Phase 2b randomized trial of OX40 inhibitor telazorlimab for moderate-to-severe atopic dermatitis.

Background: Telazorlimab is a humanized anti-OX40 monoclonal antibody being studied for treatment of T-cell-mediated diseases. Objective: This randomized, placebo-controlled, phase 2b dose-range finding study investigated efficacy, safety, pharmacokinetics, and immunogenicity of telazorlimab in subjects with atopic dermatitis. Methods: In this 2-part study (NCT03568162), adults (≥18 years) with moderate-to-severe disease were randomized to various regimens of subcutaneous telazorlimab or placebo for 16 weeks' blinded treatment, followed by 38 weeks' open-label treatment and 12 weeks' drug-free follow-up. Telazorlimab treatment groups (following a loading dose) in part 1 were 300 mg every 2 weeks; 300 mg every 4 weeks; or 75 mg every 4 weeks. Part 2 evaluated telazorlimab 600 mg every 2 weeks. The primary end point was percentage change from baseline in Eczema Area and Severity Index (EASI) at week 16. Safety assessments included incidence of treatment-emergent adverse events. Results: The study randomized 313 subjects in part 1 and 149 in part 2. At 16 weeks, the least squares mean percentage change from baseline in EASI was significantly greater in subjects receiving telazorlimab 300 mg every 2 weeks (part 1) and 600 mg every 2 weeks (part 2) versus placebo (-54.4% vs -34.2% for part 1 and -59.0% vs -41.8% for part 2, P = .008 for both). Telazorlimab was well tolerated, with similar distribution of adverse events between telazorlimab- and placebo-treated subjects in both part 1 and part 2. Conclusion: Telazorlimab, administered subcutaneously at 300 mg every 2 weeks or 600 mg every 2 weeks following a loading dose, was well tolerated and induced significant and progressive clinical improvement in adults with moderate-to-severe atopic dermatitis.

Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation.

The mechanisms regulating exhaustion of tumor-infiltrating lymphocytes (TIL) and responsiveness to PD-1 blockade remain partly unknown. In human ovarian cancer, we show that tumor-specific CD8+ TIL accumulate in tumor islets, where they engage antigen and upregulate PD-1, which restrains their functions. Intraepithelial PD-1+CD8+ TIL can be, however, polyfunctional. PD-1+ TIL indeed exhibit a continuum of exhaustion states, with variable levels of CD28 costimulation, which is provided by antigen-presenting cells (APC) in intraepithelial tumor myeloid niches. CD28 costimulation is associated with improved effector fitness of exhausted CD8+ TIL and is required for their activation upon PD-1 blockade, which also requires tumor myeloid APC. Exhausted TIL lacking proper CD28 costimulation in situ fail to respond to PD-1 blockade, and their response may be rescued by local CTLA-4 blockade and tumor APC stimulation via CD40L.

Anopheles gambiae females readily learn to associate complex visual cues with the quality of sugar sources.

The ability to learn plays a key role in tuning and adapting the behaviours of animals for their unpredictable biotopes. This also applies to insect vectors of disease. Anautogenous mosquitoes need to find both sugar and blood for survival and reproduction. Learning processes are expected to contribute to a mosquito's ability to undertake repeated feeding behaviours more efficiently with time, serving to decrease energy demands and avoid hazards. Here we report how visual learning by the Afrotropical malaria mosquito Anopheles gambiae allows it to readily associate visual cues with the quality of a sugar source. Circular black and white patterns were used as visual cues. An. gambiae females were conditioned in cages with a chequered pattern paired with sucrose and a concentric pattern paired with non-palatable sucrose-NaCl and with reverse combinations. Hours later, significantly higher numbers of feeding attempts were counted on sucrose paired with the chequered pattern following conditioning with the same combination. This was also the case on the concentric pattern paired with sucrose following conditioning with this combination. However, the effect was weaker than with sucrose paired with the chequered pattern. These findings indicate a differential capacity of visual stimuli to induce learning, explained in our experiments by a significantly higher mosquito appetence on sucrose paired with a chequered pattern that mimics floral shape. Training that induced a higher propensity for feeding attempts was found to allow the females to display a fast learning curve (<4min) on the less suitable concentric pattern paired with sucrose, several hours after conditioning on the chequered pattern paired with sucrose. This has important implications for mosquito behavioural ecology, suggesting that An. gambiae shows plasticity in its learning capacities that would allow it to readily turn to alternative sources for a sugar meal once initiated in the process by an appropriate stimulus combination.