group: meaning, views, expectations and priorities for PE.

Immune-Modified Response Evaluation Criteria In Solid Tumors (imRECIST): Refining Guidelines to Assess the Clinical Benefit of Cancer Immunotherapy.

Purpose Treating solid tumors with cancer immunotherapy (CIT) can result in unconventional responses and overall survival (OS) benefits that are not adequately captured by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. We describe immune-modified RECIST (imRECIST) criteria, designed to better capture CIT responses.

Culture and Process Change as a Priority for Patient Engagement in Medicines Development.

Patient Focused Medicines Development (PFMD) is a not-for-profit independent multinational coalition of patients, patient stakeholders, and the pharmaceutical industry with interests across diverse disease areas and conditions. PFMD aims to facilitate an integrated approach to medicines development with all stakeholders involved early in the development process. A key strength of the coalition that differentiates it from other groups that involve patients or patient groups is that PFMD has patient organizations as founding members, ensuring that the patient perspective is the starting point when identifying priorities and developing solutions to meet patients' needs.

The European Regulatory Environment of RNA-Based Vaccines.

A variety of different mRNA-based drugs are currently in development. This became possible, since major breakthroughs in RNA research during the last decades allowed impressive improvements of translation, stability and delivery of mRNA. This article focuses on antigen-encoding RNA-based vaccines that are either directed against tumors or pathogens.