Secreted by activated dendritic cells, IL-12 produces several effects that could enhance an antitumor T-cell response, including the induction of a T helper cell type 1 (Th1) response and the production of g-interferon.66 Recombinant IL-12 protein given to cancer patients at the maximum tolerated dose (MTD) in a Phase II trial produced unacceptable toxicity.67 However, based on animal models, the administration of doses well below the MTD should be sufficient for use of this agent as a tumor vaccine augmentation strategy.68,69 Gajewski and colleagues conducted Phase I69 and Phase II clinical trials70 in melanoma patients combining subcuta-neously injected IL-12 with a peptide-pulsed PBMC-based tumor vaccine. The IL-12 was given at a dose well below the MTD three times every other day after each vaccine. Toxic-ity was acceptable, and two patients (10%) had CRs. In other trials reported by Cebon et al.,71 melanoma patients were treated with IL-12 in combination with a tumor vaccine (Melan-A peptide vaccine). Cohorts of patients were treated with escalating doses of IL-12 given subcutaneously or intravenously on the day the first vaccine was given and once again 3 weeks later, with five vaccines given over an 8-week period. Toxicity was acceptable, and 1 of 21 patients had a partial response (PR). Before significant efficacy can be realized with this approach, considerable work needs to be done to determine the optimal dose and schedule of IL-12 administration as well as the optimal vaccine with which to combine it.
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Among the evils which a vitiated appetite has fastened upon mankind, those that arise from the use of Tobacco hold a prominent place, and call loudly for reform. We pity the poor Chinese, who stupifies body and mind with opium, and the wretched Hindoo, who is under a similar slavery to his favorite plant, the Betel but we present the humiliating spectacle of an enlightened and christian nation, wasting annually more than twenty-five millions of dollars, and destroying the health and the lives of thousands, by a practice not at all less degrading than that of the Chinese or Hindoo.