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...
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Chapter 065. Gene Therapy in Clinical Medicine (Part 4) Chapter 065. Gene Therapy in Clinical Medicine (Part 4) Another local approach uses adenoviral-mediated expression of the tumorsuppressor p53, which is mutated in a wide variety of cancers. This strategy hasshown complete and partial responses in squamous cell carcinoma of the head andneck, esophageal cancer, and non-small cell lung cancer after direct intratumoralinjection of the vector. Response rates (~15%) are comparable to those of othersingle agents. The use of oncolytic viruses that selectively replicate in tumor cellsbut not in normal cells has also shown promise in squamous cell carcinoma of thehead and neck and in other solid tumors. This approach is based on theobservation that deletion of certain viral genes abolishes their ability to replicate innormal cells but not in tumor cells. An advantage of this strategy is that thereplicating vector can proliferate and spread within the tumor, facilitating eventualtumor clearance. However, physical limitations to viral spread, including fibrosis,intermixed normal cells, basement membranes, and necrotic areas within thetumor, may reduce clinical efficacy. Oncolytic viruses are licensed and availablein some countries, but not in the United States. Because metastatic disease rather than uncontrolled growth of the primarytumor is the source of mortality for most cancers, there has been considerableinterest in developing systemic gene therapy approaches. One strategy has been topromote more efficient recognition of tumor cells by the immune system.Approaches have included transduction of tumor cells with immune-enhancinggenes encoding cytokines, chemokines, or co-stimulatory molecules. Sustainedclinical responses provide evidence that the transduced cells can act as a vaccine.In a related approach, patient lymphocytes have been transduced with genesencoding a T cell receptor–like molecule, with a tumor antigen–binding domainfused to an intracellular signaling domain to allow T cell activation, therebyconverting normal lymphocytes into cells capable of recognizing and destroyingtumor cells. A third immunotherapy approach relies on ex vivo manipulation ofdendritic cells to enhance the presentation of tumor antigens. These immunologicapproaches may be of particular value in treating minimal residual disease afterother anticancer modalities. Gene transfer strategies have also been developed for inhibiting tumorangiogenesis. These have included constitutive expression of angiogenesisinhibitors such as angiostatin and endostatin; use of siRNA to reduce levels ofVEGF or VEGF receptor; and combined approaches in which autologous T cellsare genetically modified to recognize antigens specific to tumor vasculature. Thesestudies are still in early-phase testing. Another novel systemic approach is the use of gene transfer to protectnormal cells from the toxicities of chemotherapy. The most extensively studied ofthese approaches has been transduction of hematopoietic cells with genesencoding resistance to chemotherapeutic agents, including the multidrug resistancegene MDRI or the gene encoding O6-methylguanine DNA methyltransferase(MGMT). Ex vivo transduction of hematopoietic cells, followed by autologoustransplantation, is being investigated as a strategy for allowing administration ofhigher doses of chemotherapy than would otherwise be tolerated. Gene Therapy for Vascular Disease The third major category addressed by gene transfer studies iscardiovascular disease. The most extensive experience has been in trials designedto increase blood flow to either skeletal (critical limb ischemia) or cardiac muscle(angina/myocardial ischemia). Initial treatment options for both of these groupsinclude mechanical revascularization or medical management, but a subset ofpatients are not candidates for, or fail, these approaches. These patients haveformed the first cohorts for evaluation of gene transfer to achieve therapeuticangiogenesis. The major transgene used has been VEGF, attractive because of itsspecificity for endothelial cells; other transgenes have included fibroblast growthfactor (FGF) and hypoxia-inducible factor 1, αsubunit (HIF-1α). The design ofmost of the trials has included direct IM (or myocardial) injection of either aplasmid or an adenoviral vector expressing the transgene. Both of these vectors arelikely to result in only short-term expression of VEGF. This strategy may beadequate, however, as there is no need for continued transgene expression once thenew vessels have formed. Direct injection favors local expression, which shouldhelp to avoid systemic effects such as retinal neovascularization or new vesselformation in a nascent tumor. ...