Grant: $109,616 - National Institutes of Health - Sep. 14, 2009
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Award Description: The tumor vaccine trial that I proposed as Aim 1 of the parent grant was opened and enrollment of all 23 patients in the first stage completed. According to the Simon Minimax design, because there were fewer than 3 responses after the first stage the trial was stopped for lack of efficacy. We now plan to progress to the next iteration of our vaccine, that is to add CCL21 (a chemoattractant for T cells and DC) production by the vaccine to improve its efficacy. The rationale for this improved vaccine is as follows: this vaccine will attract both DC and T cells to the vaccine site. The DC will process the tumor antigen supplied in the vaccine and maturation of the DC will occur by CD40 ligation. These DC will then educate and stimulate the T cells attracted into the vaccine environment. The activated T cells will then circulate to metastatic sites and mount tumoricidal responses. The pre-clinical work that needs to be performed that would be supported by this supplement is as follows: (1) engineering the GM.CD40L vaccine to express CCL21, (2) determining if the secretion of CCL21 by the vaccine induces chemotaxis of naïve T cells, and (3) evaluating the GM.CD40L - CCL21 vaccine in in vitro allogeneic mixed lymphocyte tumor cell assays to determine if CCL21 augments anti-tumor immune responses promoted by the GM.CD40L vaccine. Following completion of the preclinical work, we will submit a separate proposal to the NCI requesting support to conduct the clinical trial. Regarding Aim #3, we were successful in opening the phase I study treating adults with refractory solid malignancies with 1-MT. It has become apparent that this agent is an active, orally bioavailable, and reasonably well tolerated immunomodulator. Two patients developed hypophysitis, indicating that the drug can break tolerance resulting in autoimmunity. Given this surprising degree of biological activity even at very low doses, we are now motivated to significantly expand the correlative laboratory studies that we perform on blood specimens obtained from the treated patients. The proposed detailed immunologic analysis is designed to ascertain the immune cell networks that are operational in the biological activity that we have observed in the patients we treat with 1-MT. The translational value of this analysis will be that a more detailed understanding of the mechanisms involved will likely suggest additional combinatorial strategies that could be tested in future clinical trials in an effort to improve clinical efficacy in the treatment of cancer..
Project Description: This award was issued on 9/14/09 and, therefore, did not have any activities to report this quarter.
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This award's data was last updated on Sep. 14, 2009. Help expand these official descriptions using the wiki below.