Intrapleural administration of interleukin 2 in pleural mesothelioma: a phase I-II study

Abstract

S_mmary Twenty-three patients with pleural mesothelioma stage I-IIA were entered in a study of continuous daily intrapleural infusion of interleukin 2 (IL-2) for 14 days, repeated every Intrapleural IL-2 levels were high (>20 000 IU ml-') at levels E and F, while serum levels in most patients were not or barely detectable (<3-30 IU ml-'). Intrapleural IL-2 levels were up to 6000-fold higher than systemic levels. Intrapleural tumour necrosis factor alpha (TNF-a) levels varied greatly and did not correlate with IL-2 dosage. Intrapleural mononuclear cells (MNCs) displayed IL-2-induced lymphokine-activated killer (LAK) activity in all patients. Two patients were not evaluable for response owing to catheter-related problems which precluded the delivery of IL-2. Partial response (PR) occurred in 4 of 21 evaluable patients (19%; 95% confidence interval 5-42%) with a median time to progression of 12 months (range 5-37). Stable disease (SD) occurred in seven patients with a median time to progression of 5 months (range 2-7). There were no complete responses (CRs). The median overall survival was 15.6 months (range 3.0-43). No relationship between the dose of IL-2 and response rate was observed. We conclude that IL-2 given intrapleurally is accompanied with acceptable toxicity and has anti-tumour activity against mesothelioma. In view of the refractory nature of the disease IL-2 may be a treatment option for mesothelioma. A formal phase II study is warranted. Based on the observed toxicity, the lack of dose-response relationship and the immunomodulatory effects seen at relatively low-dose IL-2, the recommended dose for a phase II study is 3 x I06IU day-' using the present treatment schedule.

Soluble Type II Transforming Growth Factor-β Receptor Inhibits Established Murine Malignant Mesothelioma Tumor Growth by Augmenting Host Antitumor Immunity

“…A number of investigators have translated some of these animal findings into clinical trials. Several published phase I and II clinical trials have documented mesothelioma tumor responses to intrapleural infusion of IL-2, IFN-␤, and IFN-␥ (36,(41)(42)(43)(44). Given this potential to respond to immunologic therapy, we therefore hypothesized that the neutralization of TGF-␤ could be effective for treatment of MM in terms of release from immunosuppressive environment and normalization of host immune surveillance.…”

Treatment with interleukin-2 in malignant pleural mesothelioma: immunological and angiogenetic assessment and prognostic impact

“…Reduced levels of IL-2 have been associated with a lower survival of metastatic cancer patients (Herberman, 1984;Lissoni et al, 1991), and numerous trials have been performed using IL-2 alone or in combination with other forms of immunotherapy and chemotherapy (Grande et al, 2006). Several studies have shown an anti-tumoural activity of intra-pleural administration of IL-2 for the treatment of MPM, supporting the use of IL-2 in clinical trials (Goey et al, 1995;Astoul et al, 1998;Castagneto et al, 2001;Mulatero et al, 2001;Lucchi et al, 2007). However, the mechanism underlying the effects of IL-2 in the modification of the MPM microenvironment is still unknown.…”

“…Intravenous, subcutaneous or intra-pleural administration of IL-2 has shown some effects on tumour regression in MPM, supporting the use of IL-2 in clinical trial settings (Goey et al, 1995;Astoul et al, 1998;Castagneto et al, 2001;Mulatero et al, 2001;Lucchi et al, 2007). However, the mechanism underlying the biological effects of IL-2 on tumour growth is complex and it is still largely unknown.…”

Gene therapy for malignant mesothelioma: beyond the infant years

“…19 Moreover, clinical trials with intrapleural IL-2 administration have been conducted for mesothelioma, and other tumors, and have yielded encouraging results. [20][21][22][23] In our study, six mesothelioma patients were treated with the vaccinia virus recombinant. No systemic or local toxicities were observed, and, despite antibody responses, vaccinia virus-IL-2 mRNA gene expression persisted in tumor biopsies for up to 3 weeks.…”