Research ArticleInfectious Disease

TORC1 inhibition enhances immune function and reduces infections in the elderly

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Science Translational Medicine  11 Jul 2018:
Vol. 10, Issue 449, eaaq1564
DOI: 10.1126/scitranslmed.aaq1564
  • Fig. 1 Flow diagram showing participants and study design.

    The number of elderly subjects screened (assessed for eligibility), the number of subjects randomized to each treatment arm (allocation), and the number of subjects who discontinued study drug in each treatment arm. The term analyzed indicates the number of subjects in each cohort in the modified intention to treat population.

  • Fig. 2 Increase in antibody titers to influenza virus vaccine strains in mTOR inhibitor treatment groups relative to the placebo group.

    (A) Increase in the ratio (4 weeks after vaccination: baseline) in GMT for each of the three influenza virus vaccine strains in elderly subjects treated with RAD001, BEZ235, RAD001 + BEZ235, or placebo. The three influenza virus vaccine strains used were as follows: A/H1N1 (A/California/7/2009), A/H3N2 (A/Texas/50/2012), and B (B/Massachusetts/2/2012). The blue line indicates the 20% increase in GMT ratios relative to placebo that was required for two of the three influenza virus vaccine strains to meet the primary end point of the study. Asterisks indicate that the probability that the increase in GMT ratio relative to placebo exceeded 1.0 is 100%. (B) Forest plots of the data presented in (A) including 90% confidence intervals and probability that the GMT ratio compared to placebo is >1 or >1.2.

  • Fig. 3 Low doses of RAD001 and BEZ235 inhibit TORC1.

    Western blots for phosphorylated (p) and total (t) protein amounts for S6K1, S6, and 4EBP1 in rat livers after 7 days of drug treatment. (A) Rats were treated daily for 7 days with RAD001 (RAD) at the dose equivalent of 0.1 mg (0.03 mg/kg) or 0.5 mg (0.15 mg/kg) in humans. (B) Rats were treated daily for 7 days with BEZ235 (BEZ) given at the dose equivalent of 10 mg (1.7 mg/kg) in humans alone or in combination with the dose equivalent of RAD001 0.1 mg (0.03 mg/kg). Tissues were collected 4 hours after the last drug dose. Left: Each lane in the immunoblots represents liver tissue from one rat. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is shown as a loading control. Right: The amounts of p-S6K1(T389) and p-S6(Ser240/244) on the immunoblots were quantified relative to their respective total protein amounts by densitometry. Amounts of p-4EBP1 (T37/46) were quantified relative to GAPDH. Y axes represent arbitrary units. For each group, n = 4 to 6 rats. Data are mean ± SD. Data were analyzed with a one-way analysis of variance (ANOVA) followed by Dunnett’s multiple comparison tests, where means from all groups were compared to the vehicle-treated group. In (A), *P = 0.048 and *P = 0.018 for p-S6K1 and p-S6, respectively. In (B), *P = 0.015 for p-S6K1, **P ≤ 0.005 for p-4EBP1, and ***P ≤ 0.001 for p-S6.

  • Fig. 4 TORC1 inhibition decreases infection rates in the elderly.

    (A) Fitted annual rates of infections reported per person per year in the 0.1 mg of RAD001, 0.5 mg of RAD001, 10 mg of BEZ235, 0.1 mg of RAD001 + 10 mg of BEZ235, or placebo groups. *P = 0.008, **P = 0.001 versus placebo. (B) Fitted annual rates of respiratory tract infections (RTIs) reported per person per year in the placebo group and in the BEZ235 monotherapy and BEZ235 + RAD001 combination treatment groups. *P = 0.01, **P = 0.008 versus placebo. In both figures, error bars indicate 95% confidence intervals as determined by Poisson regression modeling.

  • Table 1 Adverse events (AEs) that occurred in >5% of elderly subjects in any treatment group during the 1-year study.

    Ordered by total frequency. Under one treatment, a participant with multiple occurrences of an AE is counted only once in the AE category.

    RAD001 (0.1 mg)
    N = 52 (%)
    RAD001 (0.5 mg)
    N = 54 (%)
    BEZ235 (10 mg)
    N = 53 (%)
    RAD001 (0.1 mg) +
    BEZ235 (10 mg)
    N = 53 (%)
    Placebo, pooled
    N = 52 (%)
    Total N = 264 (%)
    Total AEs3204063463194011792
    Patients with AEs50 (96.2)52 (96.3)52 (98.1)51 (96.2)51 (98.1)256 (97.0)
    Upper respiratory
    tract infection
    11 (21.2)12 (22.2)11 (20.8)14 (26.4)16 (30.8)64 (24.2)
    Headache7 (13.5)16 (29.6)13 (24.5)11 (20.8)9 (17.3)56 (21.2)
    Nasopharyngitis14 (26.9)13 (24.1)6 (11.3)7 (13.2)10 (19.2)50 (18.9)
    Diarrhea10 (19.2)12 (22.2)10 (18.9)9 (17.0)4 (7.7)45 (17.0)
    Cough7 (13.5)7 (13.0)6 (11.3)5 (9.4)10 (19.2)35 (13.3)
    Fatigue6 (11.5)4 (7.4)8 (15.1)4 (7.5)6 (11.5)28 (10.6)
    Oropharyngeal pain8 (15.4)2 (3.7)8 (15.1)1 (1.9)7 (13.5)26 (9.8)
    Arthralgia4 (7.7)7 (13.0)6 (11.3)3 (5.7)5 (9.6)25 (9.5)
    Fall4 (7.7)3 (5.6)6 (11.3)7 (13.2)5 (9.6)25 (9.5)
    Nausea4 (7.7)6 (11.1)4 (7.5)7 (13.2)4 (7.7)25 (9.5)
    Rhinitis3 (5.8)4 (7.4)3 (5.7)9 (17.0)6 (11.5)25 (9.5)
    Dizziness5 (9.6)5 (9.3)6 (11.3)3 (5.7)4 (7.7)23 (8.7)
    Back pain5 (9.6)08 (15.1)2 (3.8)5 (9.6)20 (7.6)
    Contusion5 (9.6)2 (3.7)2 (3.8)7 (13.2)4 (7.7)20 (7.6)
    Oral herpes5 (9.6)2 (3.7)7 (13.2)3 (5.7)3 (5.8)20 (7.6)
    Urinary tract
    infection
    5 (9.6)5 (9.3)2 (3.8)07 (13.5)19 (7.2)
    Lower respiratory
    tract infection
    3 (5.8)3 (5.6)1 (1.9)5 (9.4)6 (11.5)18 (6.8)
    Gastroenteritis3 (5.8)4 (7.4)3 (5.7)5 (9.4)2 (3.8)17 (6.4)
    Mouth ulceration5 (9.6)2 (3.7)2 (3.8)6 (11.3)2 (3.8)17 (6.4)
    Muscle strain3 (5.8)4 (7.4)2 (3.8)3 (5.7)5 (9.6)17 (6.4)
    Constipation3 (5.8)6 (11.1)4 (7.5)1 (1.9)2 (3.8)16 (6.1)
    Bronchitis3 (5.8)3 (5.6)2 (3.8)3 (5.7)3 (5.8)14 (5.3)
    Laceration4 (7.7)2 (3.7)2 (3.8)3 (5.7)3 (5.8)14 (5.3)
    Musculoskeletal pain1 (1.9)8 (14.8)1 (1.9)4 (7.5)014 (5.3)
    Pain in extremity1 (1.9)3 (5.6)3 (5.7)2 (3.8)5 (9.6)14 (5.3)
  • Table 2 Pathways and genes up-regulated after RAD001 + BEZ235 treatment as determined by gene expression analysis of whole blood.
    PathwayMean FC of
    genes in
    pathway
    P valueUp-regulated
    genes*
    IFN α/β signaling0.0810−21.8IFI27, IFIT2,
    IFIT1, IFIT3,
    MX1, OAS3,
    ISG15
    IFN signaling0.0410−36.7IFI27, IFIT2,
    IFIT1, IFIT3,
    MX1, OAS3,
    HERC5, ISG15
    Cytokine
    signaling in
    immune
    system
    0.0210−43.5IFI27, IFIT2,
    IFIT1, IFIT3,
    MX1, OAS3,
    HERC5, ISG15

    *Listed up-regulated genes are those determined to be outliers by the Tukey method of outlier detection.

    Supplementary Materials

    • www.sciencetranslationalmedicine.org/cgi/content/full/10/449/eaaq1564/DC1

      Fig. S1. Changes in serum cytokine concentrations.

      Fig. S2. RAD001 + BEZ235 combination treatment but not placebo treatment leads to up-regulation of IFN-induced gene expression.

      Table S1. Summary of hemagglutination inhibition titers by influenza virus strain for each treatment over time.

      Table S2. Demographic and baseline characteristics of the study subjects.

      Table S3. Full list of pathways and genes up-regulated after RAD001 + BEZ235 treatment as assessed by gene expression analysis of whole blood.

    • This PDF file includes:

      • Fig. S1. Changes in serum cytokine concentrations.
      • Fig. S2. RAD001 + BEZ235 combination treatment but not placebo treatment leads to up-regulation of IFN-induced gene expression.
      • Table S1. Summary of hemagglutination inhibition titers by influenza virus strain for each treatment over time.
      • Table S2. Demographic and baseline characteristics of the study subjects.
      • Table S3. Full list of pathways and genes up-regulated after RAD001 + BEZ235 treatment as assessed by gene expression analysis of whole blood.

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