Phase II Study of Asparagine-Glycine-Arginine–Human Tumor Necrosis Factor α, a Selective Vascular Targeting Agent, in Previously Treated Patients With Malignant Pleural Mesothelioma

Gregorc, Vanesa; Zucali, Paolo Andrea; Santoro, Armando; Ceresoli, Giovanni Luca; Citterio, Giovanni; Pas, Tommaso Martino De; Zilembo, Nicoletta; Vincenzo, Fabio De; Simonelli, Matteo; Rossoni, G.; Spreafico, Anna; Viganò, Maria Grazia; Fontana, Floriana; Braud, Filippo de; Bajetta, Emilio; Caligaris-Cappio, Federico; Bruzzi, Paolo; Lambiase, A.; Bordignon, Claudio

doi:10.1200/jco.2009.27.3649

Cited by 104 publications

(89 citation statements)

References 39 publications

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“…[3][4][5][6][7][8][9] It shows antitumor activity at low dose (0.8 mg/sqm) and has a very low toxicity profile rendering it suitable for long-term maintenance treatment.…”

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confidence: 99%

The tumor vessel targeting agent NGR-TNF controls the different stages of the tumorigenic process in transgenic mice by distinct mechanisms

et al. 2015

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NGR-TNF is a vascular targeting agent in advanced clinical development, coupling tumor necrosis factor-a (TNF) with the CNGRCG peptide, which targets a CD13 isoform specifically expressed by angiogenic vessels. Antitumor efficacy of NGR-TNF has been described in different transplantation tumor models. Nevertheless, the mechanism underlying its activity is not fully understood. In the wild type and in the immunodeficient (RAG ¡/¡ ) RIP1-Tag2 models of multistage pancreatic carcinogenesis, we demonstrate that CD13 is highly expressed on endothelial cells of hyperplastic and angiogenic islets, whereas its expression is down regulated in tumors where it partially colocalize with pericytes. In vivo CNGRCG peptides coupled to fluorescent nanoparticles (quantum dots) bind to CD13 and colocalize with anti-CD31, in pancreatic islets. At early stage, low doses of NGR-murine (m)TNF have a direct cytotoxic effect inducing endothelial cell apoptosis, reducing vessel density and eventually inhibiting the development of angiogenic islets. At a later stage, NGRmTNF is able to reduce tumor growth inducing vascular normalization, exclusively when treatment is carried out in the immunocompetent mice. Interestingly, NGR-mTNF-treated tumors from these mice are characterized by CD8 C T cell infiltration. At molecular level, overexpression of genes involved in vessels normalization was detected only in NGRmTNF-treated tumors from immunocompetent mice.These findings identified a new mechanism of action of NGR-mTNF, providing support for the development of new therapeutic strategies combining chemotherapy or active/adoptive immunotherapies to low dose NGR-TNF treatment.

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“…[3][4][5][6][7][8][9] It shows antitumor activity at low dose (0.8 mg/sqm) and has a very low toxicity profile rendering it suitable for long-term maintenance treatment.…”

mentioning

confidence: 99%

The tumor vessel targeting agent NGR-TNF controls the different stages of the tumorigenic process in transgenic mice by distinct mechanisms

et al. 2015

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“…NGR-TNF, either alone or in combination with chemotherapy, is currently being tested in various clinical studies in cancer patients (18,19).…”

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confidence: 99%

Targeting TNF-α to Neoangiogenic Vessels Enhances Lymphocyte Infiltration in Tumors and Increases the Therapeutic Potential of Immunotherapy

Calcinotto

Grioni²,

Jachetti

et al. 2012

The Journal of Immunology

129

114

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Abnormal tumor vasculature impairs T lymphocyte adhesion to endothelial cells and lymphocyte extravasation into neoplastic tissues, limiting the therapeutic potential of both active and adoptive immunotherapies. We have found that treatment of tumor-bearing mice with NGR-TNF, a Cys-Asn-Gly-Arg-Cys peptide-TNF fusion product capable of altering the endothelial barrier function and improving drug penetration in tumors, associated with the intratumor upregulation of leukocyte-endothelial cell adhesion molecules, the release of proinflammatory cytokines and chemokines, and the infiltration of tumor-specific effector CD8+ T cells. As a result, NGR-TNF enhanced the therapeutic activity of adoptive and active immunotherapy, delaying tumor growth and prolonging survival. Furthermore, we have found that therapeutic effects of these combinations can be further increased by the addition of chemotherapy. Thus, these findings might be relevant for the design of novel immunotherapeutic approaches for cancer patients.

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“…It selectively targets TNF to an aminopeptidase N/CD13 isoform overexpressed by endothelial cells in solid tumors. A single agent phase 2 trial in 57 pretreated MPM patients showed a disease control rate of 46%, these patients experienced a median progressionfree time of 4.4 months [47]. These results lead to a randomized phase 2 study NGR015 in which pemetrexed pretreated patients receive second line chemotherapy vinorelbin or doxorubicin combined with either NGR-hTNF or placebo.…”

Section: Immunomodulation and Other Pathwaysmentioning

confidence: 99%

Second line therapy in malignant pleural mesothelioma: A systematic review

et al. 2015

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a b s t r a c tAfter the implementation of standard first line chemotherapy with platinum and antifolates in pleural mesothelioma, patients are confronted with a need for second line treatment at relapse or progression. We conducted a systematic review of the literature for the activity, effectiveness and toxicity of second line treatment. The results are presented according to the class of drugs: chemotherapy and targeted or biological agent.

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Phase II Study of Asparagine-Glycine-Arginine–Human Tumor Necrosis Factor α, a Selective Vascular Targeting Agent, in Previously Treated Patients With Malignant Pleural Mesothelioma

Abstract: The tolerability and disease control of NGR-hTNF 0.8 microg/m(2) weekly warrant additional evaluation in patients with advanced MPM.

Cited by 104 publications

References 39 publications

The tumor vessel targeting agent NGR-TNF controls the different stages of the tumorigenic process in transgenic mice by distinct mechanisms

The tumor vessel targeting agent NGR-TNF controls the different stages of the tumorigenic process in transgenic mice by distinct mechanisms

Targeting TNF-α to Neoangiogenic Vessels Enhances Lymphocyte Infiltration in Tumors and Increases the Therapeutic Potential of Immunotherapy

Second line therapy in malignant pleural mesothelioma: A systematic review

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