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Lau P.K.H.,Peter MacCallum Cancer Center | Ascierto P.A.,Cancer Immunotherapy and Innovative Therapy Unit | McArthur G.,Peter MacCallum Cancer Center
Current Opinion in Immunology | Year: 2016

Melanoma is at the forefront of development of systemic therapeutics with both molecular targeted therapies and immune checkpoint inhibitors as cornerstones of treatment. Although responses to molecularly targeted therapy is largely from blockade of oncogenic pathways, evidence is emerging of the immunomodulatory effects from BRAF inhibition. Additionally programmed-death-1 (PD-1) inhibitors have revolutionized the treatment of melanoma and are set to pave future improvements in other solid tumors. Combinations of PD-1 inhibitors with novel immune checkpoints or with molecularly targeted therapies are under investigation and may improve on the considerable progress made. © 2015 Elsevier Ltd. Source


Ascierto P.A.,Cancer Immunotherapy and Innovative Therapy Unit | De Mello R.A.,University of Algarve | De Mello R.A.,University of Porto | De Mello R.A.,Ceara Cancer Institute
Immunotherapy | Year: 2016

Paolo A Ascierto and Ramon A de Mello speak to Ellen Clarke, Commissioning Editor Despite the recent success of PD-1/PD-L1-directed immunotherapy in a number of different malignancies, there are currently no effective biomarkers available to predict patient response to treatment. This question is particularly important because these immunotherapy agents are expensive and have significant toxicity profiles. Early data are emerging on biomarkers such as PD-L1 expression; however, it is clear that further studies are needed to identify alternative biomarkers and to improve understanding of the host immune system and tumor microenvironment. In a panel interview Paolo Ascierto and Ramon de Mello discuss this important clinical question. © 2016 Future Medicine Ltd. Source


Chiarion-Sileni V.,Veneto Institute of Oncology IOV IRCCS | Pigozzo J.,Veneto Institute of Oncology IOV IRCCS | Ascierto P.A.,Cancer Immunotherapy and Innovative Therapy Unit | Simeone E.,Cancer Immunotherapy and Innovative Therapy Unit | And 14 more authors.
British Journal of Cancer | Year: 2014

Background:Retreatment with ipilimumab has been shown to re-establish disease control in some patients with disease progression. Here, we report the efficacy and safety of retreatment with ipilimumab 3 mg kg-1 among patients participating in an expanded access programme in Italy.Methods:Patients who achieved disease control during induction therapy were retreated with ipilimumab upon progression (3 mg kg-1 every 3 weeks for up to four doses), providing they had not experienced toxicity that precluded further dosing. Tumour assessments were conducted after retreatment, and patients were monitored throughout for adverse events.Results:Of 855 patients treated with ipilimumab, 51 were retreated upon disease progression. Of these, 28 (55%) regained disease control upon retreatment and 42% were alive 2 years after the first induction dose of ipilimumab; median overall survival was 21 months. Eleven patients (22%) had a treatment-related adverse event of any grade during retreatment. These were generally mild-to-moderate and resolved within a median of 4 days. No new types of toxicity were reported.Conclusions:For patients who meet predefined criteria, retreatment with ipilimumab is generally well tolerated and can translate into clinical benefit. This strategy should be compared with other therapeutic options in randomised controlled trials. © 2014 Cancer Research UK. Source


Grimaldi A.M.,Cancer Immunotherapy and Innovative Therapy Unit | Simeone E.,Cancer Immunotherapy and Innovative Therapy Unit | Giannarelli D.,Regina Elena Cancer Institute | Muto P.,Radiotherapy Unit | And 14 more authors.
OncoImmunology | Year: 2014

Cancer radiotherapy (RT) may induce what is referred to as the 'abscopal effect,' a regression of non-irradiated metastatic lesions distant from the primary tumor site directly subject to irradiation. This clinical response is rare, but has been surmised to be an immune-mediated phenomenon, suggesting that immunotherapy and RT could potentially synergize. Here, we report the outcome of patients with advanced melanoma treated with the immune checkpoint blockade monoclonal antibody antagonist, ipilimumab followed by RT. Patients were selected for enrollment at the National Cancer Institute 'Fondazione G. Pascale' through the expanded access program in Italy. Those who experienced disease progression after ipilimumab thus received subsequent RT and were selected for analysis. Among 21 patients, 13 patients (62%) received RT to treat metastases in the brain and 8 received RT directed at extracranial sites. An abscopal response was observed in 11 patients (52%), 9 of whom had partial responses (43%) and 2 had stable disease (10%). The median time from RT to an abscopal response was 1 month (range 1-4). Median overall survival (OS) for all 21 patients was 13 months (range 6-26). Median OS for patients with abscopal responses was extended to 22.4 months (range 2.5-50.3) vs. 8.3 months (range 7.6-9.0) without. A local response to RT was detected in 13 patients (62%) and, of these, 11 patients (85%) had an abscopal response and abscopal effects were only observed among patients exhibiting a local response. These results suggest RT after ipilimumab may lead to abscopal responses in some patients with advanced melanoma correlating with prolonged OS. Our data also suggest that local responses to RT may be predictive of abscopal responses. Further research in larger randomized trials is needed to validate these results. © 2014 Landes Bioscience. Source


Mozzillo N.,Melanoma and Sarcoma Surgery Unit | Simeone E.,Cancer Immunotherapy and Innovative Therapy Unit | Benedetto L.,Melanoma and Sarcoma Surgery Unit | Curvietto M.,Cancer Immunotherapy and Innovative Therapy Unit | And 14 more authors.
OncoImmunology | Year: 2015

Melanoma is responsible for most skin cancer-related deaths and is one of the most common cancers diagnosed in young adults. In melanoma, tumors can become established by activation of the negative regulator of cytotoxic T lymphocytes (CTLs), CTL antigen-4 (CTLA-4). Ipilimumab blocks the interaction of CTLA-4 with CD80/CD86 and augments T-cell activation and proliferation. In electrochemotherapy (ECT), local application of short high-voltage pulses renders cell membranes transiently permeable to chemotherapeutic drugs. The combination of ipilimumab and ECT may be beneficial for the treatment of metastatic melanoma; however, no prospective data are available to date. Here, we report the retrospective analysis of patients treated with ipilimumab in an expanded access program (EAP) who also received ECT. Fifteen patients with previously treated metastatic melanoma who received ipilimumab 3 mg/kg every three weeks for four cycles and underwent ECT for local disease control and/or palliation of cutaneous lesions with bleomycin 15 mg/m2 after the first ipilimumab infusion were included in the analysis. Over the study period, a local objective response was observed in 67% of patients (27% complete response [CR] and 40% partial response [PR]). According to immune-related response criteria, a systemic response was observed in nine patients (five PR and four stable disease [SD]), resulting in a disease control rate of 60%. Evaluation of circulating T-regulatory (T-reg) cells demonstrated significant differences between responders and non-responders. Overall, treatment was well-tolerated and without notable toxicity. In conclusion, the combination of ipilimumab and ECT appears to be beneficial to patients with advanced melanoma, warranting further investigation in prospective trials. © 2015, Taylor & Francis Group, LLC. Source

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