A human CD137×PD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockade.

Immune checkpoint inhibitors demonstrate clinical activity in many tumor types, however, only a fraction of patients benefit. Combining CD137 agonists with these inhibitors increases anti-tumor activity preclinically, but attempts to translate these observations to the clinic have been hampered by systemic toxicity. Here we describe a human CD137xPD-L1 bispecific antibody, MCLA-145, identified through functional screening of agonist- and immune checkpoint inhibitor arm combinations. MCLA-145 potently activates T cells at sub-nanomolar concentrations, even under suppressive conditions, and enhances T cell priming, differentiation and memory recall responses. In vivo, MCLA-145 anti-tumor activity is superior to immune checkpoint inhibitor comparators and linked to recruitment and intra-tumor expansion of CD8 + T cells. No graft-versus-host-disease is observed in contrast to other antibodies inhibiting the PD-1 and PD-L1 pathway. Non-human primates treated with 100 mg/kg/week of MCLA-145 show no adverse effects. The conditional activation of CD137 signaling by MCLA-145, triggered by neighboring cells expressing >5000 copies of PD-L1, may provide both safety and potency advantages.

Measuring Psychological Inflexibility in Children and Adolescents: Evaluating the Avoidance and Fusion Questionnaire for Youth.

The Avoidance and Fusion Questionnaire for Youth (AFQ-Y8) was developed to measure psychological inflexibility. Although the questionnaire is a well-known tool in clinical practice, its psychometric properties have not been widely investigated in the target population of children and adolescents. The purpose of this study was to investigate the factor structure and validity of the AFQ-Y8 (N = 1,572, mean age 15.39 years, girls 51%) on a Hungarian sample. We also tested the invariance of the measurement model across two age groups (11-14 and 15-20 years old). Results confirmed the single-factor structure of the AFQ-Y8. Psychological inflexibility was also found to be positively related to emotional instability, externalizing, and internalizing problems. Furthermore, psychological inflexibility explained the variance of life satisfaction when personality dimensions, emotional, and behavioral problems were accounted for. Measurement invariance across age groups was partially supported. These results suggest that the AFQ-Y8 is a reliable and valid instrument for assessing psychological inflexibility in children and adolescents.

Profiling children's emotion regulation behaviours.

Callear, Harvey, and Bimler (2016, International Journal of Behavioral Development, 41, 456) organized children's emotion regulation behaviours into a coherent structure. However, further investigation is needed to identify core patterns of these emotion regulation behaviours. To identify clusters and prototypal constellations of emotion regulation behaviours, the 85 behavioural items comprising the Children's Emotion Regulation Inventory (ChERI) were ranked by 151 parents in order of applicability, using an ordinal sorting procedure (Method of Successive Sorts). Responses were aggregated in empirical scales, for classification of the cases using hierarchical and k-means clustering. The scales were based on nine key 'hotspots' of children's emotion regulation behaviours, interpreted as Outward Engagement, Inward or Somatic Focus, Disengagement, Disruptive, Impulsive/Labile, Social Connectedness/Compliance, Generating Closeness/Intimacy, Establishing Order and Generating Disorder. Five summary styles of children's emotion regulation emerged and are characterized on those scales. These hotspots and styles provide guidance to clinicians, parents, teachers, and other invested adults to assess and support children's emotional development. Statement of contribution What is already known on this subject? Measurements of children's emotion regulation predominantly focus on internal processes and/or isolated expressions of emotion regulation behaviours. Research detailing anger and anxiety emotion regulation styles exists (e.g., Carthy, Horesh, Apter, & Gross, 2010, Journal of Psychopathology and Behavioral Assessment, 32, 23; Zalewski, Lengua, Wilson, Trancik, & Bazinet, 2011, Journal of Experimental Child Psychology, 110, 141). Callear, Harvey, and Bimler (2016, International Journal of Behavioral Development, 41, 456) developed the Children's Emotion Regulation Inventory to identify children's observable emotion regulation strategies. What does this study add? Research does not investigate which clusters of children's emotion regulation behaviours are most commonly exhibited and nor does it investigate emotion regulation behavioural styles. Examines how children's emotion regulation behaviours co-occur. Identifies nine core clusters (groupings) of emotion regulation behaviours most commonly observed to be exhibited in children. Identifies five emotion regulation behavioural styles (common co-occurring patterns of emotion regulation behaviour clusters) in children.

Moderators of psycho-oncology therapy effectiveness: meta-analysis of therapy characteristics.

As part of a larger meta-analysis seeking moderators of the effectiveness of psycho-oncological interventions, this report focuses on intervention types and characteristics, including protocol components, means of delivery (mode, dose, and therapist variables), and mechanisms of effectiveness. The data set comprised 146 published and unpublished prospective controlled trials with outcomes of anxiety, depression, and distress. Analyses took into account two moderators from analysis of study design features. The authors conclude that each of the four main professional therapy types (education, relaxation, cognitive behavior therapy (CBT), and expressive-support) has effect and that it is more important to focus on participant variables, notably, elevated baseline distress. Therapy components delivered by nonprofessionals and interventions that affect the patient indirectly show potential. Recommendations for practice and research are made.

A meta-analysis of the effects of psychotherapy with adults sexually abused in childhood.

This paper presents the results of a meta-analysis of the treatment outcome studies of different types of psychotherapeutic approaches for adults sexually abused as children. There were 44 studies included comprising 59 treatment conditions, and most of the studies aimed to treat the psychological effects of childhood sexual abuse. Separate meta-analyses were conducted according to study design and outcome domain, in keeping with meta-analytic conventions. For most outcome domains, there was remarkable consistency in overall effect sizes across study design. Effect sizes were predominantly of moderate magnitude for post-traumatic stress disorder or trauma symptoms (g=0.72-0.77), internalizing symptoms (g=0.68-0.72), externalizing symptoms (g=0.41-0.53), self-esteem (g=0.56-0.58), and global functioning or symptoms (g=0.57-0.60). Studies measuring interpersonal functioning outcomes had inconsistent effect sizes across study design. Effects were largely maintained at follow-up, although relatively few studies provided follow-up data. A number of moderating variables were examined given the inherent heterogeneity of the studies. Moderator analysis revealed a variety of variables, particularly treatment characteristics, that were associated with better outcomes. However, different variables were identified for the diverse outcomes that were measured, emphasizing the importance of moderator analysis in looking beyond overall treatment effects to ascertain specific elements that confer additional benefit in therapy for the diverse psychological effects of child sexual abuse.

A meta-analysis of the effects of psychotherapy with sexually abused children and adolescents.

This paper presents a meta-analysis of the psychotherapy treatment outcome studies for sexually abused children and adolescents. There were 39 studies included, most of which aimed to treat the psychological effects of childhood sexual abuse. Separate meta-analyses were conducted according to study design and outcome domain, in keeping with meta-analytic conventions. However, given heterogeneity across studies and the need for sufficient n in each category for meaningful moderator analyses, the study designs were pooled into a repeated measures meta-analysis. There were large effect sizes for global outcomes (g=1.37) and PTSD/trauma outcomes (g=1.12). More moderate effect sizes were evident for internalizing symptoms (g=0.74), self-appraisal (g=0.63), externalizing symptoms (g=0.52), and sexualized behavior (g=0.49), while small effects were found for measures of coping/functioning (g=0.44), caregiver outcomes (g=0.43), and social skills/competence (g=0.38). Effects were maintained at follow-up more than six months after treatment for some outcome domains but not others. Studies represented diverse treatment approaches, and most treatments were effective in symptom reduction. Presence of probable moderators of treatment outcome varied across symptom domains, reflecting importance of targeting therapy to individual needs.

Updating a meta-analysis of intervention research with challenging behaviour: treatment validity and standards of practice.

BACKGROUND: This meta-analysis of interventions with challenging behaviour in children with disabilities updates a comprehensive meta-analysis that previously addressed reported standards of practice and effectiveness of different strategies. METHOD: Four effect-size algorithms were calculated for published intervention cases, and results analysed and compared to previous findings by behaviour target, intervention type, and other factors. RESULTS: The evidence largely supports intervention effectiveness, with some inconsistency reflecting the fact that the four metrics assess different aspects of change. Skills replacement, consequence combined with systems change, and antecedent interventions generated selective positive results, large enough to be clinically meaningful. CONCLUSIONS: Behavioural interventions effectively reduce challenging behaviour, particularly when preceded by a functional analysis. Teaching replacement skills was most effective, especially if used in combination with systems change and/or traditional antecedent and consequence manipulation. Positive changes as well as enduring limitations to both research design and standards of clinical practice in comparison to 18 years ago are discussed.