Bartlett

Dr. Bartlett has continued his research on the AAV virus in creating vectors for use in gene therapy. His work in developing these vectors provides promising opportunities for the future of ovarian cancer and other cancer treatment as an alternative method of delivering specific genetic information to cancer cells. Dr. Bartlett has also been working on engineering a resistance to the HIV-1 infection through the use of gene therapy.  

He and a team of researchers have developed and studied an anti-HIV lentiviral vector capable of generating cellular resistance to multiple strains of HIV in two different ways. Many animals treated with the vector-modified cells had no detection of the HIV virus in the bloodstream, whereas it was easily detected in the control group not treated with the cells. Dr. Bartlett’s research on vectors is likely to progress the field of gene therapy treatment for both cancer, HIV, and potentially other diseases as well. 

Ovarian cancer is one of the most common and frequently life-threatening malignancies affecting women in the U.S. today: about 25,000 new cases will be diagnosed with the disease this year and over 15,000 women will die from it. Delivering therapeutic genes efficiently and precisely, so that they reach only the targeted cancer cells, is crucial to success. My group has developed a means of delivering therapeutic genes to a specific population of cells in laboratory experiments.  

By rearranging the genetic structure of AAV, a common human virus, we have created a class of molecular Trojan horse viruses, known as vectors, from the Latin “to carry”. These vectors are aimed at ovarian cancer cells via key sequences in the virus shell that allows it to infect only cells in the body displaying a particular marker that is restricted to cancer cells. We are now testing the Trojan horse system’s ability to cure ovarian cancer in laboratory animals. If these studies are successful, this research will help pave the way for clinical trials in women with ovarian cancer and may lead to a new approach to this deadly disease. 

Griffith

Dr. Griffith’s research has moved on in looking at the application of the TRAIL gene and other T-cell therapies in treating all types of cancer, not just prostate cancer. His lab has developed a method of inducing tumor cell death through the administration of full-length TRAIL cDNA (called Ad-TRAIL) into cells using non-replicative adenoviral vectors. Incorporating this vector into tumor cells induces apoptosis, or cell death.  

This research seems to be making some promising strides and an extremely beneficial finding has been that the use of TRAIL is nontoxic against normal cells and tissues unlike other similar genes that have been employed in the same way. Dr. Griffith and his lab plan to continue their work with the TRAIL gene as well as investigating how apoptotic (dying) cells can have an impact on the immune response. 

Prostate Cancer is the second leading cause of cancer death among men in the United States. We are studying and testing a new means of inhibiting the formation of prostate tumors, using an agent called TRAIL to induce the death of tumor cells. The TRAIL gene is transferred into a cell with Ad5-TRAIL, a genetically engineered virus known as a viral vector. The vector used the cell’s own machinery to produce the TRAIL protein and induce tumor cell death. Studies with laboratory animals have shown that this form of gene therapy results in the death of tumor cells.  

My lab is currently studying Ad5-TRAIL’s ability to activate the immune system’s anti-tumor responses. Tumor cells can deceive the body’s immune system into perceiving them as normal cells rather than foreign invaders but introducing genes into a tumor can counteract this. Determining the effect of Ad5-Trail-induced apoptosis (programmed cell death) on the activation of the immune system in patients with localized prostate cancer is the next step in this ongoing research and is anticipated to begin this year. The goal is to use this type of gene therapy to achieve tumor rejection, and tumor-free survival for the patients.

Davidoff

Brain tumors are among the leading causes of cancer-related death in both adults and children, with malignant gliomas being one of the most aggressive and difficult to treat. Clearly, new strategies for treating patients with this disease are desperately needed. Type I interferons (IFN) have potent, pleiotropic anti-tumor activity. Despite exciting pre-clinical results, however, the anti-tumor efficacy of IFN in clinical trials has been limited.  

Important contributing factors have included a very short half-life, making effective dosing problematic, and significant systemic toxicity at therapeutic doses. We hypothesize that an alternative method and schedule of drug administration in which there is continuous, local delivery should avoid the systemic toxicity of IFN while maximizing its potent anti-tumor activities.  

We believe that a gene therapy approach in which adeno-associated virus (AAV) vectors are used to transfer an expression cassette for IFN-B to target cells is the safest and most effective way to establish continuous, local delivery of IFN. Because GBM, unlike most human cancers, is problematic locally, rarely being metastatic, it is a tumor particularly well suited for this approach. The overriding goal is to obtain sufficient preclinical safety and efficacy data to support and initiate a clinical trial of local AAV IFN-B mediated gene transfer for patients with recurrent malignant glioma. 

 The major specific aims are: Aim 1: To complete the demonstration of anti-tumor synergy between AAV-mediated local delivery of IFN-B and adjuvant cytotoxic therapy, in relevant brain tumor models. Aim 2: To assess the safety of AAV-mediated continuous local delivery of IFN-B in the brain using relevant rodent and nonhuman primate models. Aim 3: To perform a Phase I dose-escalating clinical trial of local administration of AAV IFN-B to the resection bed in patients with recurrent glioblastoma multiforme following surgical removal of recurrent disease. 

 We feel that our approach has a high likelihood of resulting in a successful clinical trial for the following reasons: 

 1. Pre-clinical data. We have very encouraging pre-clinical data using a highly relevant orthotopic rat resection model that AAV-IFN-B has significant anti-tumor activity against residual human GBM xenografts.  

2. GMP vector production facility. We have our own GMP facility on campus to make clinical grade AAV vectors. In addition, we have developed a baculovirus-mediated production system that generates AAV at very high titer. 

 3. Toxicity studies. We have access to nonhuman primates on campus to perform relevant, pre-clinical toxicity studies. 

 4. Experience with gene transfer clinical trials. We have just opened a clinical trial of AAV-mediated, liver-targeted gene transfer for hemophilia B.  

5. Access to patients. Through our collaboration with the Neurosurgery Department at the University of Tennessee Health Science Center, Memphis, we have access to a large number of patients.