Defining the optimal biological dose of NGR-hTNF, a selective vascular targeting agent, in advanced solid tumours.

BACKGROUND: NGR-hTNF consists of human tumour necrosis factor-alpha (hTNF-alpha) fused to the tumour-homing peptide NGR, a ligand of an aminopeptidase N/CD13 isoform, which is overexpressed on endothelial cells of newly formed tumour blood vessels. NGR-TNF showed a biphasic dose-response curve in preclinical models. This study exploring the low-dose range aimed to define safety and optimal biological dose of NGR-hTNF. PATIENTS AND METHODS: Pharmacokinetics, plasma biomarkers and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were evaluated at baseline and after each cycle in 16 patients enrolled at four doubling-dose levels (0.2-0.4-0.8-1.6 microg/m(2)). NGR-hTNF was given intravenously as 1-h infusion every 3 weeks (q3w). Tumour response was assessed q6w. RESULTS: Eighty-three cycles (median, 2; range, 1-29) were administered. Most frequent treatment-related toxicity was grade 1-2 chills (69%), occurring during the first infusions. Only one patient treated at 1.6 microg/m(2) had a grade 3 drug-related toxicity (chills and dyspnoea). Both C(max) and AUC increased proportionally with dose. No shedding of soluble TNF-alpha receptors was observed up to 0.8 microg/m(2). Seventy-five percent of DCE-MRI assessed patients showed a decrease over time of K(trans), which was more pronounced at 0.8 microg/m(2). Seven patients (44%) had stable disease for a median time of 5.9 months, including a colon cancer patient who experienced an 18-month progression-free time. CONCLUSION: Based on tolerability, soluble TNF-receptors kinetics, anti-vascular effect and disease control, NGR-hTNF 0.8 microg/m(2) will be further developed either as single-agent or with standard chemotherapy.

Prognostic factors and analysis of S100a4 protein in resected pulmonary metastases from renal cell carcinoma.

BACKGROUND: This study analyzes our experience with pulmonary resection for metastases from renal cell carcinoma. The goals were to search for factors influencing prognosis and to investigate the presence and the prognostic value of S100A4 protein in lung metastases and corresponding primary renal tumors. METHODS: Sixty-five patients underwent surgical resection for renal and pulmonary lesions between 1992 and 2007. S100A4 protein expression was immunohistochemically examined in the peritumoral infiltrate of 64 lesions (32 metastases and the 32 corresponding primary carcinomas). RESULTS: Overall 3-, 5-, and 10-year survival rates were 58, 46, and 25%, respectively. Univariate analysis revealed that surgical radicality (p = 0.0039) and stratification into groups according to the International Registry of Lung Metastases classification (p = 0.0137) were prognostic factors. Multivariate analysis confirmed that this classification was a significant prognostic factor (p = 0.01). All metastases and the corresponding primary carcinomas expressed S100A4 protein. Twenty-one metastases (66%) had weak expression and 11 (34%) had strong expression. Twelve (37.5%) primary lesions had weak expression and 20 (62.5%) had strong expression. The 5-year survival rate for patients with strong expression in primary carcinoma was 41%, significantly lower than that of patients with weak expression (78%; p = 0.05). CONCLUSIONS: Pulmonary resection in metastatic renal cell carcinoma results in long-term survival. Complete resection and stratification into groups according to the International Registry of Lung Metastases classification were prognostic factors. Overexpression of S100A4 protein in primary tumors was correlated with a poor prognosis. If confirmed in larger studies this finding could be used to schedule adjuvant treatments in patients undergoing nephrectomy for renal cell carcinoma.

Pancreatic metastasis from renal cell carcinoma: which patients benefit from surgical resection?

BACKGROUND: Pancreas is a possible site of metastases from renal cell carcinoma (RCC). The aim of this study was to define the role of surgery in their treatment. METHODS: We retrospectively analyzed 36 patients with pancreatic metastasis from RCC observed between January 1998 and February 2006. Patients were categorized into three risk groups according to the modified Memorial Sloan-Kettering prognostic factors model. RESULTS: Resective surgery was performed in 23 patients, as follows: 11 distal pancreatectomy, 5 enucleation, 4 pancreatoduodenectomy, 2 total pancreatectomy, and 1 middle pancreatectomy. No perioperative mortality was observed; the morbidity rate was 47.8%. All patients who underwent resection belonged to the favorable risk group. Surgical resection was excluded in 13 cases because of locally advanced disease (2 cases) or extrapancreatic disease (11 cases); 5 of these patients were at favorable, 7 at intermediate, and 1 at poor risk. In patients undergoing surgery, the 5-year actuarial survival rate was 88%, and median disease-free survival was 44 months. Patients who did not undergo surgery had a 5-year survival rate of 47%, with a median survival time of 27 months (P = .02). CONCLUSIONS: Patients with pancreatic metastases from RCC belonging to a favorable risk group are candidates for resection, even in the presence of another metastatic site or multifocal pancreatic disease.

Peptidome from renal cell carcinoma contains antigens recognized by CD4+ T cells and shared among tumors of different histology.

PURPOSE: Renal cell carcinoma (RCC) is considered immunogenic; nonetheless, rare tumor-associated antigens have been identified or are expressed in RCC. Peptidome (i.e., the total content of natural peptides of whole cells) from other tumors, such as melanoma, has proved to be immunogenic. The aims of this study were to determine whether peptidome from RCC is immunogenic and whether it contains tumor peptides shared among allogenic RCCs. EXPERIMENTAL DESIGN: Autologous dendritic cells pulsed with RCC peptidome were used to activate in vitro CD4(+) T cells from healthy donors and a metastatic RCC patient. CD4(+) T-cell polyclonal lines and clones were characterized for tumor cell recognition by proliferation assay, killing activity, and cytokine secretion. RESULTS: CD4(+) T-cell lines and clones recognized HLA-DR-matched allogenic RCC and, for the patient, the autologous tumor. RCC-reactive CD4(+) T cells showed a heterogeneous Th1 or Th0/Th2 pattern of cytokine secretion. Moreover, RCC-reactive CD4(+) T cells recognized also melanoma, colon carcinoma, cervical carcinoma, pancreas carcinoma, lung carcinoma, gastric carcinoma, and lymphoma cells but not autologous T-cell blasts. CONCLUSIONS: Our results show that (a) the RCC peptidome contain antigens recognized by CD4(+) T cells and (b) shared among tumors of different histology and (c) it induces both Th1-type and Th2/Th0-type immune responses. These data support the use of the peptidome from allogenic RCC for specific immunotherapy in RCC and possibly in other neoplastic diseases. Moreover, the CD4(+) T-cell clones generated here are useful tools for tumor antigen identification.