ANTITUMOR RESPONSE TO RECOMBINANT MURINE INTERFERON-GAMMA CORRELATES WITH ENHANCED IMMUNE FUNCTION OF ORGAN-ASSOCIATED, BUT NOT RECIRCULATING CYTOLYTIC T-LYMPHOCYTES AND MACROPHAGES

The mechanism of therapeutic activity for recombinant murine interfero n-gamma (rMu IFNgamma) in the treatment of metastatic disease was inve stigated by comparing effector cell augmentation with therapeutic acti vity in mice bearing experimental lung metastases (B16-BL6 melanoma). Effector cell functions in spleen, peripheral blood, and lung (the tum or-bearing organ) were tested after 1 week and 3 weeks of rMu IFNgamma administration (i. v. three times per week). Natural killer (NK), lym phokine-activated killer (LAK), cytolytic T lymphocyte (CTL) activitie s against specific and nonspecific targets, and macrophage tumoristati c activity were measured. rMu IFNgamma demonstrated immunomodulatory a ctivity in most assays of immune function. The optimal therapeutic pro tocol of rMu IFNgamma (2.5 x 10(6) U/kg, three times per week) prolong ed survival and decreased the number of pulmonary metastatic foci. Thi s therapeutic activity was correlated with specific CTL activity from pulmonary parenchymal mononuclear cells (PPMC), but not from spleen or blood. Macrophage tumoristatic activity in PPMC also correlated with therapeutic activity, but activity in alveolar macrophages did not. Ho wever, therapeutic activity did not correlate with NK or LAK activity at any site. These results demonstrate that the optimal therapeutic pr otocol is the same as the optimal immunomodulatory dose for pulmonary CTL and macrophage activities. Furthermore, while immunological monito ring may help to optimize treatment protocols, current monitoring proc edures that use readily accessible sites, particularly peripheral bloo d, may not accurately predict the therapeutic efficacy of biological r esponse modifiers in clinical trials.