Therapeutic approaches in metastatic renal cell carcinoma: local immunotherapy

Since 1990, aerosol interleukin (IL)-2 has been used to treat pulmonary metastatic renal cell carcinoma (pmRCC). Inhalation therapy deposits a drug into the airways to achieve a high, local, clinical effect while avoiding serious systemic side effects. We report three studies to describe safety and efficacy of aerosol IL-2 in patients with pmRCC. In a multicenter study, 24 patients received exclusive inhalation (study I) of natural IL-2 (three dose levels, 48 weeks) and response and toxicity were evaluated. The survival of high-risk patients (study II) with mainly inhaled IL-2 (n=94) was compared with that of patients receiving systemic IL-2 (n=103). In ten patients we analyzed in detail lung function and markers of airway inflammation before and during inhalational IL-2 therapy (study III). Study I: The response of exclusive inhalation was 33.3% at 3 months and 16.7% at 6 months. Treatment was well tolerated, cough being the most frequent adverse event. Study II: The probabilities of survival at 5 years were 21% for the inhalational group and 0% for the systemic group. Study III: Inhaled IL-2 induced a moderate decline of forced expiratory volume (FEV), while exhaled nitric oxide (NO) and sputum eosinophils rose accompanied by moderate cough and dyspnea. In conclusion, inhalational IL-2 combines good efficacy and improves tolerability. This is especially important for patients who are not able to benefit from systemic IL-2 therapy. Whether the local eosinophilic response additionally supports the antitumor effect remains a challenging question.