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Milano, Italy

Biffi A.,San Raffaele Scientific Institute | Montini E.,San Raffaele Scientific Institute | Lorioli L.,San Raffaele Scientific Institute | Lorioli L.,Vita-Salute San Raffaele University | And 38 more authors.
Science | Year: 2013

Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disease caused by arylsulfatase A (ARSA) deficiency. Patients with MLD exhibit progressive motor and cognitive impairment and die within a few years of symptom onset. We used a lentiviral vector to transfer a functional ARSA gene into hematopoietic stem cells (HSCs) from three presymptomatic patients who showed genetic, biochemical, and neurophysiological evidence of late infantile MLD. After reinfusion of the gene-corrected HSCs, the patients showed extensive and stable ARSA gene replacement, which led to high enzyme expression throughout hematopoietic lineages and in cerebrospinal fluid. Analyses of vector integrations revealed no evidence of aberrant clonal behavior. The disease did not manifest or progress in the three patients 7 to 21 months beyond the predicted age of symptom onset. These findings indicate that extensive genetic engineering of human hematopoiesis can be achieved with lentiviral vectors and that this approach may offer therapeutic benefit for MLD patients.

Zucali P.A.,Humanitas Cancer Center | Simonelli M.,Humanitas Cancer Center | De Vincenzo F.,Humanitas Cancer Center | Lorenzi E.,Humanitas Cancer Center | And 13 more authors.
British Journal of Cancer | Year: 2013

Background:NGR-hTNF exploits the peptide asparagine-glycine-arginine (NGR) for selectively targeting tumour necrosis factor (TNF) to CD13-overexpressing tumour vessels. Maximum-tolerated dose (MTD) of NGR-hTNF was previously established at 45 μg m-2 as 1-h infusion, with dose-limiting toxicity being grade 3 infusion-related reactions. We explored further dose escalation by slowing infusion rate (2-h) and using premedication (paracetamol).Methods:Four patients entered each of 12 dose levels (n=48; 60-325 μg m-2). Pharmacokinetics, soluble TNF receptors (sTNF-R1/sTNF-R2), and volume transfer constant (K trans) by dynamic imaging (dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)) were assessed pre-and post-treatment.Results:Common related toxicity included grade 1/2 chills (58%). Maximum-tolerated dose was not reached. Both C max (P<0.0001) and area under the plasma concentration-time curve (P=0.0001) increased proportionally with dose. Post-treatment levels of sTNF-R2 peaked significantly higher than sTNF-R1 (P<0.0001). Changes in sTNF-Rs, however, did not differ across dose levels, suggesting a plateau effect in shedding kinetics. As best response, 12/41 evaluable patients (29%) had stable disease. By DCE-MRI, 28/37 assessed patients (76%) had reduced post-treatment K trans values (P<0.0001), which inversely correlated with NGR-hTNF C max (P=0.03) and baseline K trans values (P<0.0001). Lower sTNF-R2 levels and greater K trans decreases after first cycle were associated with improved survival.Conclusion:asparagine-glycine- arginine-hTNF can be safely escalated at doses higher than MTD and induces low receptors shedding and early antivascular effects. © 2013 Cancer Research UK. All rights reserved.

Lorusso D.,Catholic University of Rome | Scambia G.,Catholic University of Rome | Amadio G.,Catholic University of Rome | Di Legge A.,Catholic University of Rome | And 10 more authors.
British Journal of Cancer | Year: 2012

Background: The NGR-hTNF (asparagine-glycine-arginine-human tumour necrosis factor) is able to promote antitumour immune responses and to improve the intratumoural doxorubicin uptake by selectively damaging tumour blood vessels. Methods: Patients progressing after ≥ 1 platinum/taxane-based regimen received NGR-hTNF 0.8 g m -2 and doxorubicin 60 mg m -2 every 3 weeks. Primary endpoint was a Response Evaluation Criteria in Solid Tumors-defined response rate with a target of more than 6 out of 37 responding patients. Results: A total of 37 patients with platinum-free interval lower than 6 months (PFI=6; n=25), or between 6 and 12 months (PFI=6-12; n=12) were enrolled. Median baseline peripheral blood lymphocyte count (PBLC) was 1.6 per ml (interquartile range, 1.2-2.1). In all, 18 patients (49%) received more than 6 cycles. Febrile neutropaenia was registered in one patient (3%). Among 35 assessable patients, 8 (23%; 95% CI 12-39%) had partial response (2 with PFI6; 6 with PFI=6-12) and 15 (43%) had stable disease (10 with PFI=6; 5 with PFI=6-12). Median progression-free survival (PFS) was 5.0 months for all patients, 3.8 months for patients with PFI6, and 7.8 months for patients with PFI=6-12. Median overall survival (OS) was 17.0 months. Patients with baseline PBLC higher than the first quartile had improved PFS (P=0.01) and OS (P=0.001). Conclusion: Tolerability and activity of this combination warrant further randomised testing in patients with PFI=6. The role of PBLC as a blood-based biomarker deserves further investigation. © 2012 Cancer Research UK All rights reserved.

Corti A.,Tumor Biology and Vascular Targeting Unit | Caligaris-Cappio F.,Vita-Salute San Raffaele University | Maschio A.D.,Vita-Salute San Raffaele University | Troysi A.,MolMed | And 3 more authors.
European Journal of Cancer | Year: 2010

Background: NGR-hTNF consists of human tumour necrosis factor-alpha (hTNF-α) 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 μg/m2). 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 μg/m2 had a grade 3 drug-related toxicity (chills and dyspnoea). Both Cmax and AUC increased proportionally with dose. No shedding of soluble TNF-α receptors was observed up to 0.8 μg/m2. Seventy-five percent of DCE-MRI assessed patients showed a decrease over time of Ktrans, which was more pronounced at 0.8 μg/m2. 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 μg/m2 will be further developed either as single-agent or with standard chemotherapy. © 2009 Elsevier Ltd. All rights reserved.

Santoro A.,Istituto Clinico Humanitas | Pressiani T.,Istituto Clinico Humanitas | Citterio G.,Istituto Scientif Ico San Raffaele | Rossoni G.,Istituto Scientif Ico San Raffaele | And 13 more authors.
British Journal of Cancer | Year: 2010

Background:Hepatocellular carcinoma (HCC) is a highly vascularised and poor-prognosis tumour. NGR-hTNF is a vascular-targeting agent consisting of human tumour necrosis factor-alpha fused to the tumour-homing peptide NGR, which is able to selectively bind an aminopeptidase N overexpressed on tumour blood vessels.Methods:Twenty-seven patients with advanced-stage disease resistant to either locoregional (59%; range, 1-3), systemic treatments (52%; range, 1-3) or both (33%) received NGR-hTNF 0.8 gm-2 once every 3 weeks. The primary aim of the study was progression-free survival (PFS).Results:No grade 3-4 treatment-related toxicities were noted. Common toxicity included mild-to-moderate, short-lived chills (63%). Median PFS was 2.3 months (95% CI: 1.7-2.9). A complete response ongoing after 20 months was observed in a sorafenib-refractory patient and a partial response in a Child-Pugh class-B patient, yielding a response rate of 7%. Six patients (22%) experienced stable disease. The disease control rate (DCR) was 30% and was maintained for a median PFS time of 4.3 months. Median survival was 8.9 months (95% CI: 7.5-10.2). In a subset of 12 sorafenib-resistant patients, the response rate was 8% and the median survival was 9.5 months.Conclusion:NGR-hTNF was well tolerated and showed single-agent activity in HCC. Further investigation in HCC is of interest. © 2010 Cancer Research UK All rights reserved.

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