In recent years the investigators have studied the immune responses and developed vaccines against virus-induced tumors. Especially human papilloma virus type 16 related to cervical cancer has been the focus of their attention. In order to design a peptide based therapeutic vaccine for human use, they have developed two important mouse tumor models namely human papilloma virus type 16 plus activated ras induced tumors and human adenovirus plus activated ras induced tumors. Despite successes in prevention of tumor outgrowth through vaccination in these tumor models, only very limited success was obtained in therapeutic use of these vaccines. Several hurdles like immune suppression and immune escape in these tumor models stood or could stand in the way of therapeutic results. These potential hurdles are: 1) Activated ras induced immune suppression and immune escape, 2) Local radiation or certain chemotherapy induced immune suppression and surprisingly, 3) Vaccine induced immune suppression. In order to characterize and overcome these hurdles, they will address the following aims: 1) Analysis and development of methods to antagonize activated ras induced immune suppression and immune escape, 2) Analysis of the effects of clinically relevant local radiation and certain chemotherapies on the potency of therapeutic vaccines in these virus-induced tumor models in aging mice and, 3) Analysis and development of methods to antagonize peptide based vaccine induced immune suppression. To achieve these aims the following methodology will be used: 1a) Neutralizing TGFb induced by the activated ras oncogene, 1b) Blocking activated ras with farnesyl protein transferase inhibitors, as well as 1c) Defining a general antigen processing blocking effect by activated ras, and 1d) Characterizing other immune escape mechanisms induced in activated ras express cells. 2) Measuring the effects of local irradiation or certain chemotherapies on the potency of therapeutic vaccines to induce T cell responses in aging mice. 3A) Characterizing the immune suppression frequently induced by peptide based cancer vaccines through analyzing the pharmacokinetics of the vaccine components and, 3b) Converting immuno-suppressive peptide based cancer vaccines into immunizing vaccines by alternative delivery systems. This combined analysis will shed light on the immune suppression and immune escape mechanisms in the virus induced cancer models and on ways of counteracting them. Such mechanisms could also play a role in other clinically, relevant tumors. Therefore, the results could have direct implications on the design and execution of ongoing and future therapeutic cancer vaccine trials.
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