Targeting pulmonary metastases of renal cell carcinoma by inhalation of interleukin-2

Abstract

Inhalation of IL-2 for the treatment of pulmonary metastases in RCC is feasible, tolerable and beneficial in controlling progressive disease for considerable periods of time. The definition of response of biological therapy may need to be re-assessed and modified: stable disease should be regarded as a favorable response.

Acrolein in cigarette smoke inhibits T-cell responses

“…25 Acrolein inhibits production of a wide variety of T-cell cytokines that are thought to be critical in pulmonary immunity to infectious agents and cancer, including IL-2, IL-4, IFN-g, GM-CSF, and TNF-a. [26][27][28][29][30][31][32] However, production of IL-8 by T cells was notably more resistant to the effects of both cigarette smoke and acrolein. In fact, CSE and acrolein have been shown to induce IL-8 production in epithelial cells and neutrophils, and inhibition of IL-8 production by T cells was seen only with toxic doses of acrolein.…”

Complete Regression of Metastatic Renal Cell Carcinoma by Multiple Injections of Engineered Mesenchymal Stem Cells Expressing Dodecameric TRAIL and HSV-TK

“…As RCC generally possesses inherent resistance to chemotherapy and radiotherapy (5), other treatment modalities, such as cytokine-based immunotherapy or targeted therapy using multikinase inhibitors, have been actively investigated in the clinic. Immunotherapies using interleukin-2 (IL-2) or IFN-a have shown beneficial effects in some clinical settings, and even complete remissions in small cohort of patients using high-dose IL-2, but low response rates and systemic toxicities have limited their clinical use (6). Tyrosine kinase inhibitors, including sunitinib and sorafenib, have substantially improved the overall survival of patients with RCC, but complete remission has rarely been achieved (7).…”

Interleukin-2/interferon-α2a/13-retinoic acid-based chemoimmunotherapy in advanced renal cell carcinoma: results of a prospectively randomised trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN)

“…There were also no significant differences in PFS and objective response between arms A (sc-IL-2/sc-IFN-a/po-13cRA) and B (arm A plus inhaled-IL-2), and between arms C (arm A plus iv-5-FU) and D (arm A plus po-Capecitabine). Inhaled IL-2 in poor-risk patients unfit for systemic cytokine therapy has been reported to induce remarkable effects on lung metastases leading to objective responses between 2.5 -21% (inhaled-IL-2) (Lorenz et al, 1996;Merimsky et al, 2004) and 47% (inhaled-IL-2/10% sc-IL-2/INFa) (Huland et al, 1994). In this multicentre trial, inhaled-IL-2 (arm B) at a dose 5.3-fold the subcutaneous (sc) dose did not significantly enhance treatment efficacy when compared to arm A.…”

“…In preliminary reports on oral 13-cis-retinoic acid (po-13cRA), a cell differentiation regulator, po-13cRA could enhance antitumour efficacy in IL-2/IFN-a-or chemoimmunotherapy-treated metastatic renal cell carcinoma patients, with objective response rates between 17 and 42% (Atzpodien et al, 1995;Stadler et al, 1998). In the presence of pulmonary metastases, locoregional administration of inhaled-IL-2 was reported to yield low toxicity combined with objective response rates of pulmonary disease of 2.5 -21% (Lorenz et al, 1996;Merimsky et al, 2004). Other reports showed that the combination of cytokines with intravenous 5-fluorouracil (iv-5-FU) could increase objective response rates to between 12 and 39% (van Herpen et al, 2000;Atzpodien et al, 2001Atzpodien et al, , 2004.…”