|IL-12p70-producing patient DC vaccine elicits Tc1-polarized immunity.|
Carreno, BM; Becker-Hapak, M; Huang, A; Chan, M; Alyasiry, A; Lie, WR; Aft, RL; Cornelius, LA; Trinkaus, KM; Linette, GP
The Journal of clinical investigation
Systemic administration of IL-12p70 has demonstrated clinical activity in cancer patients, but dose-limiting toxicities have hindered its incorporation in vaccine formulations. Here, we report on the immunological and clinical outcomes upon vaccination with CD40L/IFN-γ-matured, IL-12p70-producing DCs.7 HLA-A*0201+ newly diagnosed stage IV melanoma patients were immunized against the gp100 melanoma antigen using autologous peptide-pulsed, CD40L/IFN-γ-matured DCs. PBMCs were taken weekly for immune monitoring by tetramer analysis and functional assays. CT imaging was performed at baseline, week 9, and week 18 for clinical assessment using RECIST.6 of 7 treated patients developed sustained T cell immunity to all 3 melanoma gp100 antigen-derived peptides. 3 of the 6 immunological responders developed confirmed clinical responses (1 complete remission >4 years, 2 partial response). Importantly, DC vaccine-derived IL-12p70 levels positively correlated with time to progression (P = 0.019, log-rank), as did T-cytotoxic 1 (Tc1) immunity, as assessed by IFN-γ/IL-13 and IFN-γ/IL-5 ratios (P = 0.035 and P = 0.030, respectively, log-rank). In contrast, a pathway-specific defect in IL-12p35 transcription was identified upon CD40L/IFN-γ activation in clinical nonresponder patient DCs, and gp100-specific T cells from these patients displayed a Tc2 phenotype. Incorporation of TLR3 and TLR8 agonists into the CD40L/IFN-γ activation protocol corrected the IL-12p70 production defect in DCs derived from clinical nonresponder patients.These findings underscore the essential role of IL-12p70 in the development of therapeutic type 1 antigen-specific CD8+ T cell immunity in humans with cancer.
|Evidence of enhanced systemic inflammation in stable kidney transplant recipients with low Framingham risk scores.|
Mansell, H; Rosaasen, N; Dean, J; Shoker, A
While the Framingham risk score (FRS) predicts cardiovascular risk in the general population, it underestimates cardiovascular events in renal transplant recipients (RTR). Inflammation is common in RTR, and it is also a hallmark of vascular injury contributing to cardiovascular events.To explore the relationship between inflammatory chemokines (CCL family) and FRS in a stable RTR.The modified FRS (2009) was used to calculate the 10-yr probability of CVE in 150 RTR. A cross-sectional study measured plasma levels of 14 CCLs by Luminex technique in 53% (79/150) of the cohort and 28 controls.43.3% of RTR was classified as low, 16% moderate, and 40.7% high FRS. FRS correlated with eGFR and all CCLs with R of <0.2(p = n.s). Compared with controls, CCL 1,4,8,15, and 27 were equally increased in both the high and low FRS groups (p < 0.04 and 0.03, respectively). The percentage of patients with low FRS and CCL 8,15, and 27 values above the 95% cutoff control levels was 46.1%, 76.9%, and 53.8%, respectively.Over one half of stable RTR, including those with low FRS, have increased inflammatory chemokine levels. Inflammation is not accounted for in the FRS, and this may explain the poor performance of FRS in transplant patients.