The tumour-targeting human L19-IL2 immunocytokine: preclinical safety studies, phase I clinical trial in patients with solid tumours and expansion into patients with advanced renal cell carcinoma.

BACKGROUND: L19-IL2, a tumour-targeting immunocytokine composed of the recombinant human antibody fragment L19 (specific to the alternatively-spliced EDB domain of fibronectin, a well characterised marker of tumour neo-vasculature) and of human IL2, has demonstrated strong therapeutic activity in animal cancer models. This phase I/II trial was performed to evaluate safety, tolerability, recommended phase II dose (RD) and early signs of activity of L19-IL2. PATIENTS AND METHODS: Five cohorts of patients with progressive solid tumours (n=21) received an intravenous infusion of L19-IL2 (from 5 to 30 Mio IU IL2 equivalent dose) on days 1, 3 and 5 every 3 weeks. This treatment cycle was repeated up to six times. In the following expansion phase, patients with metastatic renal cell carcinoma (RCC) (n=12) were treated at the RD of L19-IL2. Clinical data and laboratory findings were analysed for safety, tolerability and activity. RESULTS: Preclinical studies in rats and monkeys did not raise any safety concerns. The RD was defined to be 22.5 Mio IU IL2 equivalent. Pharmacokinetics of L19-IL2 was dose proportional over the tested range, with a terminal half-life of 2-3h. Toxicities were manageable and reversible with no treatment-related deaths. We observed stable disease in 17/33 patients (51%) and 15/18 with mRCC (83%) after two cycles. Median progression-free survival of RCC patients in the expansion phase of the study was 8 months (1.5-30.5). CONCLUSIONS: L19-IL2 can be safely and repeatedly administered at the RD of 22.5 Mio IU IL2 equivalent in advanced solid tumours. Preliminary evaluation suggests clinical activity of L19-IL2 in patients with mRCC.

The ratio of prostate-specific antigen (PSA) to prostate volume (PSA density) as a parameter to improve the detection of prostate carcinoma in PSA values in the range of < 4 ng/mL.

BACKGROUND: The objective of this study was to evaluate the prostate specific antigen (PSA) density (PSAD) (the quotient of PSA and prostate volume) compared with the percent free PSA (%fPSA) in different total PSA (tPSA) ranges from 2 ng/mL to 20 ng/mL. Possible cut-off levels depending on the tPSA should be established. METHODS: In total, 1809 men with no pretreatment of the prostate were enrolled between 1996 and 2004. Total and free PSA were measured with the IMMULITE PSA and Free PSA kits (Diagnostic Products, Los Angeles, CA). Prostate volume was determined by transrectal ultrasound. The diagnostic validity of tPSA, %fPSA, and PSAD was evaluated by receiver operation characteristic (ROC) curve analysis. RESULTS: The PSAD differed significantly (P < 0.0001) between patients with prostate carcinoma and patients with benign prostatic hyperplasia in all analyzed ranges of tPSA and prostate volume. At the 90% and 95% sensitivity levels and regarding the area under the ROC curve (AUC) within the tPSA range of 2-4 ng/mL, The PSAD was significantly better than tPSA and %fPSA. Within the tPSA range of 4-10 ng/mL, the PSAD did not perform better than %fPSA. CONCLUSIONS: PSAD showed a better performance than %fPSA at tPSA concentrations < 4 ng/mL for detecting prostate carcinoma, with a significantly larger AUC for PSAD (0.739) compared with %fPSA (0.667). PSAD did not perform better than %fPSA when the tPSA range of 4-10 ng/mL was analyzed. Different PSAD cut-off values of 0.05 at tPSA 2-4 ng/mL, 0.1 at tPSA 4-10 ng/mL, and 0.19 at 10-20 ng/mL were necessary to reach 95% sensitivity.

The membrane proteases adams and hepsin are differentially expressed in renal cell carcinoma. Are they potential tumor markers?

PURPOSE: ADAMs (a disintegrin and metalloproteinases) as cell surface proteins with adhesion and protease activity, and hepsin as a transmembrane protease have important roles in many biological processes. We assessed the expression of various ADAMs and of hepsin in human renal cell carcinoma (RCC), and correlated expression with clinicopathological data. MATERIALS AND METHODS: mRNA expression of ADAM-8, 17, 19, 28, TS1 and TS2, and of hepsin was investigated in paired tissue samples from cancerous and noncancerous parts of the kidneys of 27 patients with RCC who underwent tumor nephrectomy. Measurements were performed by quantitative real-time reverse transcriptase-polymerase chain reaction on a LightCycler instrument (Roche Applied Science, Mannheim, Germany). The data were related to housekeeping gene porphobilinogen deaminase mRNA. RESULTS: All ADAMs except ADAM-TS1 were significantly higher but hepsin was less expressed (at least p <0.05) in cancerous vs matched noncancerous tissue. Expression was differentially related to tumor stage. ADAM-8 and ADAM-TS2 over expression as well as decreased hepsin expression were associated with shorter patient survival. The Cox proportional hazards regression model revealed that ADAM-TS2 was an independent prognostic factor for cancer related death. ADAM-8 was the best predictor of distant metastases. CONCLUSIONS: The differential expression of hepsin and ADAMs suggests early and late involvement of membrane proteases in the development of RCC. Their association with the clinical outcome illustrates their potential usefulness as biomarkers for RCC.

Increased mRNA expression of ADAMs in renal cell carcinoma and their association with clinical outcome.

ADAMs (a disintegrin and metalloproteinase) are cell-surface proteins with adhesion and protease activity which play important roles in many biological processes. Little is known about their role in cancer. The aim of the study was to assess the quantitative expression of the ADAMs in human renal cell carcinoma (RCC) and to associate expression levels with clinicopathological data. We investigated the mRNA expression of ADAM-8, -17, -19, -28, ADAM-TS1, and ADAM-TS2 in paired tissue samples from cancerous and non-cancerous parts of the kidneys of 27 patients with RCC who underwent tumour nephrectomy. Measurements were performed by means of the quantitative real-time RT-PCR on a LightCycler instrument. ADAM-8, -17, and -19 were significantly higher expressed (p<0.05 at least) in cancerous compared with the matched non-cancerous tissue in pT1 and > or =pT2 tumours, ADAM-28 and ADAM-TS2 only in pT1 tumours, and ADAM-TS1 was not differently expressed. All ADAMs except ADAM-TS1 showed an increase of expression in the non-cancerous tissue with rising pT stage suggesting an early involvement of ADAMs in the development of RCC. The expression of ADAM-8 was related to a shorter survival of patients and was the best predictor of distant metastases. Our results indicate a potential role for ADAMs in RCC and that the overexpression might be a useful predictive tool.