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 |
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Authors: | Albert Faradji Alain Bohbot Marion Schmitt-Goguel Norbert Roeslin Serge Dumont Marie-Louise Wiesel Christian Lallot Michel Eber Jacques Bartholeyns Philippe Poindron Georges Morand Jean-Paul Witz Francis Oberling |
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Affiliation: | (1) Département d'Onco-Hématologie CHU Hautepierre, Avenue Molière, 67 098 Strasbourg, France;(2) Service de Chirurgie Thoracique, Hôpital Civil, Avenue Molière, 67 098 Strasbourg, France;(3) Département d'Immunologie-Immunopharmacologie, UER Pharmacie, Avenue Molière, 67 098 Strasbourg, France;(4) Centre Regional de Transfusion Sanguine, Avenue Molière, 67 098 Strasbourg, France;(5) Centre Anticancereux Paul Strauss, Avenue Molière, 67 098 Strasbourg, France |
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Abstract: | Summary 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 (rhuIFN) [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 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 × 107 to 5 × 108 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 × 108 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 postinfusion and in vitro by secretory products (IL-1. TNF, neopterin, and thromboplastin-like substance) in the culture supernatants. The in vivo traffic patterns of autologous MAK cells labelled ex-vivo with111In oxine were studied in 7 patients. Gamma imaging showed an immediate but transient lung uptake (<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.This work was supported in part by a grant 6911 from the Association pour la Recherche contre le Cancer (ARC), grants from the Ligue Nationale contre le cancer and the Ligues Regionales (Bas-Rhin, Haut-Rhin) contre le cancer, and contract 891013 from the Institut National pour la Santé et la Recherche Médicale (INSERM), France |
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Keywords: | Human macrophages Interferon /content/p642w5483484q358/xxlarge947.gif" alt=" gamma" align=" MIDDLE" BORDER=" 0" > Adoptive immunotherapy Non-small-cell lung cancer |
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