Down-regulation of the pharmacokinetic-pharmacodynamic response to interleukin-12 during long-term administration to patients with renal cell carcinoma and evaluation of the mechanism of this "adaptive response" in mice.

BACKGROUND: Interleukin-12 (IL-12) is a cytokine that promotes type-1 helper T-cell responses and may have therapeutic utility in the treatment of cancer, asthma, and a variety of infectious diseases. METHODS: In a phase I trial, recombinant human IL-12 (rHuIL-12) was administered subcutaneously once a week at a fixed dose of 0.1 to 1.0 microg/kg to 24 patients with renal cell carcinoma. A similar study was later performed in mice to evaluate the mechanism of down-regulation of pharmacokinetic-pharmacodynamic response observed in patients with cancer. RESULTS: Adverse events, serum IL-12 levels, and serum levels of interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) produced in response to IL- 12 were all maximum in the week after the first dose of rHuIL-12 and decreased after long-term administration. Similar to these results, repetitive subcutaneous administration of recombinant mouse IL-12 (rMoIL-12) to normal mice led to down-regulation of serum levels of IL-12 and IFN-gamma measured 5 hours after rMoIL-12 injection. Down-regulation of IL-12 serum levels was inversely correlated with the up-regulation of IL-12 receptor expression and may be the result of increased clearance of rMoIL-12 from serum by binding to lymphoid cells expressing increased amounts of IL-12 receptor. The down-regulation of serum IFN-gamma levels correlated with decreased IFN-gamma messenger ribonucleic acid expression and may result from feedback inhibition of IL-12 signaling or from a more specific inhibition of IFN-gamma synthesis. CONCLUSION: Administration of rHuIL-12 in fixed weekly doses resulted in decreased serum levels of IL-12 and of IFN-gamma, a secondary cytokine believed to be critical to response of IL-12. A better understanding of the complex regulation of the pharmacokinetic-pharmacodynamic response to IL-12 should facilitate the development of more effective dosing regimens for its use in the clinic.     

Human gamma delta T cells recognize alkylamines derived from microbes, edible plants, and tea: implications for innate immunity.

Approximately 4% of peripheral blood T cells in humans express a T cell receptor with markedly restricted germline gene segment usage (V gamma 2 V delta 2). Remarkably, these T cells expand 2- to 10-fold (8%-60% of all circulating T cells) during many microbial infections. We show here that these T cells recognize a family of naturally occurring primary alkylamines in a TCR-dependent manner. These antigenic alkylamines are secreted to millimolar concentrations in bacterial supernatants and are found in certain edible plants. Given the large numbers of memory V gamma 2 V delta 2 T cells in adult humans, recognition of alkylamine antigens offers the immune system a response of the magnitude of major superantigens for alpha beta T cells and may bridge the gap between innate and adaptive immunity.     

The effect of occult diabetic status and oral glucose intake on brachial artery vasoactivity in patients with peripheral vascular disease.

Brachial artery vasoactivity is a well known non-invasive method of assessing arterial endothelial function in vivo. Brachial artery vasoactivity has been found to be impaired in overt diabetes and in patients with coronary artery disease. Impaired brachial artery vasoactivity is felt to be an early indicator of atherosclerosis. The authors identified a group of patients with lower extremity peripheral vascular disease, who had normal fasting glucose level and were not known to be diabetics. An oral glucose tolerance test was performed in this group of patients. Brachial artery vasoactivity was assessed at each step of the oral glucose tolerance test to examine their occult diabetic status and correlate brachial artery vasoactivity to that status. The authors studied 23 randomly selected patients from the vascular surgery clinic between the ages of 50 and 79 years. Serum glucose level was assessed after a 10-h fast and at 30, 60 and 120 min after a 75-g oral glucose challenge. Any patient with two serum glucose values > 140 mg/dl was considered to have a positive oral glucose tolerance test. Using duplex ultrasound, the brachial artery diameter (cm) and blood volume (ml/min) were assessed before and after tourniquet occlusion at each step of the oral glucose tolerance test. Paired and unpaired t-tests were used to evaluate the results, P < 0.05 was considered significant. Nine patients had abnormal oral glucose tolerance test for a prevalence of 39%. There was no significant difference in fasting glucose levels between positive and negative oral glucose tolerance test patients (97.4+/-16.7 versus 88.5+/-5.8, P = 0.23). Patients with a positive oral glucose tolerance test had impaired vasoactivity at fasting and at each step of the test with no significant changes in brachial artery diameter or blood flow in response to brachial artery occlusion. Patients with a negative oral glucose tolerance test exhibited increased brachial artery diameter at fasting in response to brachial artery occlusion (0.43+/-0.02 versus 0.46+/-0.02, P = 0.03), but not after oral glucose challenge. In patients with a negative oral glucose tolerance test, brachial artery flow volume increased significantly in response to hyperemia at fasting (240+/-61 versus 578+/-262, P = 0.001) and at 30 min after glucose intake (260+/-53 versus 358+/-72, P = 0.01). At 60 and 120 min after glucose intake, brachial artery flow volume did not significantly increase in response to brachial artery occlusion. These results indicate that individuals with PVD and normal fasting glucose levels have a high prevalence of positive oral glucose tolerance test (39%). Patients with normal fasting glucose levels and abnormal oral glucose tolerance test have impaired brachial artery vasoactivity at fasting and after oral glucose challenge, this is in contrast to patients with normal oral glucose tolerance test who have normal fasting hyperemic response to brachial artery occlusion. However, this normal brachial artery vasoactivity is lost in the negative oral glucose tolerance test group in response to oral glucose load. These results suggest that endothelial function in diabetics is impaired in the early stages of the disease even before overt hyperglycemia occurs. Tight control of blood glucose level in glucose-intolerant patients prior to occurrence of overt fasting hyperglycemia may prove protective.     

Efficacy and safety of sorafenib in patients with advanced renal cell carcinoma with and without prior cytokine therapy, a subanalysis of TARGET

Before the development of targeted therapies, administration of cytokines (e.g., interleukin-2, interferon-α) was the primary systemic treatment option for advanced renal cell carcinoma. Sorafenib, an oral targeted, multikinase inhibitor, significantly prolonged progression-free survival and overall survival in the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET), a large (N = 903) phase III, double-blind, randomised, placebo-controlled study of patients with advanced renal cell carcinoma resistant to standard therapy. This analysis of a patient subgroup from TARGET evaluated the safety and efficacy of sorafenib in patients who had received prior cytokine therapy (sorafenib: n = 374; placebo: n = 368) and in patients who were cytokine-naïve (sorafenib: n = 77; placebo: n = 84). Progression-free survival was significantly prolonged with sorafenib therapy compared with placebo among patients with and without prior cytokine therapy (respectively 5.5 vs. 2.7 months; hazard ratio, 0.54; 95% confidence interval, 0.45–0.64 and 5.8 vs. 2.8 months; hazard ratio, 0.48; 95% confidence interval, 0.32–0.73). Clinical benefit rates for sorafenib-treated patients compared with placebo patients were also higher (cytokine-treated: 83 vs. 54.3%; cytokine-naïve: 85.7 vs. 56.0%). Sorafenib was well tolerated in both subgroups (grade 3/4: 20 and 22%, respectively). Sorafenib demonstrated a consistent, significant clinical benefit against advanced renal cell carcinoma, with a twofold improvement in progression-free survival and disease control rate, with similar toxicities in patients with or without prior cytokine treatment.     

Burden of metastatic bone disease from genitourinary malignancies

Bone metastases are common among patients with stage IV genitourinary cancers. Most patients with bone metastases develop at least one debilitating and potentially life-limiting skeletal-related event. These events are associated with increased medical expenses and decreased quality of life. Current guidelines recommend screening for bone metastases in men with high-risk prostate cancer, but guidance for screening and treatment of bone metastases from genitourinary cancers varies by country and setting. Several bisphosphonates have been evaluated in the advanced genitourinary cancer setting. Zoledronic acid has demonstrated efficacy in significantly reducing the risk of skeletal-related events in patients with bone metastases from a broad range of solid tumors including prostate, renal and bladder cancers, and is recommended for preserving bone health.     

Co-development of internalizing and externalizing problem behaviors: causal direction and common vulnerability

Latent growth curve modeling was used to study the co-development of internalizing and externalizing problems in a sample of 2844 Korean fourth graders followed over four years. The project integrated two major theoretical viewpoints positing developmental mechanism: directional model and common vulnerability model. Findings suggest that (a) boys and girls follow different developmental trajectories in both domains in early adolescence; (b) bidirectional progression from initial levels of each domain to the developmental pattern of the other domain emerged among boys, while only unidirectional progression from externalizing to internalizing problem emerged among girls; and (c) all risk factors are not equally risky across domain and gender; parental violence was a common cross-domain risk factor for boys, whereas affiliation with delinquent friends was a common cross-domain risk factor for girls. Implications for future research and intervention were discussed.     

Randomized multicenter phase II trial of subcutaneous recombinant human interleukin-12 versus interferon-alpha 2a for patients with advanced renal cell carcinoma.

Recombinant human interleukin-12 (rHuIL-12) is a pleiotropic cytokine with anticancer activity against renal cell carcinoma (RCC) in preclinical models and in a phase I trial. A randomized phase II study of rHuIL-12 compared with interferon-alpha (IFN-alpha) evaluated clinical response for patients with previously untreated, advanced RCC. Patients were randomly assigned 2:1 to receive either rHuIL-12 or IFN-alpha2a. rHuIL-12 was administered by subcutaneous (s.c.) injection on days 1, 8, and 15 of each 28-day cycle. The dose of IL-12 was escalated during cycle 1 to a maintenance dose of 1.25 microg/kg. IFN was administered at 9 million units by s.c. injection three times per week. Serum concentrations of IL-12, IFN-gamma, IL-10, and neopterin were obtained in 10 patients treated with rHuIL-12 after the first full dose of 1.25 microg/kg given on day 15 (dose 3) of cycle 1 and again after multiple doses on day 15 (dose 6) of cycle 2. Thirty patients were treated with rHuIL-12, and 16 patients were treated with IFN-alpha. Two (7%) of 30 patients treated with rHuIL-12 achieved a partial response, and the trial was closed to accrual based on the low response proportion. IL-12 was absorbed rapidly after s.c. drug administration, with the peak serum concentration appearing at approximately 12 h in both cycles. Serum IL-12 concentrations remained stable on multiple dosing. Levels of IFN-gamma, IL-10, and neopterin increased with rHuIL-12 and were maintained in cycle 2. rHuIL-12 is a novel cytokine with unique pharmacologic and pharmacodynamic features under study for the treatment of malignancy and other medical conditions. The low response proportion associated with rHuIL-12 single-agent therapy against metastatic RCC was disappointing, given the preclinical data. Further study of rHuIL-12 for other medical conditions is underway. For RCC, the study of new cytokines is of the highest priority.