Since 1984 we have performed laboratory immune assessments with specimens obtained from patients receiving experimental cancer immunotherapy to measure the influence of treatment on these patients' immune function. Utilizing the results of the immune monitoring, we have formulated subsequent studies based on our understanding of the mechanisms of action of the biological response modifier therapy. We propose now to monitor the immune responses and biological effects of patients receiving cancer gene therapy with treatments including cytokine genes and co-stimulatory molecules. The initial clinical trial will evaluate the effects of immunization with a freshly prepared irradiated tumor cell vaccine transfected by particle mediated gene transfer (PMGT) with cDNA coding for GM-CSF. This GM-CSF transfected tumor vaccine will be given intradermally and patients will be monitored via biopsy of the vaccine site, serum and peripheral blood samples. A subsequent trial also utilizing GM-CSF will compare the effect of PMGT into the tumor vaccine preparation versus direct in vivo PMGT into the intradermal vaccine site. Additional protocols will evaluate the effects of gene therapy with IL-12, or combined therapy with co-stimulatory molecule B7-1, interferon gamma and the melanoma tumor antigen, MART-1. In these protocols our goals will be to evaluate biopsy specimens as well as peripheral blood specimens. Specifically, we will determine: 1) The induction of delayed type hypersensitivity (DTH) to autologous tumor; 2) The local and systemic level of cytokine produced after gene transfer; 3) The immunophenotype of the cellular infiltrate at the vaccine site and the tumor, and 4) In patients with positive DTH reactions, effector cells obtained from the biopsy of the skin test site will be expanded; these will be restimulated with autologous tumor, and secondary cytokine secretion, proliferation and cytotoxicity will be evaluated. The combined clinical, immunologic, morphologic and molecular data will establish the clinical tolerance of local gene delivery and its efficacy at activating gene expression and inducing tumor reactive immunity. Information regarding the molecular and cellular mechanisms of cytokine and tumor antigen induced activation will be obtained, essential to the design of subsequent Phase II trials to assess the antitumor effect of local gene delivery.
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