PHASE-I TRIAL OF ADOPTIVE IMMUNOTHERAPY OF CANCER-PATIENTS USING MONOCYTE-DERIVED MACROPHAGES ACTIVATED WITH INTERFERON-GAMMA AND LIPOPOLYSACCHARIDE

Cells of the monocyte/macrophage lineage have shown antitumor activity in vitro and in murine models after activation with interferon (IFN) gamma. In vitro data suggest an additional effect on macrophage antitu mor activity when IFN gamma is combined with endotoxin (lipopolysaccha rides; LPS). In this study we treated nine cancer patients with a tota l of 62 MAK infusion cycles with autologous macrophages given intraven ously (i.v.) after in vitro activation with IFN gamma and LPS. Low-gra de fever (WHO I/II) was the commonest side-effect. Chills, nausea, and headache were noted when the number of transfused macrophages exceede d 2x10(8). One WHO IV toxicity occurred, consisting of hypotension aft er transfer of 3x10(8) cells, defining this dose as the maximum cell n umber tolerated. After pretreatment with ibuprofen, however, the maxim um cell number could be increased without reaching dose-limiting toxic ity. The highest number of cells reinfused was 15x10(8). Circulating i nterleukin(IL)-6 increased in a dose-dependent manner as did IL-1 rece ptor antagonist (IL-1RA) and IL-8. Tumor response consisted of one cas e of stable disease (12 weeks) in a patient with formerly progressing colorectal cancer and progressive diseases in eight patients. This stu dy indicates that reinfusion of autologous LPS-activated macrophages u pon pretreatment with ibuprofen is feasible and tolerated without majo r side-effects.