Another local approach uses adenoviral-mediated expression of the tumor suppressor p53, which is mutated in a wide variety of cancers. This strategy has shown complete and partial responses in squamous cell carcinoma of the head and neck, esophageal cancer, and non-small cell lung cancer after direct intratumoral injection of the vector. Response rates (~15%) are comparable to those of other single agents. The use of oncolytic viruses that selectively replicate in tumor cells but not in normal cells has also shown promise in squamous cell carcinoma of the head and neck and in other solid tumors. This approach is. | Chapter 065. Gene Therapy in Clinical Medicine Part 4 Another local approach uses adenoviral-mediated expression of the tumor suppressor p53 which is mutated in a wide variety of cancers. This strategy has shown complete and partial responses in squamous cell carcinoma of the head and neck esophageal cancer and non-small cell lung cancer after direct intratumoral injection of the vector. Response rates 15 are comparable to those of other single agents. The use of oncolytic viruses that selectively replicate in tumor cells but not in normal cells has also shown promise in squamous cell carcinoma of the head and neck and in other solid tumors. This approach is based on the observation that deletion of certain viral genes abolishes their ability to replicate in normal cells but not in tumor cells. An advantage of this strategy is that the replicating vector can proliferate and spread within the tumor facilitating eventual tumor clearance. However physical limitations to viral spread including fibrosis intermixed normal cells basement membranes and necrotic areas within the tumor may reduce clinical efficacy. Oncolytic viruses are licensed and available in some countries but not in the United States. Because metastatic disease rather than uncontrolled growth of the primary tumor is the source of mortality for most cancers there has been considerable interest in developing systemic gene therapy approaches. One strategy has been to promote more efficient recognition of tumor cells by the immune system. Approaches have included transduction of tumor cells with immune-enhancing genes encoding cytokines chemokines or co-stimulatory molecules. Sustained clinical responses provide evidence that the transduced cells can act as a vaccine. In a related approach patient lymphocytes have been transduced with genes encoding a T cell receptor-like molecule with a tumor antigen-binding domain fused to an intracellular signaling domain to allow T cell activation thereby converting .
