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.

Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues

“…11,160 Macrophages have also been transfected ex vivo with such anticancer genes as the immunostimulatory cytokine, IFN-␥, and colonystimulating factor (CSF-1) 161 or the immunosuppressive/antiangiogenic cytokine, IL-10. 162 However, these approaches have failed to produce a significant antitumor response in mouse tumor models or cancer patients because only a small proportion of macrophages were recruited to the tumor while many became trapped in such healthy tissues as the lungs, liver, and kidneys, 163,164 so the antitumor activity of the cells was not concentrated at the tumor site. This may reflect the fact that macrophages rather than monocytes were used in the above studies, and it is the latter that is normally recruited from the vasculature into the tumor.…”

Adoptive immunotherapy of cancer using monocyte-derived macrophages: rationale, current status, and perspectives

“…First dose escalation studies starting with 10 5 cells were initiated in 1988 first in Freiburg [43] and later in Strasbourg [44,45]. It was demonstrated in these and subsequent studies [46][47][48][49] that in vitro-grown MAC could be safely administered at up to 3 ϫ 10 9 cells per single infusion (maximum cell number achieved by leukapheresis) without major toxicity.…”

Therapy of Peritoneally Disseminated Colon Cancer by TAP-Deficient Embryonic Stem Cell–Derived Macrophages in Allogeneic Recipients

“…For example, administration of autologous macrophages preactivated with IFN-g to cancer patients has been tried (19)(20)(21)(22)(23)(24)(25). In the reported clinical trials, macrophages used for anticancer therapies were generated from donor peripheral blood monocytes isolated by leukapheresis.…”