Phase II study of NGR-hTNF in combination with doxorubicin in relapsed ovarian cancer patients

Lorusso, Domenica; Scambia, Giovanni; Amadio, Giulia; Legge, A. Di; Pietragalla, Antonella; Vincenzo, Rosa De; Masciullo, Valeria; Stefano, Mariella Di; Mangili, Giorgia; Citterio, Giovanni; Mantori, M; Lambiase, A.; Bordignon, Claudio

doi:10.1038/bjc.2012.233

Cited by 39 publications

(22 citation statements)

References 30 publications

(36 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Notably, a recent phase II study of NGR-TNF (0.8 μg/m2) in combination with doxorubicin in relapsed ovarian cancer patients showed that patients with baseline peripheral blood lymphocyte count higher than the first quartile had improved progression-free survival and overall survival (53), therefore suggesting that a similar effect may occur in humans.…”

Section: Ways To Favor T Cell Adhesion To Tumor-associated Endotheliamentioning

confidence: 99%

Ways to Enhance Lymphocyte Trafficking into Tumors and Fitness of Tumor Infiltrating Lymphocytes

Bellone¹,

Calcinotto²

2013

Front. Oncol.

135

110

View full text Add to dashboard Cite

The tumor is a hostile microenvironment for T lymphocytes. Indeed, irregular blood flow, and endothelial cell (EC) anergy that characterize most solid tumors hamper leukocyte adhesion, extravasation, and infiltration. In addition, hypoxia and reprograming of energy metabolism within cancer cells transform the tumor mass in a harsh environment that limits survival and effector functions of T cells, regardless of being induced in vivo by vaccination or adoptively transferred. In this review, we will summarize on recent advances in our understanding of the characteristics of tumor-associated neo-angiogenic vessels as well as of the tumor metabolism that may impact on T cell trafficking and fitness of tumor infiltrating lymphocytes. In particular, we will focus on how advances in knowledge of the characteristics of tumor ECs have enabled identifying strategies to normalize the tumor-vasculature and/or overcome EC anergy, thus increasing leukocyte-vessel wall interactions and lymphocyte infiltration in tumors. We will also focus on drugs acting on cells and their released molecules to transiently render the tumor microenvironment more suitable for tumor infiltrating T lymphocytes, thus increasing the therapeutic effectiveness of both active and adoptive immunotherapies.

show abstract

Section: Ways To Favor T Cell Adhesion To Tumor-associated Endotheliamentioning

confidence: 99%

Ways to Enhance Lymphocyte Trafficking into Tumors and Fitness of Tumor Infiltrating Lymphocytes

Bellone¹,

Calcinotto²

2013

Front. Oncol.

135

110

View full text Add to dashboard Cite

show abstract

“…Recently, peptides containing the asparagine-glycine-arginine (Asn-Gly-Arg, NGR) motif [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75] and their deamidation products containing the iso DGR motif [38,41,46,48,56,59,74,76,77,78,79,80,81...…”

Section: Introductionmentioning

confidence: 99%

Succinimide Formation from an NGR-Containing Cyclic Peptide: Computational Evidence for Catalytic Roles of Phosphate Buffer and the Arginine Side Chain

Kirikoshi

Manabe

Takahashi

2017

IJMS

View full text Add to dashboard Cite

The Asn-Gly-Arg (NGR) motif and its deamidation product isoAsp-Gly-Arg (isoDGR) have recently attracted considerable attention as tumor-targeting ligands. Because an NGR-containing peptide and the corresponding isoDGR-containing peptide target different receptors, the spontaneous NGR deamidation can be used in dual targeting strategies. It is well known that the Asn deamidation proceeds via a succinimide derivative. In the present study, we computationally investigated the mechanism of succinimide formation from a cyclic peptide, c[CH2CO-NGRC]-NH2, which has recently been shown to undergo rapid deamidation in a phosphate buffer. An H2PO4− ion was explicitly included in the calculations. We employed the density functional theory using the B3LYP functional. While geometry optimizations were performed in the gas phase, hydration Gibbs energies were calculated by the SM8 (solvation model 8) continuum model. We have found a pathway leading to the five-membered ring tetrahedral intermediate in which both the H2PO4− ion and the Arg side chain act as catalyst. This intermediate, once protonated at the NH2 group on the five-membered ring, was shown to easily undergo NH3 elimination leading to the succinimide formation. This study is the first to propose a possible catalytic role for the Arg side chain in the NGR deamidation.

show abstract

“…[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

View full text Add to dashboard Cite

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.

show abstract

Phase II study of NGR-hTNF in combination with doxorubicin in relapsed ovarian cancer patients

Cited by 39 publications

References 30 publications

Ways to Enhance Lymphocyte Trafficking into Tumors and Fitness of Tumor Infiltrating Lymphocytes

Ways to Enhance Lymphocyte Trafficking into Tumors and Fitness of Tumor Infiltrating Lymphocytes

Succinimide Formation from an NGR-Containing Cyclic Peptide: Computational Evidence for Catalytic Roles of Phosphate Buffer and the Arginine Side Chain

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

Contact Info

Product

Resources

About