Recombinant adenovirus-engineered dendritic cells (Ad.DC) are potent vaccines for induction of anti-viral and anti-cancer T cell immunity. The effectiveness of Ad.DC vaccines may depend on the newly described ability of Ad.DC to crosstalk with natural killer (NK) cells via cell-to-cell contact, and to mediate activation, polarization and bridging of innate and adaptive immunity. For this interaction to occur in vivo, Ad.DC must be able to attract NK cells from surrounding tissues or peripheral blood. We developed a novel live mouse imaging system-based NK-cell migration test, and demonstrated for the first time that human Ad.DC induced directional migration of human NK cells across subcutaneous tissues, indicating that Ad.DC-NK cell contact and interaction could occur in vivo. We examined the mechanism of Ad.DC-induced migration of NK cells in vitro and in vivo. Ad.DC produced multiple chemokines previously reported to recruit NK cells, including immunoregulatory CXCL10/IP-10 and proinflammatory CXCL8/IL-8. In vitro chemotaxis experiments utilizing neutralizing antibodies and recombinant human chemokines showed that CXCL10/IP-10 and CXCL8/IL-8 were critical for Ad.DC-mediated recruitment of CD56 hi CD16 - and CD56 lo CD16 + NK cells, respectively. The importance of CXCL8/IL-8 was further demonstrated in vivo. Pretreatment of mice with the neutralizing anti-CXCL8/IL-8 antibody led to significant inhibition of Ad.DC-induced migration of NK cells in vivo. These data show that Ad.DC can recruit spatially distant NK cells toward a vaccine site via specific chemokines. Therefore, an Ad.DC vaccine can likely induce interaction with endogenous NK cells via transmembrane mediators, and consequently mediate Th1 polarization and amplification of immune functions in vivo.

At the dose and schedule used in this trial, 9-AC lacked antitumor activity in metastatic colorectal cancer. 9-AC infusion schedules of longer duration are currently being investigated in this disease.

Compliance with the consultant's recommendations is one measure of the effectiveness of a consultation. A previous study showed that compliance was better when fewer recommendations were made. In the subsequent year, consultants were encouraged to limit their recommendations to five or fewer. Despite a significant decrease in the number of recommendations, compliance rates remained essentially unchanged (72%). Multivariate analysis demonstrated that the clinical severity of the patient's disease and the number of associated problems, as well as the types of recommendations, were significant predictors of compliance. Compliance was best for recommendations involving medications (84%) and worst for recommendations involving diagnostic tests (62%). Compliance was also evaluated in the context of a surgeon's view of the appropriateness of the recommendations. For recommendations felt to be essential to patient care the compliance rate was 75%, but it was only 44% for recommendations judged nonessential (p less than 0.001). The consulting internist should be aware that the surgeon's view of the relevance of the recommendations to patient care needs may have an important effect on compliance.

No abstract

No abstract