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Adoptive Transfer of Tumor Cytotoxic Macrophages Generated in Vitro from Circulating Blood Monocytes: A New Approach to Cancer Immunotherapy¹

Medizinische Klink I und Frauenklinik der Albert-Ludwigs-Universität Freiburg im Breisgau, Freiburg, West Germany

Cells of the macrophage lineage are considered to be of special importance in the defense of the host against tumor development and spread. Immunotherapeutic strategies to stimulate macrophage (MAC) tumor cytotoxicity make use of activating compounds such as -interferon which are given systemically. However, there are several lines of evidence that in malignant disease the generation of cytotoxic effector MACs is impaired. Both defective cell maturation and loss of responsiveness to activation are described. Here, a first clinical phase I trial of adoptive immunotherapy in cancer patients using autologous MACs generated in vitro from blood monocytes (MOs) is reported. Mononuclear cells were isolated by cytapheresis and density centrifugation and cultured in hydrophobic Teflon bags for 7 days with 2% autologous serum and recombinant human -interferon being present for the last 18 h. Cytotoxic MO-derived MACs were then purified by countercurrent elutriation and reinfused into the patient. A total of 72 therapies have been performed with patients being treated i.v. (n = 8) and i.p. (n = 7). In vitro generated MACs proved to be mature as judged by the expression of maturationassociated surface molecules (MAX antigens, CD16, CD51, CD71), were cytotoxic to U937 tumor cells, and were efficient secretory cells. Cell dose escalation was performed in the first patients beginning with 10⁸ MACs to finally infuse the total number of cells recovered from one single cycle of isolation and culture. MAC yield varied from 1 to 17 x 10⁸ representing 13–79% of MOs initially seeded. Adoptive MAC transfer was well tolerated. Side effects observed were low-grade fever (<38.5°C), induction of the coagulation cascade, and abdominal discomfort after i.p. application. The procoagulant activity of MAC autografts was cell dose dependent and demonstrated by the detection of circulating fibrin monomers and thrombin-antithrombin complexes. Biological responses observed included elevated serum neopterin levels and the appearance of interleukin-6 in sera and ascitic fluids. Indication of a possible therapeutic effect was only observed in i.p.-treated patients and consisted of disappearance of malignant ascites in 2 of 7 patients.

¹ Supported by Bundesminister für Forschung and Technologie und Deutsche Forschungsgemeinschaft.

² To whom requests for reprints should be addressed, at Medizinische Klinik 1, Hugstetter Str. 55, D-7800 Freiburg, West Germany

Received 3/28/90. Accepted 8/30/90.

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