Tumor necrosis factor (
TNF)-alpha was originally identified in the 1970s as the serum mediator of innate immunity capable of inducing hemorrhagic
necrosis in
tumors. Today, a wide spectrum of
biological activities have been attributed to this molecule, and clinical translation has mainly occurred not in using it to treat
cancer, but rather to inhibit its effects to treat autoimmunity. Clinical trials utilizing systemic
TNF-alpha administration have resulted in an unacceptable level of toxicities, which blocked its development. In contrast, localized administration of
TNF-alpha in the form of isolated limb perfusion have yielded excellent results in
soft tissue sarcomas. Here we describe a novel approach to leveraging the potent
antineoplastic activities of
TNF-alpha by enhancing activity of locally produced
TNF-alpha through extracorporeal removal of soluble
TNF-alpha receptors. Specifically, it is known that cancerous tissues are infiltrated with monocytes, T cells, and other cells capable of producing
TNF-alpha. It is also known that
tumors, as well as cells in the tumor microenvironment produce soluble
TNF-alpha receptors. The authors believe that by selectively removing soluble
TNF-alpha receptors local enhancement of endogenous
TNF-alpha activity may provide for enhanced
tumor cell death without associated systemic toxicities.