Overview of interleukin-2 inhalation therapy

Locoregional administration of interleukin (IL)-2, which acts physiologically as a local hormone, is an effective therapeutic modality. Diverse preclinical and clinical models have described methods of administration that expose tumor tissues to continuously high levels of cytokines. Regional administration of IL-2 that does not raise intravascular IL-2 levels induces local and systemic immunomodulation and produces objective local tumor responses. Most importantly, regional therapy is much less toxic than systemic IL-2 therapy.

We review clinical experiences using inhaled IL-2 therapy for the treatment of pulmonary metastases in roughly 300 patients with a variety of primary tumors. This includes our own 10-year single-institution experience with inhaled IL-2 therapy in the treatment of 188 metastatic renal cell carcinoma patients with progressive pulmonary metastases. Patients in our clinic are treated with 18 to 36 million IU of recombinant IL-2, administered 90% by inhalation and 10% subcutaneously, until disease progression. A variety of doses and schedules of inhaled IL-2 have been investigated alone and in combination with systemic therapies.

Inhalation of IL-2 has been reported to prevent progression of pulmonary and mediastinal metastases of metastatic renal cell carcinoma, breast and ovarian carcinoma, and melanoma. Inhaled IL-2 alone is well tolerated; a dose-dependent cough is the major adverse event. A significant dose-dependent increase in lymphocytes and eosinophils has been observed in bronchoalveolar lavage in patients and animals. Dose and schedule can influence outcome. In a phase I trial using inhaled IL-2 alone in patients with a variety of primary malignancies, once-daily inhalation of IL-2 at doses up to 15 million IU/m2 was well tolerated but did not result in prolonged stabilization of pulmonary disease. In a multidose phase I trial, using 5-times-daily inhalation of natural IL-2, pulmonary lesions in three of 14 (21%) metastatic renal cell carcinoma patients responded, and a similar multicenter trial demonstrated a 29% response rate. Among 188 metastatic renal cell carcinoma patients treated with inhaled recombinant IL-2 at the Clinic Eppendorf, progression of pulmonary metastases was prevented in 68% of patients for a median duration of 7 months, and overall survival was significantly improved compared with expected survival (Elson's risk analysis; 17.2 vs 5.3 mo). All patients, including high-risk patients, appeared to benefit. Encouraging results have also been reported in patients with metastatic melanoma and gynecologic tumors when inhaled IL-2 was used as second-line therapy to treat pulmonary metastases.

The efficacy of inhaled IL-2, alone or in combination with systemic immunotherapy, immunochemotherapy, or chemotherapy, has been documented in a variety of malignancies. All reports confirm low toxicity, thus providing important quality-of-life benefits. Moreover, patients not eligible for systemic IL-2 therapy may be treated with inhalation therapy.