There is an urgent need for efficient, non-toxic biological therapies for lung cancer, particularly for advanced disease, where current therapies are often inadequate. Tumor suppressor gene therapy involving the p53 and p14ARF tumor suppressor genes is highly suppressive of lung cancer cells. However, presently available gene delivery vehicles are rejected by the immune system if they are administered through the blood stream (systemically). This is true of the widely used adenovirus (a type of cold virus) that has been modified to carry the p53 gene, and which is presently being evaluated in clinical trials. The p53 adenovirus and other current gene delivery vehicles work best for local treatment of isolated tumors, and do not adequately address the problems of disseminated, metastatic disease where systemic delivery of the genes would be required. An efficient systemic gene delivery method would enable us to fully exploit the therapeutic potential of the p53/p14ARF gene combination for early or advanced lung cancer and provide a highly effective, cancer-specific, non-toxic way to suppress all or most lung cancers.

We want to develop a systemic gene delivery strategy that uses mesenchymal stem cells. Mesenchymal stem cells are derived from the bone marrow and contribute to tissue regeneration. We have shown that they can be engineered to produce adenovirus. Because they are not rejected by the immune system and can be administered systemically, and because they migrate to tumors and preferentially integrate there, they are attractive as therapy-delivery vehicles for primary or advanced cancers. We hypothesize that these cells can be used to deliver therapeutic p53/p14ARF adenovirus to advanced lung cancer and suppress the disease.

We have already generated Mesenchymal stem cells capable of producing adenoviral particles of the type used for therapy. We have also constructed a therapeutic adenovirus that includes the p53 and p14ARF tumor suppressor genes. We will use a mouse model for lung cancer to examine the ability of Mesenchymal stem cells to migrate to lung tumors and to disseminate within the tumor. We will then test the anti-tumor activity of mesenchymal stem cells engineered to produce the p53/p14ARF adenovirus and carry it to tumors.

Mesenchymal stem cell-based delivery of the p14ARF and p53 tumor suppressor genes is a highly innovative and novel approach to gene delivery. If successful, it could establish an entirely new approach to tumor suppressor gene therapy for lung cancer and have a major impact on treatment for advanced disease. Gene-based therapeutic strategies are among the most specific and potentially most effective and least toxic ways to treat cancer. A cell-based strategy for targeting therapeutic tumor suppressor genes to lung tumors, addresses the need for highly effective, minimally toxic treatments, that preserve quality of life while providing for long-term survival.