A long-acting interleukin-7, rhIL-7-hyFc, enhances CAR T cell expansion, persistence, and anti-tumor activity.

Chimeric antigen receptor (CAR) T cell therapy is routinely used to treat patients with refractory hematologic malignancies. However, a significant proportion of patients experience suboptimal CAR T cell cytotoxicity and persistence that can permit tumor cell escape and disease relapse. Here we show that a prototype pro-lymphoid growth factor is able to enhance CAR T cell efficacy. We demonstrate that a long-acting form of recombinant human interleukin-7 (IL-7) fused with hybrid Fc (rhIL-7-hyFc) promotes proliferation, persistence and cytotoxicity of human CAR T cells in xenogeneic mouse models, and murine CAR T cells in syngeneic mouse models, resulting in long-term tumor-free survival. Thus, rhIL-7-hyFc represents a tunable clinic-ready adjuvant for improving suboptimal CAR T cell activity.

Mitochondrial Pyruvate Import Promotes Long-Term Survival of Antibody-Secreting Plasma Cells.

Durable antibody production after vaccination or infection is mediated by long-lived plasma cells (LLPCs). Pathways that specifically allow LLPCs to persist remain unknown. Through bioenergetic profiling, we found that human and mouse LLPCs could robustly engage pyruvate-dependent respiration, whereas their short-lived counterparts could not. LLPCs took up more glucose than did short-lived plasma cells (SLPCs) in vivo, and this glucose was essential for the generation of pyruvate. Glucose was primarily used to glycosylate antibodies, but glycolysis could be promoted by stimuli such as low ATP levels and the resultant pyruvate used for respiration by LLPCs. Deletion of Mpc2, which encodes an essential component of the mitochondrial pyruvate carrier, led to a progressive loss of LLPCs and of vaccine-specific antibodies in vivo. Thus, glucose uptake and mitochondrial pyruvate import prevent bioenergetic crises and allow LLPCs to persist. Immunizations that maximize these plasma cell metabolic properties might thus provide enduring antibody-mediated immunity.

Chia seed supplementation and disease risk factors in overweight women: a metabolomics investigation.

OBJECTIVE/SETTING: This study assessed the effectiveness of milled and whole chia seed in altering disease risk factors in overweight, postmenopausal women using a metabolomics approach. DESIGN/INTERVENTION: Subjects were randomized to chia seed (whole or milled) and placebo (poppy seed) groups, and under double-blinded procedures ingested 25 g chia seed or placebo supplements each day for 10 weeks. SUBJECTS: Subjects included 62 overweight (body-mass index 25 kg/m(2) and higher), nondiseased, nonsmoking, postmenopausal women, ages 49-75 years, with analysis based on the 56 subjects who completed all phases of the study. OUTCOME MEASURES: Pre- and poststudy measures included body mass and composition, blood pressure and augmentation index, serum lipid profile, inflammation markers from fasting blood samples, plasma fatty acids, and metabolic profiling using gas chromatography-mass spectrometry with multivariate statistical methods including principal component analysis and partial least-square discriminant analysis (PLS-DA). RESULTS: Plasma α-linolenic acid (N=ALA) increased 58% (interaction effect, p=0.002) and eicosapentaenoic acid (EPA) 39% (p=0.016) in the milled chia seed group (N=14) compared to nonsignificant changes in the whole chia seed (N=16) and placebo (N=26) groups. Pre-to-post measures of body composition, inflammation, blood pressure, augmentation index, and lipoproteins did not differ between chia seed (whole or milled) and placebo groups (all interaction effects, p>0.05). Global metabolic difference scores for each group calculated through PLS-DA models were nonsignificant (Q(2)Y<0.40), and fold-changes for 28 targeted metabolites associated with inflammation and disease risk factors did not differ between groups. CONCLUSIONS: Ingestion of 25 g/day milled chia seed compared to whole chia seed or placebo for 10 weeks by overweight women increased plasma ALA and EPA, but had no influence on inflammation or disease risk factors using both traditional and metabolomics-based measures.

Variance in the acute inflammatory response to prolonged cycling is linked to exercise intensity.

This study investigated the influence of age, body composition, physical fitness, training volume and intensity, and underlying systemic inflammation on exercise-induced inflammation and innate immune function in a heterogeneous group of cyclists. Subjects included 31 male cyclists (mean ± standard deviation, age 38.8 ± 10.6 years, body fat 17.8%± 5.6%, VO(2max) 55.8 ± 8.4 mL kg(-1) min(-1)) who cycled for 1.75 h at 60% watts(max) followed by a 10-km time trial (18.3 ± 0.3 min). Blood samples were collected pre-, post-, and 1-h-postexercise, and analyzed for WBCs, 9 cytokines [interleukin (IL)-6, tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor, interferon-γ, IL-1ß, IL-2, IL-8, IL-10, and IL-12p70], and granulocyte and monocyte phagocytosis (GR-PHAG and MO-PHAG) and oxidative burst activity (GR-OBA and MO-OBA). Exercise-induced changes varied widely, with significant increases measured for 8 of 9 cytokines, GR-PHAG (mean change 99%) (95% confidence limits, 69%, 128%) and MO-PHAG (43%) (28%, 58%), and WBC (160%) (133%, 187%), and decreases for GR-OBA (-30%) (-43%,-16%) and MO-OBA (-23%) (-36%,-10%). Correlation and stepwise regression analysis revealed that changes in these variables were not related to age, body fat percentage, VO(2max), training volume, or pre-exercise C-reactive protein. Performance measures, specifically the average heart rate and rating of perceived exertion, were correlated with changes in several variables, including IL-8 (r=0.68 and 0.67, respectively, P<0.001) and IL-6 (r=0.51, P=0.004, and r=0.46, P=0.011, respectively). In summary, variance in exercise-induced inflammation and innate immunity in male cyclists in response to 2 h of endurance exercise is best explained by exercise intensity.

The acute effect of ingesting a quercetin-based supplement on exercise-induced inflammation and immune changes in runners.

This study tested the acute anti-inflammatory and immune-modulating influence of a quercetin-based supplement consumed by endurance athletes 15 min before an intense 2-hr run. In this randomized, crossover study, 20 runners (11 men, 9 women, age 38.4 ± 2.1 yr) completed two 2-hr treadmill runs at 70% VO(2max) (3 wk apart). Subjects ingested either 4 quercetin-based chews (Q-chew) or placebo chews (PL) 15 min before the runs. The 4 Q-chews provided 1,000 mg quercetin, 120 mg epigallocatechin 3-gallate, 400 mg isoquercetin, 400 mg each eicosapentaenoic acid and docosahexaenoic acid, 1,000 mg vitamin C, and 40 mg niacinamide. Subjects provided blood samples 30 min before, immediately after, and 1 hr postexercise and were analyzed for plasma quercetin, total blood leukocytes (WBC), C-reactive protein (CRP), 9 cytokines (IL-6, TNFα, GM-CSF, IFNγ, IL-1ß, IL-2, IL-8, IL-10, and IL-12p70), granulocyte (GR) and monocyte (MO) phagocytosis (PHAG), and oxidative-burst activity (OBA). Plasma quercetin increased from 80.0 ± 26.0 µg/L to 6,337 ± 414 µg/L immediately postexercise and 4,324 ± 310 µg/L 1 hr postexercise after ingestion of Q-chews, compared with no change in PL (p < .001). Exercise caused significant increases in, CRP, GM-CSF, IL-10, IL-1ß, IL-2, IL-6, IL-8, TNFα, GR-PHAG, and MO-PHAG and decreases in GR-OBA and MO-OBA, but no differences in the pattern of change were measured between Q-chew and PL trials. Acute ingestion of Q-chews 15 min before heavy exertion caused a strong increase in plasma quercetin levels but did not counter postexercise inflammation or immune changes relative to placebo.