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Altered Genes Used To Deliver Antitumor Cytokine Therapy

Altered Genes Used To Deliver Antitumor Cytokine Therapy

MONTREAL-Altering genes to express therapeutic cytokines may represent an improved approach to direct delivery of these increasingly utilized recombinant proteins, Michael T. Lotze, MD, said during a plenary session at the 19th International Congress of Chemotherapy (ICC).

Although cytokines will be among the most useful agents for clinical treatment of a multitude of infectious diseases and malignancies in the future, he predicted, many of these products are currently associated with considerable toxicities.

Dr. Lotze and his colleagues in the Department of Surgery, University of Pittsburgh Medical Center, are exploring techniques by which genes that control expression of appropriate proteins may be introduced into cells. It is hoped that antitumor cytokines, for example, expressed by cells with altered genes, will exert their effects with reduced toxicity.

According to Dr. Lotze, T-cell growth factors may be thought of as either "growth factors" (ie, IL-2) or "die factors" (antiapoptosis factors, ie, IL-10, IL-12, interferon-gamma). And while different cytokines sometimes share common receptors, intracellular signaling may be quite distinct.

Some cytokines, such as IL-10, are considered to have immunosuppressive properties, while others enhance cellular reactivity. Many cytokines can have both immunosuppressive and immunostimu-lating properties, depending on how the proteins are generated, he said.

In their own preclinical studies, Dr. Lotze and his colleagues observed that IL-4 promoted cellular activity. The
combination of IL-1 plus IL-4 had excellent antitumor activity; and despite toxicity (capillary leak syndrome), the combination of IL-2 plus IL-4 was also active against tumors.

Based on these findings, Dr. Lotze and his colleagues developed a cancer vaccine protocol using IL-4 transfected autologous fibroblasts. A total of 18 patients were treated with high levels of IL-4, delivered into the skin of patients' backs via transfected fibroblasts.

Interim findings of the study include expression of message for up to 7 days, induction of VCAM and E-selectin on dermal epithelium, generation of tumor-specific CD4+ cells in patients with melanoma, profound lymphocytic infiltration, and correlation of VCAM expression with S100+ dendritic cell infiltration, Dr. Lotze said.

He also described a new protocol involving IL-12 delivered with retroviral vectors that was designed to administer high doses without the severe toxicities associated with direct IL-12 treatment. Studies of IL-12 have demonstrated enhanced tumor immunogenicity, delayed tumor progression, and increased survival in animals.

Gene Transport Systems

Viral vectors have been widely used over the past few years to transport genes in gene therapy protocols. "Over millions of years," Dr. Michael Lotze said in his talk at the ICC (see story above), "microbes have waged war on the human immune system. Somewhere along the line, they learned how to get in."

Many viruses have the ability, for example, to subvert interferon functions or downstream events, he said. Ironically, researchers are now trying to harness these microbes, using them to penetrate and ultimately enhance the human immune system.

Nonviral methods for transferring genetic information into cells include liposomal delivery, intramuscular injection of naked DNA, and "bioballistic," or gene-gun, devices, which shoot tiny gold beads containing genetic material into a target.

 
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