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Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003.
Holland-Frei Cancer Medicine. 6th edition.
Show detailsBiology and Preclinical Rationale
A nonglycosylated, 17-kDa polypeptide, TNF-α, is expressed in both secreted and membrane-bound forms, with the secreted form circulating as a homotrimer. TNF binds to either of two distinct cell surface receptors of 55- and 75-kDa molecular weight, respectively; these different receptor forms are independently expressed on different cell types.86 The lack of homology between the intracellular domains of these two receptor proteins suggests that they may subserve distinct cellular responses.87 Some information exists concerning these differential functions, particularly for the p55 receptor, which is important in the mediation of TNF-induced cytolytic activity, antiviral activity, IL-6 induction, and other biologic effects. A distinct role of the p75 receptor beyond facilitating the binding of TNF to p55, was less clear until the recent observation that p75 is critical to the inflammatory skin reaction noted with TNF-α.
A second cytokine, termed TNF-β, or lymphotoxin, is produced by a distinct gene closely linked within the MHC complex on the short arm of chromosome 6; a 28% amino acid homology exists between the two cytokines.88 While activated monocytes and macrophages represent a major cellular source of TNF-α, it is also produced by activated T and NK cells and by a wide variety of other cells. IL-4 is a potent downregulator of TNF production, similar to its effects on the production of interferon-γ and IL-6.89
Tumor necrosis factor has direct, in vitro antitumor cytotoxicity on 30% to 50% of tumor cell lines, and it has been demonstrated to be active in vivo against both murine tumors and human tumor xenografts, particularly when they have reached a size of at least 5 mm in diameter.90–93 Which of the pleiotropic biologic activities of TNF contributes primarily antitumor effects is unclear. Subcutaneous tumors undergo hemorrhagic necrosis after TNF administration, which suggests that interference with tumor neovasculature is important. Indeed, TNF affects endothelial cells directly, resulting in the appearance on the tumor vessel endothelial cell surface of procoagulant activity and leading to fibrin formation, leukocyte infiltration, defective perfusion, and hemorrhagic necrosis.
Considerable rationale exists for the use of TNF with chemotherapy. In vitro, enhanced cell killing is noted when TNF is combined with chemotherapeutic agents that inhibit DNA topoisomerases I and II, including agents such as doxorubicin, teniposide, etoposide, and actinomycin D.94,95 The apparent mechanism involves TNF-mediated increases in DNA strand breakage. This enhanced effect also was observed in preclinical in vivo models, where enhanced antitumor activity was observed when TNF was combined with doxorubicin or etoposide.96,97
Clinical Applications
Systemic Therapy
Based on the preclinical information described earlier, a series of Phase I and Phase II clinical trials were performed involving the systemic administration of TNF-α, and, as recently reviewed,98 results indicate that severe toxicity was a result of pleiotropic effects on immunocompetent cells. The maximum tolerated dose (MTD) of bolus TNF in patients has consistently been in the range of 200 to 400 mg/m2, five- to tenfold lower than the doses achievable in rodents that were active against tumors. The single-dose MTD was quite similar regardless of whether TNF was administered as a single dose, three times weekly, or 5 days a week. Shortly after TNF infusion, rigors, hypertension, and tachycardia develop, followed within 1 to 2 h by fever and several hours later by hypotension. The dose-limiting toxicity consistently has been hypotension, which responds to therapy with fluid and vasopressors, although patients also develop a variety of constitutional symptoms. In studies where continuous infusion TNF has been administered, side effects of reversible thrombocytopenia, leukopenia, and hepatotoxicity, in addition to constitutional symptoms, including fatigue, malaise, diarrhea, headache, and confusion, have been observed. Minimal antitumor activity was observed in patients who were treated with systemically administered TNF, either in the Phase I studies or in a series of Phase II trials performed across the spectrum of common solid tumors, including renal cell carcinoma, melanoma, sarcomas, and adenocarcinomas of the colon, stomach, and pancreas. Phase I clinical trials involving TNF in combination with either chemotherapeutic agents or other biologic agents have also been conducted. Several clinical trials of TNF combined with IL-2 have been conducted based on compelling preclinical evidence for synergy, particularly when TNF was administered before IL-2.99,100 These trials show no evidence for an increased clinical benefit to the combination, but do show evidence for an increased toxicity when TNF is administered either together with or following IL-2, which is not surprising given that IL-2 is a powerful inducer of TNF in patients.8,9,11,101 Similarly, despite some preclinical data suggesting an interaction, no apparent clinical benefit, or increased immunologic stimulation has been observed in clinical trials of TNF and combined with interferon-γ.61,91,102,103 To date, results with TNF used together with chemotherapy have been disappointing given the impressive evidence from in vitro and animal studies. Myelosuppression was dose-limiting when using a combination of TNF and etoposide.104 In a randomized, Phase II trial of carmustine (BCNU) administered either alone or with TNF, no apparent benefit, but increased toxicity, was observed with the combination.105 As noted later in the section “Regional Perfusion Therapy”, the development of isolation-perfusion limb therapy with TNF has allowed exploration of therapeutic activity of levels of the cytokine similar to those that are achievable in preclinical models.106
Regional Perfusion Therapy
The paradox between the remarkable antitumor activity of high-dose TNF in animal systems and its lack of clinical utility when administered systemically at tolerable doses in humans has led to extensive clinical study of TNF administered locoregionally.106–110 TNF has been administered intratumorally, intraperitoneally, and by intravesical or intraarterial infusion. The most interesting and clinically beneficial results, however, have followed isolated limb perfusion of TNF together with melphalan, interferon-γ, and hyperthermia in patients with regionally recurrent melanoma or primary limb sarcomas. This strategy allows the achievement of high peak TNF concentrations, while greatly limiting systemic exposure. One complete response was noted among three patients treated using isolated limb perfusion with TNF alone111; all other patients have been treated with one or another variant of the biologic-chemotherapeutic combination therapy. The origin of the combination infusion approach with melphalan, interferon-γ, and hyperthermia was the demonstrated synergy between TNF and each of these agents or modalities.91,112 Systemic leakage is monitored continuously during the perfusion procedure by using radioactive serum albumin and a gamma detector placed above the heart.113 Clinical results using this approach are dramatic, with objective response rates of 100% in patients with regional extremity melanoma metastases and complete response rates in several studies exceeding 70%. Systemic toxicities are minimal, with hypotension managed by fluid supplement and administration of vasoactive amines. Regional toxicities appear to be similar to those observed with hyperthermic melphalan perfusion alone. Responses appear to be durable, and although this locoregional approach in melanoma is unlikely to affect median survival, the palliative effects can be significant in individual patients. Angiographic and immunohistologic studies show rapid elimination of tumor hypervascularization and endothelial cell destruction, suggesting that the interruption of tumor blood supply is an important mechanism of this approach, which is consistent with the biologic properties of TNF.114
- Tumor Necrosis Factor-α - Holland-Frei Cancer MedicineTumor Necrosis Factor-α - Holland-Frei Cancer Medicine
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