GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas.

Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system1. We have previously shown that the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells2, providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1 (1 × 106 GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly3. Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care. On-target, off-tumour toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes. These early results underscore the promise of this therapeutic approach for patients with H3K27M-mutated DIPG or spinal cord DMG.

Turn off the TV and dance! Participation in culturally tailored health interventions: implications for obesity prevention among Mexican American girls.

Our evaluation study identifies facilitators and barriers to participation among families participating in the treatment arm of Stanford ECHALE. This culturally tailored obesity prevention trial consisted of a combined intervention with two main treatment components: 1) a folkloric dance program; and 2) a screen time reduction curriculum designed for 7-11 year old Latinas and their families. We conducted 83 interviews (40 parents and 43 girls) in participant homes after 6 months of enrollment in the ECHALE trial. The Spradley ethnographic method and NVivo 8.0 were used to code and analyze narrative data. Three domains emerged for understanding participation: 1) family cohesiveness; 2) perceived gains; and 3) culturally relevant program structure. Two domains emerged for non-participation: program requirements and perceived discomforts. Non-parametric, Spearman's rank correlation coefficients were calculated to assess the relationships with participant attendance data. Sustained participation was most strongly influenced by the domain perceived gains when parents reported better self-esteem, confidence, improved attitude, improved grades, etc. (Spearman r = .45, P = .003). Alternatively, under the domain, perceived discomforts, with subthemes such as child bullying, participation in the combined intervention was inversely associated with attendance (Spearman r = -.38, P = .02). Family-centered, school-based, community obesity prevention programs that focus on tangible short-term gains for girls may generate greater participation rates, enhance social capital, and promote community empowerment. These factors can be emphasized in future obesity prevention program design and implementation.

A randomized controlled trial of culturally tailored dance and reducing screen time to prevent weight gain in low-income African American girls: Stanford GEMS.

OBJECTIVE: To test a 2-year community- and family-based obesity prevention program for low-income African American girls: Stanford GEMS (Girls' health Enrichment Multi-site Studies). DESIGN: Randomized controlled trial with follow-up measures scheduled at 6, 12, 18, and 24 months. SETTING: Low-income areas of Oakland, California. PARTICIPANTS: African American girls aged 8 to 10 years (N=261) and their parents or guardians. INTERVENTIONS: Families were randomized to one of two 2-year, culturally tailored interventions: (1) after-school hip-hop, African, and step dance classes and a home/family-based intervention to reduce screen media use or (2) information-based health education. MAIN OUTCOME MEASURE: Changes in body mass index (BMI). RESULTS: Changes in BMI did not differ between groups (adjusted mean difference [95% confidence interval] = 0.04 [-0.18 to 0.27] per year). Among secondary outcomes, fasting total cholesterol level (adjusted mean difference, -3.49 [95% confidence interval, -5.28 to -1.70] mg/dL per year), low-density lipoprotein cholesterol level (-3.02 [-4.74 to -1.31] mg/dL per year), incidence of hyperinsulinemia (relative risk, 0.35 [0.13 to 0.93]), and depressive symptoms (-0.21 [-0.42 to -0.001] per year) decreased more among girls in the dance and screen time reduction intervention. In exploratory moderator analysis, the dance and screen time reduction intervention slowed BMI gain more than health education among girls who watched more television at baseline (P = .02) and/or those whose parents or guardians were unmarried (P = .01). CONCLUSIONS: A culturally tailored after-school dance and screen time reduction intervention for low-income, preadolescent African American girls did not significantly reduce BMI gain compared with health education but did produce potentially clinically important reductions in lipid levels, hyperinsulinemia, and depressive symptoms. There was also evidence for greater effectiveness in high-risk subgroups of girls.

Team sports for overweight children: the Stanford Sports to Prevent Obesity Randomized Trial (SPORT).

OBJECTIVE: To evaluate the feasibility, acceptability, and efficacy of an after-school team sports program for reducing weight gain in low-income overweight children. DESIGN: Six-month, 2-arm, parallel-group, pilot randomized controlled trial. SETTING: Low-income, racial/ethnic minority community. PARTICIPANTS: Twenty-one children in grades 4 and 5 with a body mass index at or above the 85th percentile. INTERVENTIONS: The treatment intervention consisted of an after-school soccer program. The "active placebo" control intervention consisted of an after-school health education program. MAIN OUTCOME MEASURES: Implementation, acceptability, body mass index, physical activity measured using accelerometers, reported television and other screen time, self-esteem, depressive symptoms, and weight concerns. RESULTS: All 21 children completed the study. Compared with children receiving health education, children in the soccer group had significant decreases in body mass index z scores at 3 and 6 months and significant increases in total daily, moderate, and vigorous physical activity at 3 months. CONCLUSION: An after-school team soccer program for overweight children can be a feasible, acceptable, and efficacious intervention for weight control.

Stanford GEMS phase 2 obesity prevention trial for low-income African-American girls: design and sample baseline characteristics.

OBJECTIVE: African-American girls and women are at high risk of obesity and its associated morbidities. Few studies have tested obesity prevention strategies specifically designed for African-American girls. This report describes the design and baseline findings of the Stanford GEMS (Girls health Enrichment Multi-site Studies) trial to test the effect of a two-year community- and family-based intervention to reduce weight gain in low-income, pre-adolescent African-American girls. DESIGN: Randomized controlled trial with measurements scheduled in girls' homes at baseline, 6, 12, 18 and 24 month post-randomization. SETTING: Low-income areas of Oakland, CA. PARTICIPANTS: Eight, nine and ten year old African-American girls and their parents/caregivers. INTERVENTIONS: Girls are randomized to a culturally-tailored after-school dance program and a home/family-based intervention to reduce screen media use versus an information-based community health education Active-Placebo Comparison intervention. Interventions last for 2 years for each participant. MAIN OUTCOME MEASURE: Change in body mass index over the two-year study. RESULTS: Recruitment and enrollment successfully produced a predominately low-socioeconomic status sample. Two-hundred sixty one (261) families were randomized. One girl per family is randomly chosen for the analysis sample. Randomization produced comparable experimental groups with only a few statistically significant differences. The sample had a mean body mass index (BMI) at the 74 th percentile on the 2000 CDC BMI reference, and one-third of the analysis sample had a BMI at the 95th percentile or above. Average fasting total cholesterol and LDL cholesterol were above NCEP thresholds for borderline high classifications. Girls averaged low levels of moderate to vigorous physical activity, more than 3 h per day of screen media use, and diets high in energy from fat. CONCLUSIONS: The Stanford GEMS trial is testing the benefits of culturally-tailored after-school dance and screen-time reduction interventions for obesity prevention in low-income, pre-adolescent African-American girls.