REGIONAL ADMINISTRATION OF RECOMBINANT TUMOR-NECROSIS-FACTOR-ALPHA INCANCER, WITH SPECIAL REFERENCE TO MELANOMA

Recombinant tumour necrosis factor-alpha (rTNF alpha) possesses the un ique property of activating and selectively destroying the tumour-asso ciated microvasculature. Systemic application of rTNF alpha has shown that the maximum tolerated dose (MTD) is 10 times lower than the effic ient dose in animals. The main toxicity corresponds to the systemic in flammatory response syndrome (SIRS), with a decrease of vascular resis tance and hypotension. We found that it is possible to administer rTNF alpha at 10 times the MTD in an isolated limb perfusion system, using a heart-lung machine, for advanced melanoma and sarcoma of the limbs. Our results, using the combination of high dose rTNF alpha, interfero n-gamma and melphalan (TIM), produced an overall objective response ra te of 100% in 2 successive studies on melanoma, with 90% and 78% compl ete response, respectively. In sarcoma, there was an overall response rate of 64%, with 36% complete response. Angiographic and immunohistol ogical studies demonstrated selective and early damage of the tumour-a ssociated microvasculature, preceded by upregulation of adhesion molec ules and intratumoural leak of von Willebrand factor. Tumour invasion by platelets and, in some cases, by polymorphonuclear cells, appeared within hours after the application of rTNF alpha, long before the lysi s of the tumour. Systemic changes after rTNF alpha treatment included the production of soluble TNF alpha receptors and of interleukin-6. A typical acute phase reaction was observed within 3 days, with increase of C-reactive protein parallelled by an increase of tenascin-C. A sel ective effect on intratumoural endothelial cells seems to be involved in the mechanism of the impressive antitumour effect of rTNF alpha, bu t the rule of acute phase protein production is not fully understood. In selected cases of melanoma, specific cytotoxic T lymphocytes were i ncreased after perfusion.