ASGCT Press Release

Researchers Report Innovations in Cancer Gene Therapy

Denver, Colo (June 2, 2000) - Gene therapy researchers reported on innovative approaches to cancer treatment today at a press conference held in conjunction with the American Society of Gene Therapy's 3^rd Annual Meeting in Denver, Colo. The scientists discussed the progress that has been made in the use of viral vectors to deliver genes directly to tumors or to immune cells that then target and destroy the malignant cells.

"Gene therapy is a new biomedical discipline that is still in its infancy," commented said ASGT President, Savio L. C. Woo, PhD, Professor and Director of the Institute for Gene Therapy and Molecular Medicine at the Mount Sinai School of Medicine, NY. "In order to realize its full potential to treat a variety of diseases in the future, much basic science research and pre-clinical studies will need to be pursued to rigorously establish efficacy and safety in relevant animal models of disease. The work presented here is a promising beginning."

The following summaries of presented material reflect the most up-to-date information in cancer gene therapy research. 

"IL-18 Gene Therapy to Enhance Specific Tumor Immunity through Modulation of the Innate Immune Response"

Presenter: Hideaki Tahara, University of Tokyo, Institute of Medical Science

Immunity is an intricate and tightly regulated system of many diverse molecules and cells, and even small imbalances can have deadly consequences. Nevertheless, certain immune proteins are known to enhance aspects of the immune response. One area of great interest is how to enhance the immune response to cancer. Animal studies have shown that systemic treatment with a combination of two specific proteins, interleukin-12 and interleukin-18, can have significant anti-tumor effects, stimulating immune cells that are critical to tumor destruction. Unfortunately, this same combination has the side-effect of causing the release of deadly amounts of another immune protein, interferon gamma.

One possible way around this problem is to have the immune-stimulating proteins present only at the site of the tumor. Hideaki Tamara and his collaborators have investigated this possibility by treating mouse tumors with a viral vector carrying the gene for interleukin-18. This treatment alone resulted in eradication of tumors in one mouse model. Furthermore, antitumor activity was enhanced with a combination of local interluekin-18 and systemic interleukin-12 treatment, without the side effects seen in the systemic combination of both proteins. The researchers have discovered that this effect is largely due to the stimulation of the specific type of immune cells known as Natural Killer (NK) cells.

These studies demonstrate that interleukin-18 gene therapy of tumors, especially when combined with systemic interleukin-12 administration, may be a viable alternative cancer therapy.

Presenter: Mien-Chie Hung

Although viruses are often considered bad news, certain viral proteins appear to have beneficial properties to its host. One such virus, which is also used extensively as a vector for gene therapy, is adenovirus. An adenoviral protein known as E1A has proved to have particular and multiple anti-cancer properties. These observations have led to many clinical trials of the E1A protein to determine its ability to fight tumors such as breast, ovarian, and head and neck cancer. As Mien-Chie Hung reports, these studies have led to a greater understanding of the particular biochemical pathways that are important in the anti-tumor activities of the E1A protein. Not only will this help the continued development of E1A as an effective anticancer agent, but it also opens up other possible targets for future therapeutic developments.

"Immuno-Gene Therapy of Cancer Using the T-Body Approach
OR: Redirecting Genetically Programmed Effector Lymphocytes to Cancer Using Chimeric Receptors"
Presenter: Zelig Eshhar, Department of Immunology, The Weizmann Institute of Science

A major problem in achieving a complete cure of an advanced cancer is that the therapeutic agent fails to reach each and every diseased cell, which are disseminated throughout the body. Nevertheless, our major defense system, the immune system, is characterized by its ability to monitor, identify and eliminate foreign elements including tumor cells. The gene transfer technology provides us with means to manipulate the immune system, induce and enhance it in a specific manner so that it will selectively recognize and efficiently eliminate cancer.

One of the most effective mechanisms by which the immune system rejects infected cells, cancer and foreign tissue grafts is by specialized killer cells (also known as cytotoxic T cells and natural killer cells). In a cancer patient, these cells fail to react against the individual's own tumor, by and large, because the tumor evolved a variety of mechanisms to escape and avoid these bodyguards. Our team at the Weizmann Institute has developed a new approach to direct the patient lymphocytes to selectively recognize and kill his own tumor cells. In this approach, lymphocytes isolated from the patient's blood are manipulated to carry a special sensing apparatus (receptor) that uses predefined antibody recognition.

The major player in this approach is a chimeric receptor- a hybrid receptor composed of two functional parts, which are linked together in a single molecule. On one end, on the outside of the cell this receptor contains the part of the antibody molecule that binds antigen; on the other end, on the part of the receptor that is inside the cell, we link a subunit or a portion of the authentic T cell receptor which is capable of activating the T cell by binding to the tumor cell. We have shown previously that in the test tube and in tissue culture conditions, killer lymphocytes into which the chimeric receptor genes were introduced, can indeed redirect their specificity towards the tumor cells and eventually kill them. Various forms of such chimeric receptors designed to fit different types of tumors and cytotoxic lymphocytes have been prepared.

In order to select the best form and optimize it for clinical application a special system has been developed. In this model system, we developed a mouse model to study how patients' lymphocytes, into which the chimeric receptor genes are introduced, will respond against their own tumor.

In this meeting we report for the first time our experiments in which human lymphocytes programmed with a chimeric receptor specific to - HER2 (tumor antigen which is overexpressed on human breast, prostate, kidney and some other cancer) could slow very significantly the growth of prostate cancer in the mouse model system. We believe that these encouraging results and further studies done in our laboratory and elsewhere (including preliminary phase I clinical trials) will pave the way to the application of this new immunotherapeutic approach to cancer treatment.

"Adenovirus Therapies for Cancer: From Gene Replacement to Replicating Vectors"
Presenter: Stephen M. W. Chang, Canji, Inc. and Schering-Plough Research Institute

To evaluate the therapeutic potential of p53 - a tumor suppressor gene - for cancer, we have developed a replication-deficient recombinant human adenovirus encoding wild-type p53 (rAd-p53). Pre clinical studies confirm the p53-specific anti-tumor effects of rAd-p53, but highlight the challenges for efficient delivery to tumors in vivo. We have developed clinical strategies to maximize rAd-p53 (SCH 58500) delivery to tumors focusing on loco-regional delivery to intraperitoneal ovarian cancer and liver malignancies. Over 150 patients have been treated in Phase I clinical trials, and safe doses for ongoing investigation have been identified.

Cancer cells can also be targeted for destruction by modified adenoviruses that replicate conditionally in neoplastic cells. We have developed conditionally replicating adenovirus vectors (CRAVs) as an alternative to gene replacement therapy with non replicating vectors. Replication of CRAVS is selective for cells harboring lesions in key growth control pathways. Preclinical data from these adenovirus-based therapies will be presented together with results from ongoing clinical investigation with SCH 58500.

The American Society of Gene & Cell Therapy (ASGCT) is a professional non-profit medical and scientific organization dedicated to the understanding, development and application of genetic and cellular therapies and the promotion of professional and public education in the field. For more information on ASGCT, visit its website, www.asgct.org.

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