The following are brief overviews of select ongoing research projects in the Gene and Virus Therapy Program:
Hepatocellular carcinoma virotherapy
The incidence of hepatocellular carcinoma (HCC) has risen by 75 percent in the United States in the past 20 years. Even if detected early, only ten to twenty percent of those with this form of cancer survive five years, partly due to the difficulty of early diagnosis -- less than one percent of patients with HCC are treated with radical, potentially curative treatments such as liver transplantation or surgical resection. Stephen Russell, M.D., Ph.D., and his Cancer Center colleagues are currently developing a new program that will enlist the cooperation of researchers on all three Mayo campuses in Phoenix/Scottsdale, Ariz., Jacksonville, Fla., and Rochester, Minn. The program looks at patients who are not viable candidates for liver transplantation or surgical resection and could offer them a new option through a treatment which injects vesicular stomatitis virus interferon clinical grade directly into the tumor site. This vector (substance which seeks to bind to a specific cell type), derived by engineering a virus obtained originally from domestic cattle, indicates great promise for treatment of liver cancer as well as for head and neck cancers. The implications it offers to the future of cancer and cancer treatment are profound.
Radioiodine imaging and therapy after NIS gene transfer
John Morris III, M.D., is an endocrinologist and clinician-scientist working on gene therapy for cancer, with a particular focus on prostate cancer. Dr. Morris' work focuses on the protein product of a gene called the sodium iodide symporter (NIS). The NIS protein product from the thyroid gland is responsible for uptake of iodine, which is required for normal function of the thyroid. That same protein attracts radiolabeled iodine when it is being used to treat thyroid cancer. Dr. Morris has taken that gene and put it into an adenoviral vector - a common cold virus.
He originally tested the gene therapy in mice with prostate cancer tumors and breast cancer tumors. The vector was injected into the tumor to deliver this specific gene. Treated mice were then administered a harmless form of radioactive iodine, and the radioactivity (and the tumor) were followed by images from a gamma camera that specifically "sees" radioactivity in the mice. The mice were next given a very potent form of radioactive iodine that was taken up by the tumors thereby delivering a large dose of therapeutic radiation, which led to significant shrinkage of these tumors. Based on these encouraging animal studies, Dr. Morris is now studying patients who have relapsed prostate cancer by non-invasively monitoring the expression of the NIS gene by whole body gamma camera imaging after the therapy has been administered.
In all other gene therapy studies for cancer, there is no way to clearly define the outcome of the gene therapy, especially early after treatment. Because of the versatility of the NIS gene to allow noninvasive monitoring and radioiodine therapy of cancer, the NIS gene is being introduced into different cancer gene therapy vectors. For example, Roberto Cattaneo, Ph.D., and Dr. Russell have collaborated with Dr. Morris to generate a replicating measles virus containing the NIS gene. The spread of this virus can be followed non-invasively by gamma camera imaging and there are already plans to test the agent in patients with multiple myeloma.
Making novel cancer vaccines
Richard Vile, Ph.D., is interested in harnessing the immune system to fight cancer. He previously made the important discovery that the way in which cancer cells are killed makes a big difference to how the immune system responds to them. This observation helped to shape his thinking about cancer vaccines and took his research in unexpected, but fruitful directions. When cancer cells die, their remnants are taken up and "processed" by scavenger dendritic cells that then orchestrate the anticancer immune response.
The key to Dr. Vile's original observation was that dendritic cells pick up and process tumor cell remnants more or less efficiently depending on the mode of cell death. So he developed a strategy whereby the efficiency of this dendritic cell feeding process could be maximized - by fusing the dendritic cells with entire intact tumor cells. Now Dr. Vile is using another highly original genetic approach to cancer vaccination that he devised. Since cancers are derived from normal tissues, he attempted to attack the cancer by provoking the immune system to attack the normal tissue from which the cancer was derived.
For this to be a viable approach the normal tissue would have to be 'dispensable' - so his studies focus on malignant melanoma, which is derived from melanocytes, the pigment producing cells in the skin. To kill normal melanocytes, he delivered a 'suicide' gene into the normal skin of mice with melanoma. A drug is then administered to selectively kill the genetically modified melanocytes in a way that would lead to efficient transfer of melanocyte remnants into dendritic cells, and growth of the melanoma tumors was monitored. Tumor growth was delayed in the treated mice and in some cases complete regression of established tumors was observed providing a dramatic validation of this novel concept. He is now working to clinically translate this approach.
Yasuhiro Ikeda, Ph.D., has been studying cellular factors, TRIMM5 alpha and APOBEC3G, which are known to inhibit the replication of HIV and is applying this information to the development of vectors that can give more efficient transduction and higher level expression in human cells.
Mark Federspiel, Ph.D., is studying the mechanisms whereby retroviruses enter cells, focusing particularly on the avian leucosis virus system. Michael Barry, Ph.D., has been conducting basic studies of the relationship between adenovirus entry and its structure. Dr. Cattaneo is studying the interactions of measles virus and canine distemper virus with the host immune system. He is also studying the measles proteins, C, V, and P, which combat innate immunity and has identified a mutation in the P-protein that abrogates the ability of the virus to block STAT1 protein phosphorylation. Lastly Greg Poland, Ph.D., is studying the relationship between human leukocyte antigen haplotypes and the genetic control of immune responses to measles viruses, showing quite significant differences in antiviral cytokine responses dependent upon the specific HLA haplotypes expressions.
Advancing the technology base from which novel gene-based therapies are created
Drs. Barry and Morris also work with adenoviral vectors. Dr. Morris has been generating new transcriptionally targeted adenoviruses expressing the NIS transgene, whereas Dr. Barry has been generating adenoviral vectors displaying various cell targeting peptide ligands on their surfaces and has been exploring the use of polymer shielding to protect adenoviruses from host immune responses. He has been using near infrared fluorescent imaging to determine the biodistribution of these retargeted adenoviruses in vivo. Kah Whye Peng, Ph.D., and Evanthia Galanis, M.D., along with Drs. Russell, Federspiel, and Cattaneo continue to advance the technology based for oncolytic measles virotherapy. A number of targeted measles viruses have been generated.
In addition, Drs. Vile and Russell are studying the therapeutic properties of oncolytic vesicular stomatitis viruses and have established strong collaborations with the colleagues in other institutions. Stephanie Carlson, M.D., along with Drs. Morris, Russell, and Peng continue to collaborate to incorporate non-invasive imaging technologies into all aspects of the gene therapy program and oncolytic virus therapy research.
Improving the outcome of cancer therapy by developing clinical testing of novel gene-based therapies
Work in this area can be divided into those projects that demonstrate proof of efficacy in pre-clinical cancer models and those that are truly translational and which involve the clinical testing of novel genetically based therapies. Dr. Morris is collaborating with Sandra Gendler, Ph.D., to demonstrate that transcriptionally targeted adenoviruses coding for the NIS gene show promising activity in pre-clinical models of pancreatic and breast cancer.
In other efforts, Dr. Vile has continued to work with pre-clinical models of melanoma, colorectal, prostate, and pancreatic cancer in immunocompetent mice, focusing on a number of different strategies whereby the host immune response to the tumor can be enhanced to mediate tumor regression. He is also working with fusigenic membrane glycoproteins to generate tumor cell-dendritic cell hybrids, which behave as potent tumor vaccines. Dr. Vile's research team has refined their approach to bring about the inflammatory killing of normal melanocytes, prostate cells or pancreatic cells using plasmids or adenoviruses coding for HSP70 and CD40 ligand. This has confirmed previous observations that the killing of normal cells can stimulate a strong immune response against tumor cells derived from the same tissue.
Dr. Russell continues to collaborate with Drs. Galanis, Peng, and Cattaneo to develop strategies for more efficient systemic delivery of oncolytic measles virus to tumor deposits, either by targeting them to specific locations in the body or by delivering them inside cells which protect them from antibody mediated destruction.
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