Tumor necrosis factor as an antineoplastic agent: pitfalls and promises

Abstract

The discovery and cloning of the cytokine tumor necrosis factor alpha (TNF) gave rise to new hopes for a significant victory in the war against cancer. Preclinical in vitro studies in cell cultures and in vivo studies in animal models demonstrated the antitumor capacities of TNF. Although clinical studies were largely made possible by the availability of recombinant TNF, phase I and II clinical trials showed very quickly that the systemic administration of TNF induced severe side effects mainly due to its pleiotropic action on immunocompetent cells. The clinical manifestations of the side effects were similar to those observed during a severe infection and inflammation. Very recently, lessons from these clinical studies yielded refined approaches whereby the toxicity of TNF is limited through local administration, a combination with other therapeutic regimens and targeted gene therapy. These new approaches are slated for larger clinical trials and in the near future might demonstrate the limited but powerful usefulness of TNF as an antineoplastic agent for different types of cancer.

The Roles Of Academia, Rare Diseases, And Repurposing In The Development Of The Most Transformative Drugs

“…For example, for many years inhibitors of the cytokine tumor necrosis factor (TNF) were studied as antisepsis and anticancer agents, based on century-old observations that patients with bacterial infections sometimes demonstrated reductions in the size of cancerous tumors. 17 However, recurrent testing of TNF-inhibitors to treat patients with sepsis or inhibit tumor growth showed no efficacy. 18 In particular, Centocor's nebacumab (Centoxin), an anti-TNF monocolonal antibody, was approved in Europe but subsequently withdrawn after the failure of sepsis clinical trials completed to secure FDA approval.…”

Modulation of TNF-α Gene Expression by IFN-γ and Pamidronate in Murine Macrophages: Regulation by STAT1-Dependent Pathways

“…This enhancement of IFN-␥-mediated TNF-␣ production by pamidronate is the result of prolonged STAT1 phosphorylation as a result of inhibition of protein tyrosine phosphatases (PTPs). 3 Certain types of malignant tumors are sensitive to TNF-␣ (34,35), and low dose TNF-␣ enhances the cytotoxic effects of chemotherapeutic agents on tumor cells (36,37). Activation of macrophages by aminobisphosphonates might therefore be useful in cytokine-mediated cancer therapy.…”

Pegylated liposomal tumor necrosis factor‐α results in reduced toxicity and synergistic antitumor activity after systemic administration in combination with liposomal doxorubicin (Doxil®) in soft tissue sarcoma‐bearing rats

“…1 However, the systemic application of TNF is hampered by its severe toxicity. 2,3 Effective systemic treatment requires dosages 20 -50-fold higher than the maximal tolerated dose (MTD), which indicates that other modes of delivery are necessary for the treatment of systemic disease or regions that are difficult to isolate. One way of diminishing systemic toxicity, and at the same time increasing delivery of TNF to the tumor site, is the encapsulation of the cytokine in liposomes with long-circulating characteristics such as pegylated (STEALTH) liposomes.…”