title: Phase I trial of intravenous infusion of ex-vivo-activated autologous blood-derived macrophages in patients with non-small-cell lung cancer: toxicity and immunomodulatory effects.
abstract: The purpose of this phase I study was to evaluate the toxicity and biological activity of autologous blood-derived macrophages activated ex-vivo with recombinant human interferon gamma (rhuIFN gamma) [monokine-activated killer (MAK) cells] and administered intravenously to 11 lung cancer patients once a week for 6 consecutive weeks. Peripheral blood monocytes were collected by leukapheresis and then purified by counterflow elutriation. The MAK cells were generated by culturing the purified monocytes in Teflon bags for 7 days and adding rhuIFN gamma to the cultured cells for the last 18 h. These MAK cells expressed differentiation-associated surface antigen MAX1, and were cytotoxic in vitro against tumour cell line U937. The MAK cells were infused at dose levels from 1 x 10(7) to 5 x 10(8) on an intrapatient dose-escalating schedule. No severe adverse side-effects occurred. Toxicity was mild to moderate [primarly fever (75%) and chills (32%)], non-dose-dependent, and non-cumulative. No consistent change in haemostatic function, or liver or renal function was observed. Dose-limiting toxicity was not reached at 5 x 10(8) cells (optimal dose reproduced for each patient). The maximum tolerated dose was not determined. The immunomodulatory activity of i.v. infused MAK cells was demonstrated both in vivo by significant increases in granulocyte count and neopterin level in the patients' peripheral blood post-infusion and in vitro by secretory products (IL-1. TNF alpha, neopterin, and thromboplastin-like substance) in the culture supernatants. The in vivo traffic patterns of autologous MAK cells labelled ex-vivo with 111In oxine were studied in 7 patients. Gamma imaging showed an immediate but transient lung uptake (less than 24 h), and a progressive uptake of radioactivity in the liver and spleen was seen from 6 h to 72 h post-infusion. Our results indicate that the preparation of high numbers of autologous, blood-derived MAK cells is a feasible procedure, and their transfusion is safe for patients. This immunotherapeutic approach seems to be encouraging from the point of view of establishing an adjuvant therapeutic modality in cancer patients with minimal residual disease.
authors.affiliation: Département d'Onco-Hématologie CHU Hautepierre, Strasbourg, France.
authors.forename: A
authors.initials: A
authors.lastname: Faradji
authors.forename: A
authors.initials: A
authors.lastname: Bohbot
authors.forename: M
authors.initials: M
authors.lastname: Schmitt-Goguel
authors.forename: N
authors.initials: N
authors.lastname: Roeslin
authors.forename: S
authors.initials: S
authors.lastname: Dumont
authors.forename: M L
authors.initials: ML
authors.lastname: Wiesel
authors.forename: C
authors.initials: C
authors.lastname: Lallot
authors.forename: M
authors.initials: M
authors.lastname: Eber
authors.forename: J
authors.initials: J
authors.lastname: Bartholeyns
authors.forename: P
authors.initials: P
authors.lastname: Poindron
mesh_terms: D000368:Aged; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D001772:Blood Cell Count; D002097:C-Reactive Protein / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000276:immunology / Q000628:therapy*; D016207:Cytokines / Q000378:metabolism; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D007205:Indium Radioisotopes; D007371:Interferon-gamma / Q000494:pharmacology / Q000633:toxicity; D007937:Leukapheresis; D008175:Lung Neoplasms / Q000097:blood / Q000276:immunology / Q000628:therapy*; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D016260:Monocytes, Activated Killer / Q000276:immunology; D019798:Neopterin; D011994:Recombinant Proteins
chemical_list: D016207:Cytokines; D007205:Indium Radioisotopes; D011994:Recombinant Proteins; D001708:Biopterins; D019798:Neopterin; D007371:Interferon-gamma; D002097:C-Reactive Protein