Vaccine-induced memory CD8+ T cells provide clinical benefit in HER2 expressing breast cancer: a mouse to human translational study
PURPOSE/OBJECTIVE:Immune-based therapy for metastatic breast cancer has had limited success, particularly in molecular subtypes with low somatic mutations rates. Strategies to augment T cell infiltration of tumors include vaccines targeting established oncogenic drivers like the genomic amplification of HER2. We constructed a vaccine based on a novel alphaviral vector encoding a portion of HER2 (VRP-HER2). EXPERIMENTAL DESIGN/METHODS:In preclinical studies, mice were immunized with VRP-HER2 before or after implantation of hHER2+ tumor cells and HER2-specific immune responses and anti-tumor function were evaluated. We tested VRP-HER2 in a Phase I clinical trial where subjects with advanced HER2-overexpressing malignancies in cohort 1 received VRP-HER2 every 2 weeks for a total of three doses. In cohort 2, subjects received the same schedule concurrently with a HER2-targeted therapy. RESULTS:Vaccination in preclinical models with VRP-HER2 induced HER2-specific T cells and antibodies while inhibiting tumor growth. VRP-HER2 was well tolerated in patients and vaccination induced HER2-specific T cells and antibodies. Although a phase I study, there was one partial response and two patients with continued stable disease. Median OS was 50.2 months in cohort 1 (n=4) and 32.7 months in cohort 2 (n=18). Perforin expression by memory CD8 T cells post-vaccination significantly correlated with improved PFS. CONCLUSIONS:VRP-HER2 increased HER2-specific memory CD8 T cells and had anti-tumor effects in preclinical and clinical studies. The expansion of HER2-specific memory CD8 T cells in vaccinated patients was significantly correlated with increased PFS. Subsequent studies will seek to enhance T cell activity by combining with anti-PD-1.
Teacher perception of child fatigue and behavioral health outcomes among black first graders in high-poverty schools [Meeting Abstract]
Introduction: Child fatigue has been associated with behavioral outcomes, including aggression, hyperactivity, and conduct problems, which may affect academic performance. We explored whether fatigue was associated with external behavioral health outcomes in a predominantly Black (Afro-Caribbean and African-American) student population (90%). Ratings of parent and teacher agreement of child fatigue was evaluated. This analysis was part of a larger research program, which included a cluster randomized controlled trial in ten public elementary schools in historically disinvested neighborhoods.
Method(s): A total of 804 first-graders (7+/- 0.6 years old) participated in the study focused on child self-regulation, mental health achievement, parenting and parent involvement. Externalizing behaviors (i.e., conduct problems, aggression, and hyperactivity) were reported by teachers using the Behavior System for Children (BASC-2). A composite score of teacher-perceived child fatigue was created based on ratings of child fatigue, morning alertness, and falling asleep in class. Parent perception of child fatigue was assessed using the Children's Sleep Habits Questionnaire. Regression analysis was conducted to determine the association between teacher's reports of child fatigue and externalizing behavior problems. Cohen's kappa coefficient assessed parent and teacher agreement of child fatigue based on categorical classification of presence of child fatigue.
Result(s): Children who were perceived as fatigued (i.e., tiredness and falling asleep in class) by their teacher were more likely to have a high BASC externalizing composite score (T=60 cut off) (beta = -0.24, p<.001). Cohen's kappa of 0.004 (p<0.05) showed a slight discordance in perception of child fatigue comparing reports from teachers and parents, although results were not significant.
Conclusion(s): Teacher perception of child fatigue was significantly associated with teacher BASC T-score of child externalizing behavior outcomes. Future studies should explore longitudinal relationships between fatigue and mental health