Tumor necrosis factor-alpha antitumor and immunomodulatory effects

In the first part of this thesis we examined the possibilities of using the cytokine tumor necrosis factor-alpha (TNFcx) for the latter aproach. Although multiple studies have been performed regarding the antitumor action of TNFcx, it is still not clear whether TNFcx has sufficient potential to be used as immunotherapeutic agent in vivo. In this part of this thesis an answer to this important question is given Whereas cancer immunotherapy might benefit from immunostimulation with cytokines such as TNFa, immunosuppression through the inhibition of the release or activities of cytokines might be to the advantage of recipients of organ grafts. Rejection of a donor organ by a recipient is known to be an immunological process in which various cells of the immune system work together. Immune cells recognize the graft, either directly or indirectly, as being "non-self', and according to their task, they generate an immune response to rid the recipient of the "non-self' graft. Cytokines play a crucial role in this proces. Inhibition of cytokine production via cyclosporin-A delays or prevents graft rejection. The role of the cytokine interleukin-2 has been well established in this proces. Less attention has been paid to the involvement of TNFa. Maury and Teppo (1987) demonstrated that TNFa is present in the serum of patients with rejecting kidney grafts. This, however, did not prove that TNFa is actually involved in the process of graft rejection. Therefore experiments were performed in rats to assess the significance of TNFa

Injection of recombinant tumor necrosis factor directly into liver metastases: an experimental and clinical approach

__Abstract__ Systemic treatment with tumor necrosis factor (TNF) is associated with side-effects, limiting its clinical use in the treatment of malignancies. To investigate the feasibility of other routes of administration experimental and clinical studies were started to establish the toxicity and antitumor activity of TNF after intratumoral (i.t.) injection. In a rat model for colon adenocarcinoma, tumor fragments, implanted subcutaneously or under the hepatic capsule, were treated with TNF injected i.v. or i.t. A dosage of 40 μg/kg was lethal when given i.v., but not i.t. Injection of TNF (40 μg/kg) directly into the tumor resulted in inhibition of tumor growth in the subcutaneous as well as subhepatic tumor model. A phase I study was started in patient