Liposomal Muramyl Tripeptide Phosphatidylethanolamine: Targeting and Activating Macrophages for Adjuvant Treatment of Osteosarcoma

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Current Cancer Drug Targets (Impact Factor: 3.52). 04/2006; 6(2):123-33. DOI: 10.2174/156800906776056473
Source: PubMed

ABSTRACT About one third of osteosarcoma patients develop lung metastasis refractory to chemotherapy. Recent studies indicate that biological response modifiers activating the patient's immune system may help controlling minimal residual disease via pathways distinct from those used by cytotoxic drugs, and therefore prove effective against tumor resistance. Muramyl tripeptide phosphatidylethanolamine (MTP-PE) is a synthetic lipophilic glycopeptide capable of activating monocytes and macrophages to a tumoricidal state. When intercalated in multilamellar liposomes (L-MTP-PE) and injected intravenously, it targets lung, liver, and spleen macrophages. Therapeutic activity of L-MTP-PE was demonstrated in several preclinical models of experimental lung metastasis and in clinical trials in dogs with osteosarcoma. Although macrophage activation was shown to be directly involved in the in vivo anti-metastatic activity of this molecule, cytokine and chemokine secretion by activated macrophages could induce recruitment and stimulation of other immune cells, which may in turn indirectly contribute to the anti-tumor effect. L-MTP-PE has undergone clinical development in humans. In early trials, most side effects of L-MTP-PE were minimal. L-MTP-PE showed signs of efficacy in treatment of patients with recurrent osteosarcoma and the encouraging results from phase II studies led to a phase III trial conducted by the Children's Oncology Group in patients with newly diagnosed high-grade osteosarcoma. Patients were treated with or without L-MTP-PE in combination with multi-drug chemotherapy in adjuvant setting; significantly higher overall survival and disease-free survival were observed in the group receiving L-MTP-PE.

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Available from: Jean-Pierre Abastado, Sep 27, 2015
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    • "IFN-γ was originally described as macrophage-activating factor [36]. ‘Priming’ of macrophages by IFN-γ may enhance liposome uptake and improve the response to bacterial components by, for instance, intracellular NOD2, which is the receptor for MDP and presumably MTP-PE [21,37-39]. The significance of IFN-γ observed in our experiments reproduces previous studies using different tumor cells which showed that activation of human/murine monocytes/macrophages by L-MTP-PE was enhanced by simultaneous or preceding stimulation with IFN-γ [17,21,38]. Furthermore, addition of IFN-γ to L-MTP-PE was reported to improve survival and inhibit metastases in murine renal adenocarcinoma [40]. "
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    ABSTRACT: In osteosarcoma, the presence of tumor-infiltrating macrophages positively correlates with patient survival in contrast to the negative effect of tumor-associated macrophages in patients with other tumors. Liposome-encapsulated muramyl tripeptide (L-MTP-PE) has been introduced in the treatment of osteosarcoma patients, which may enhance the potential anti-tumor activity of macrophages. Direct anti-tumor activity of human macrophages against human osteosarcoma cells has not been described so far. Hence, we assessed osteosarcoma cell growth after co-culture with human macrophages. Monocyte-derived M1-like and M2-like macrophages were polarized with LPS + IFN-gamma, L-MTP-PE +/- IFN-gamma or IL-10 and incubated with osteosarcoma cells. Two days later, viable tumor cell numbers were analyzed. Antibody-dependent effects were investigated using the therapeutic anti-EGFR antibody cetuximab. M1-like macrophages inhibited osteosarcoma cell growth when activated with LPS + IFN-gamma. Likewise, stimulation of M1-like macrophages with liposomal muramyl tripeptide (L-MTP-PE) inhibited tumor growth, but only when combined with IFN-gamma. Addition of the tumor-reactive anti-EGFR antibody cetuximab did not further improve the anti-tumor activity of activated M1-like macrophages. The inhibition was mediated by supernatants of activated M1-like macrophages, containing TNF-alpha and IL-1beta. However, specific blockage of these cytokines, nitric oxide or reactive oxygen species did not inhibit the anti-tumor effect, suggesting the involvement of other soluble factors released upon macrophage activation. While LPS + IFN-gamma-activated M2-like macrophages had low anti-tumor activity, IL-10-polarized M2-like macrophages were able to reduce osteosarcoma cell growth in the presence of the anti-EGFR cetuximab involving antibody-dependent tumor cell phagocytosis. This study demonstrates that human macrophages can be induced to exert direct anti-tumor activity against osteosarcoma cells. Our observation that the induction of macrophage anti-tumor activity by L-MTP-PE required IFN-gamma may be of relevance for the optimization of L-MTP-PE therapy in osteosarcoma patients.
    Journal of Experimental & Clinical Cancer Research 03/2014; 33(1):27. DOI:10.1186/1756-9966-33-27 · 4.43 Impact Factor
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    • "Adoptive cellular immunotherapy is currently accepted as a suitable alternative to surgery and chemotherapy for osteosarcoma patients because of its easy and painless administration and improved safety [7], [8]. It is well known that optimal activation of antigen-specific lymphocytes requires a combination of T-cell receptors (TCRs) and costimulatory signals [9]. "
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    ABSTRACT: B7-H3 is a member of the B7-family of co-stimulatory molecules, which has been shown to be broadly expressed in various tumor tissues, and which plays an important role in adaptive immune responses. The role of B7-H3 in osteosarcoma, however, remains unknown. In this study we used immunohistochemistry to analyze B7-H3 expression in 61 primary osteosarcoma tissues with case-matched adjacent normal tissues, and 37 osteochondroma and 20 bone fibrous dysplasia tissues. B7-H3 expression was expressed in 91.8% (56/61) of the osteosarcoma lesions, and the intensity of B7-H3 expression in osteosarcoma was significantly increased compared with adjacent normal tissues, osteochondroma and bone fibrous dysplasia tissues (p<0.001). Patients with high tumor B7-H3 levels had a significantly shorter survival time and recurrence time than patients with low tumor B7-H3 levels (p<0.001). Moreover, tumor B7-H3 expression inversely correlated with the number of tumor-infiltrating CD8(+) T cells (p<0.05). In vitro, increasing expression of B7-H3 promotes osteosarcoma cell invasion, at least in part by upregulating matrix metalloproteinase-2 (MMP-2). In conclusion, our study provides the first evidence of B7-H3 expression in osteosarcoma cells as a potential mechanism controlling tumor immunity and invasive malignancy, and which is correlated with patients' survival and metastasis.
    PLoS ONE 08/2013; 8(8):e70689. DOI:10.1371/journal.pone.0070689 · 3.23 Impact Factor
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    • "Macrophages can be targeted and activated to confer tumor suppressive properties in cancer treatment.77,78 Activation of macrophages results in augmenting antitumor immune responses by the induction of proinflammatory mediators such as TNF-α, IL-8, and nitric oxide.79,80 "
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    ABSTRACT: Liposomes are biodegradable and can be used to deliver drugs at a much higher concentration in tumor tissues than in normal tissues. Both passive and active drug delivery by liposomal nanoparticles can significantly reduce the toxic side effects of anticancer drugs and enhance the therapeutic efficacy of the drugs delivered. Active liposomal targeting to tumors is achieved by recognizing specific tumor receptors through tumor-specific ligands or antibodies coupled onto the surface of the liposomes, or by stimulus-sensitive drug carriers such as acid-triggered release or enzyme-triggered drug release. Tumors are often composed of tumor cells and nontumor cells, which include endothelial cells, pericytes, fibroblasts, stromal, mesenchymal cells, innate, and adaptive immune cells. These nontumor cells thus form the tumor microenvironment, which could be targeted and modified so that it is unfavorable for tumor cells to grow. In this review, we briefly summarized articles that had taken advantage of liposomal nanoparticles as a carrier to deliver anticancer drugs to the tumor microenvironment, and how they overcame obstacles such as nonspecific uptake, interaction with components in blood, and toxicity. Special attention is devoted to the liposomal targeting of anticancer drugs to the endothelium of tumor neovasculature, tumor associated macrophages, fibroblasts, and pericytes within the tumor microenvironment.
    International Journal of Nanomedicine 01/2013; 8:61-71. DOI:10.2147/IJN.S37859 · 4.38 Impact Factor
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