Immunotherapy Articles

Intralesional cytokine therapy in cancer: a pilot study of GM-CSF infusion in mesothelioma

J Immunother 1998 Sep;21(5):389-98
Davidson JA, Musk AW, Wood BR, Morey S, Ilton M, Yu LL, Drury P, Shilkin K, Robinson B.
University Department of Medicine, Sir Charles Gairdner Hospital, Queen Elizabeth II Medical Centre, Perth, Australia.

Systemic cytokine therapy in cancer has major side effects, and we reasoned that the local infusion of cytokines into tumors could induce local immunologic responses with minimal toxicity and potentially strong systemic anticancer effects. This study investigated the toxicity and effectiveness of intralesional granulocyte/macrophage-colony-stimulating factor (GM-CSF) infusion in solid-tumor masses. We studied 14 patients (12 men, two women) with malignant mesothelioma (MM), aged 60 years (range, 46-70 years), with stage 2 disease, in whom the tumor was of sufficient size and accessibility for an intralesional catheter to be inserted. Recombinant human GM-CSF (Molgramostim; Schering Plough) was infused intralesionally for 8 weeks, by using a portable pump, at a dose of 2.5-10 micrograms/kg/day. One patient using GM-CSF developed histologically confirmed necrosis of tumor surrounding the distal catheter, one developed a marked lymphocytic infiltrate in the tumor and had a partial response measured by chest computed tomography (CT) scan, 10 progressed, and three had no response. Neutrophilia with morphologic evidence of neutrophil activation and clinical features suggestive of neutrophil plugging of blood vessels occurred at doses > 5 micrograms/kg/day. In vitro, GM-CSF doubled human neutrophil/CD11b/CD18 expression, suggesting that neutrophil clumping as seen in vivo might be due to integrin upregulation. Intralesional infusion of cytokines is feasible but can be associated with systemic toxicity and has considerable technical problems. It produces a localized immune reaction with tumor regression in a minority of patients.

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Immunotherapy for Malignant Mesothelioma

Nonspecific immunotherapy approaches, such as systemic or intrapleural administrations of interferons or interleukins, have shown limited clinical benefit in the treatment of patients with MM.

Single-agent studies of systemic interferon-alpha (IFN-alpha) produced response rates of about 12%.[5] A number of trials have examined the use of systemic IFN-alpha in combination with various chemotherapy agents. Despite encouraging initial studies that showed impressive response rates of 36% and 27% with a 12-month median survival, most combination trials have produced response rates similar to those seen with single-agent chemotherapy, generally with added toxicity.[5,41-43]

Intrapleural administration of interleukin-2 (IL-2) has yielded high response rates in patients with early-stage disease. Astoul and colleagues,[44] in France, administered intrapleural IL-2 to 23 patients with MPM. The response rate was 55% (11 partial responses and 1 complete response), and the therapy was well tolerated. The median survival time was 18 months. The majority of the patients in this trial had stage 2 or less disease. A recently published trial examined intrapleural IL-2 followed by low-dose systemic IL-2 and demonstrated a response rate of 22%.[45] Unfortunately, despite the promising response rates, the applicability of this therapy is limited to the few patients who have early-stage disease at diagnosis.

PMID: 9789201, UI: 99005630