Extended continuous infusion low-dose recombinant interleukin-2 in advanced cancer: prolonged immunomodulation without significant toxicity.

Abstract

In previous clinical trials, recombinant interleukin-2 (rIL-2) has been infused at high doses over short periods of time to generate lymphokine-activated killer (LAK) cells in vivo. These trials have been limited by severe toxicities, and the immunologic effects of rIL-2 have been transient. The present study was designed to assess the toxicity and immunologic effects of prolonged administration of low doses of rIL-2. In this phase I study, patients with advanced cancer were scheduled to receive intravenous (IV) infusion of rIL-2 without interruption for 3 months in an outpatient setting. Twenty-one patients received rIL-2 at doses ranging from 0.5 x 10(5) to 6.0 x 10(5) U/m2/d. Treatment was extremely well tolerated, and no patient experienced grade 3 or grade 4 toxicity. The lowest dose level (0.5 x 10(5) U/m2/d) did not have demonstrable immunologic activity. At doses of 1.5 x 10(5) and 4.5 x 10(5) U/m2/d, rIL-2 infusion resulted in the specific expansion of natural-killer (NK) cells (sixfold and ninefold increases, respectively, at these two dose levels) without any changes in B cells, T cells, neutrophils, or monocytes. Grade 2 toxicity was observed at the dose of 6.0 x 10(5) U/m2/d, as three patients required interruption of therapy and two patients who completed therapy developed transient hypothyroidism. In patients with increased NK cells, enhancement of non-major histocompatibility complex (MHC)-restricted cytotoxicity and increased generation of LAK cells in vitro were also demonstrated. Therapy with low-dose rIL-2 can be given safely in an uninterrupted fashion for prolonged periods of time in an outpatient setting. This results in selective expansion of NK cells in vivo with minimal toxicity. Further investigation of this schedule for immunomodulation in vivo should be pursued in phase II studies of both malignant and immunodeficient disease states.

Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect

“…9,[117][118][119][120] In most studies, it has been difficult to convincingly demonstrate a clinical benefit, especially in small phase I and II clinical trials. Although it is not known to what extent cytokines, such as IL-2, may alter the balance between activating and inhibitory receptors on NK cells, it is likely that the inhibitory signals delivered by MHC class I molecules expressed on the autologous target cancer are a major limitation to successful treatment.…”

Low dose interleukin‐2 following intensification therapy with high dose cytarabine for acute myelogenous leukemia in first complete remission

“…Low concentrations of IL-2 are known to induce the cytotoxic effector function of NK cells in vitro [12]. Low dose continuous rIL-2 has been safely applied to patients with solid tumors [34] and to those who had undergone autologous or allogeneic transplant [45]. In both settings, companion studies demonstrated that NK cells obtained from patients receiving IL-2 were active and could kill surrogate targets.…”

“…We previously conducted several studies assessing prolonged continuous infusion of low dose rIL-2 for patients with metastatic solid cancers [34,35]. Treatment was very well tolerated and immunophenotypic analysis of peripheral blood mononuclear cells revealed a significant increase in NK cells with a less notable change in T-cell number.…”

IL2 treatment for cancer: from biology to gene therapy

“…The immunological changes may be summarised by the expression of activation markers, as well as by the amplification of the NK and LAK functions and by the in vivo release of two cytokines-IFN gamma and Tumour Necrosis Factor (TNFa)-with known anti-proliferative activity Hank et al, 1988;Gottlieb et al, 1989;Heslop et al, 1989;Foa et al, 1991b). (West et al, 1987), continuous infusion protocols using a daily dose escalating scheme (Foa et al, 1990b;1991a), prolonged low-dose daily infusion (Caligiuri et al, 1991), as well as loco-regional injections of IL2 directly in the tumour area or around tumour-draining lymphnodes (Cortesina et al, 1988 More relevantly, the constitutive release of IL4 (Tepper et al, 1989;Golumbek et al, 1991), IL6 (Porgador et al, 1992), IL7 (Hock et al, 1991), IFN gamma (Watanabe et al, 1989;Gansbacher et al, 1990a), TNF alpha (Blankenstein et al, 1991;Asher et al, 1991) and G-CSF (Colombo et al, 1991) by the genetically engineered tumour cells has resulted in a decreased or abrogated tumorigenicity. The mechanisms by which this anti-tumour response, induced by the release of the different cytokines and growth factors, is obtained is most likely heterogeneous, including in some models local intra-tumoural inflammation and in others the generation of cytotoxic T-lymphocytes.…”