Hemostatic changes in human adoptive immunotherapy with activated blood monocytes or derived macrophages

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Abstract
Human blood monocytes (Mo) and monocyte-derived macrophages (Mψ) possess cytotoxic effects against tumor cell lines when appropriately stimulated by various biological response modifiers, e.g., gamma interferon (γIFN) and muramyltripeptide (MTP). Activated Mo/Mψ represent a new tool for the treatment of human malignancies, termed “adoptive cellular immunotherapy”. Activated Mo/Mψ express tissue factor procoagulant activity (PCA), which is a physiological trigger of blood coagulation. PCA was evaluated in vitro using a modification of the one-stage recalcification clotting time, and hemostatic changes were studied in vivo in cancer patients. Nine patients with peritoneal carcinomatosis were injected intraperitoneally with activated Mo and 11 patients with non-small cell lung carcinomas were infused intravenously with activated Mψ. Hemostatic changes were followed using activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), fibrinogen level, antithrombin HI (ATIII) and protein C (PC) activities. Fibrinolytic activity was estimated by euglobulin lysis time and assays for plasminogen and fibrin/fibrinogen degradation products (FDP). These assays were performed before and after each autologous infusion and on days 2 and 3. Activated Mo and Mψ expressed potent PCA (85.5±7.5 U/ml for MTP activated Mo and 50±5.3 U/ml for γIFN activated Mψ suspensions). In both groups of patients, APTT, PT, and TT underwent no significant variations. There was no significant consumption of ATIII or PC, and fibrinolysis was not activated during the study period. In the group injected intraperitoneally with MTP-activated Mo, fibrinogen showed a significant and progressive increase in relation to the development of an inflammatory reaction, reaching a maximum average value of 6.1 g/l at the end of the therapy with a concomitant increase in FDP levels. This increase was not observed after intravenous therapy with γIFN-activated Mψ. No patient suffered from hemorrhagic or thrombotic events. In our experience, repeated injections of activated Mo or Mψ expressing potent tissue factor PCA did not induce significant in vivo activation of the coagulation system in cancer patients.