Peptide-Mediated Targeting of Cytokines to Tumor Vasculature: The NGR-hTNF Example

Abstract

A growing body of evidence suggests that the efficacy of cytokines in cancer therapy can be increased by targeting strategies based on conjugation with ligands that recognize receptors expressed by tumor cells or elements of the tumor microenvironment, including the tumor vasculature. The targeting approach is generally conceived to permit administration of low, yet pharmacologically active, doses of drugs, thereby avoiding toxic reactions. However, it is becoming clear that, in the case of cytokines, this strategy has another inherent advantage, i.e. the possibility of administering extremely low doses that do not activate systemic counter-regulatory mechanisms, which may limit their potential therapeutic effects. This review is focused on the use of tumor vasculature-homing peptides as vehicles for targeted delivery of cytokines to tumor blood vessel. In particular, we provide an overview of peptide-cytokine conjugates made with peptides containing the NGR, RGD, isoDGR or RGR sequences and describe, in more details, the biological and pharmacological properties of NGR-hTNF, a peptide-tumor necrosis factor-α conjugate that is currently being tested in phase II and III clinical studies. The results of preclinical and clinical studies performed with these products suggest that peptide-mediated vascular-targeting is indeed a viable strategy for delivering bioactive amounts of cytokines to tumor endothelial cells without causing the activation of counter-regulatory mechanisms and toxic reactions.

Self-targeting of TNF-releasing cancer cells in preclinical models of primary and metastatic tumors

“…Thus, we reasoned that "armed" tumor cells genetically manipulated to express anticancer cytokines and subsequently administered into the bloodstream should be able to deliver such factors focally to both primary and metastatic lesions as a therapeutic strategy. This delivery method may circumvent toxicity and activation of systemic counterregulatory mechanisms, which currently cause major limitations for cytokine biotherapy against cancer (8). To address this hypothesis experimentally, we engineered murine mammary adenocarcinoma, melanoma, and lung carcinoma cells to produce and release tumor necrosis factor alpha (TNF), a cytokine that damages the tumor vascular endothelia and has anticancer activity (9-11).…”

A pilot Phase I study combining peptide-based vaccination and NGR-hTNF vessel targeting therapy in metastatic melanoma

“…Since we have previously shown that CgA and sTNF-Rs can negatively affect the antitumor activity of NGR-TNF in mice, 12,14 the circulating levels of these proteins at baseline were analyzed. Except for patients 05 and 04, who had CgA and soluble tumor necrosis factor receptor 1 (sTNF-R1) or sTNF-R2 levels greater than normal values, all other patients had relatively low levels of these proteins in the circulation.…”

“…These mechanisms associate with increased tumor infiltration of endogenous or adoptively transferred cytotoxic T lymphocytes in transplantable models of melanoma and can enhance the response to adoptive and active immunotherapy even in animal models of spontaneous prostate cancer. 13,14 Various Phase I and II studies have been performed with human NGR-TNF (NGR-hTNF) in patients with solid tumors, both as a single agent and in combination with chemotherapy. (reviewed in 14 ) Phase I studies have shown that NGR-hTNF is well tolerated (maximum tolerated dose was 45 mg/m 2 administered in 1 h).…”

“…13,14 Various Phase I and II studies have been performed with human NGR-TNF (NGR-hTNF) in patients with solid tumors, both as a single agent and in combination with chemotherapy. (reviewed in 14 ) Phase I studies have shown that NGR-hTNF is well tolerated (maximum tolerated dose was 45 mg/m 2 administered in 1 h). 14,15 Chills and fever were the most frequently observed toxicities.…”

“…(reviewed in 14 ) Phase I studies have shown that NGR-hTNF is well tolerated (maximum tolerated dose was 45 mg/m 2 administered in 1 h). 14,15 Chills and fever were the most frequently observed toxicities. Based on soluble receptors shedding, tolerability, anti-vascular effects and disease control, the dose of 0.8 mg/m 2 of NGR-hTNF was chosen for subsequent studies, either alone or with standard chemotherapy.…”