CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naive/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma.

To address antigen escape and loss of T-cell functionality, we report a phase I clinical trial (NCT04007029) evaluating autologous naive and memory T (TN/MEM) cells engineered to express a bispecific anti-CD19/CD20 chimeric antigen receptor (CAR; CART19/20) for patients with relapsed/refractory non-Hodgkin lymphoma (NHL), with safety as the primary endpoint. Ten patients were treated with 36 × 106 to 165 × 106 CART19/20 cells. No patient experienced neurotoxicity of any grade or over grade 1 cytokine release syndrome. One case of dose-limiting toxicity (persistent cytopenia) was observed. Nine of 10 patients achieved objective response [90% overall response rate (ORR)], with seven achieving complete remission [70% complete responses (CR) rate]. One patient relapsed after 18 months in CR but returned to CR after receiving a second dose of CART19/20 cells. Median progression-free survival was 18 months and median overall survival was not reached with a 17-month median follow-up. In conclusion, CART19/20 TN/MEM cells are safe and effective in patients with relapsed/refractory NHL, with durable responses achieved at low dosage levels. SIGNIFICANCE: Autologous CD19/CD20 bispecific CAR-T cell therapy generated from TN/MEM cells for patients with NHL is safe (no neurotoxicity, maximum grade 1 cytokine release syndrome) and demonstrates strong efficacy (90% ORR, 70% CR rate) in a first-in-human, phase I dose-escalation trial. This article is highlighted in the In This Issue feature, p. 517.

Single-cell transcriptomic analysis of the lateral hypothalamic area reveals molecularly distinct populations of inhibitory and excitatory neurons.

The lateral hypothalamic area (LHA) coordinates an array of fundamental behaviors, including sleeping, waking, feeding, stress and motivated behavior. The wide spectrum of functions ascribed to the LHA may be explained by a heterogeneous population of neurons, the full diversity of which is poorly understood. We employed a droplet-based single-cell RNA-sequencing approach to develop a comprehensive census of molecularly distinct cell types in the mouse LHA. Neuronal populations were classified based on fast neurotransmitter phenotype and expression of neuropeptides, transcription factors and synaptic proteins, among other gene categories. We define 15 distinct populations of glutamatergic neurons and 15 of GABAergic neurons, including known and novel cell types. We further characterize a novel population of somatostatin-expressing neurons through anatomical and behavioral approaches, identifying a role for these neurons in specific forms of innate locomotor behavior. This study lays the groundwork for better understanding the circuit-level underpinnings of LHA function.

Internet-delivered obesity treatment improves symptoms of and risk for depression.

OBJECTIVE: In-person lifestyle interventions for obesity treatment yield significant improvements in depression. These improvements may be attributed to the excellent weight losses produced by in-person interventions. In contrast, Internet programs yield more modest weight losses, and their effect on depression is unknown. This study is the first to examine whether Internet-delivered obesity treatment impacts depressive symptoms. METHODS: Participants (N = 136) were randomized to either a community campaign plus Internet behavioral weight loss (IBWL) or community campaign alone (Control). IBWL did not include online social support components. A measure of depressive symptoms was administered, and weight was objectively assessed. RESULTS: Of the total sample, 24% met the clinical cutoff for elevated depression risk at baseline. IBWL participants lost more weight during treatment (P = 0.005) and experienced significantly greater improvements in depressive symptoms (P = 0.02). Among participants who met the clinical cutoff for elevated risk for depression at baseline, those assigned to IBWL had greater improvements in depressive symptoms during treatment compared to Control (P = 0.033). Consequently, at post-treatment, a smaller percentage of IBWL participants were at elevated risk for depression. CONCLUSIONS: This study is the first to show that Internet-delivered obesity treatment improves depression risk and depressive symptoms in individuals with overweight or obesity.