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


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
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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.
    Full-text · Article · Mar 2014 · Journal of Experimental & Clinical Cancer Research
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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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    Full-text · Article · Aug 2013 · PLoS ONE
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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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