Successful treatment of metastatic melanoma by adoptive transfer of blood-derived polyclonal tumor-specific CD4+ and CD8+ T cells in combination with low-dose interferon-alpha

A phase I/II study was conducted to test the feasibility and safety of the adoptive transfer of tumor-reactive T cells and daily injections of interferon-alpha (IFNα) in metastatic melanoma patients with progressive disease. Autologous melanoma cell lines were established to generate tumor-specific T cells by autologous mixed lymphocyte tumor cell cultures using peripheral blood lymphocytes. Ten patients were treated with on average 259 (range 38–474) million T cells per infusion to a maximum of six infusions, and clinical response was evaluated according to the response evaluation criteria in solid tumors (RECIST). Five patients showed clinical benefit from this treatment, including one complete regression, one partial response, and three patients with stable disease. No treatment-related serious adverse events were observed, except for the appearance of necrotic-like fingertips in one patient. An IFNα-related transient leucopenia was detected in 6 patients, including all responders. One responding patient displayed vitiligo. The infused T-cell batches consisted of tumor-reactive polyclonal CD8+ and/or CD4+ T cells. Clinical reactivity correlated with the functional properties of the infused tumor-specific T cells, including their in vitro expansion rate and the secretion of mainly Th1 cytokines as opposed to Th2 cytokines. Our study shows that relatively low doses of T cells and low-dose IFNα can lead to successful treatment of metastatic melanoma and reveals a number of parameters potentially associated with this success

Transcriptomic and functional analysis of the Anopheles gambiae salivary gland in relation to blood feeding

<p>Abstract</p> <p>Background</p> <p>The <it>Anopheles gambiae </it>salivary glands play a major role in malaria transmission and express a variety of bioactive components that facilitate blood-feeding by preventing platelet aggregation, blood clotting, vasodilatation, and inflammatory and other reactions at the probing site on the vertebrate host.</p> <p>Results</p> <p>We have performed a global transcriptome analysis of the <it>A. gambiae </it>salivary gland response to blood-feeding, to identify candidate genes that are involved in hematophagy. A total of 4,978 genes were found to be transcribed in this tissue. A comparison of salivary gland transcriptomes prior to and after blood-feeding identified 52 and 41 transcripts that were significantly up-regulated and down-regulated, respectively. Ten genes were further selected to assess their role in the blood-feeding process using RNAi-mediated gene silencing methodology. Depletion of the salivary gland genes encoding <it>D7L2</it>, <it>anophelin</it>, <it>peroxidase</it>, the <it>SG2 precursor</it>, and a <it>5'nucleotidase </it>gene significantly increased probing time of <it>A. gambiae </it>mosquitoes and thereby their capacity to blood-feed.</p> <p>Conclusions</p> <p>The salivary gland transcriptome comprises approximately 38% of the total mosquito transcriptome and a small proportion of it is dynamically changing already at two hours in response to blood feeding. A better understanding of the salivary gland transcriptome and its function can contribute to the development of pathogen transmission control strategies and the identification of medically relevant bioactive compounds.</p