What is the role of MTP-PE in immunotherapeutic targeting in pediatric oncology?

Updated: Mar 20, 2018
  • Author: Crystal L Mackall, MD; Chief Editor: Jennifer Reikes Willert, MD  more...
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Answer

Answer

Muramyl tripeptide phosphatidylethanolamine (MTP-PE) is an analog of muramyl dipeptide, a substance contained within the cell wall of mycobacteria that has immune-activating activity. When MTP-PE is encapsulated in multilamellar liposomes (L-MTP-PE), it is efficiently delivered to the liver, spleen, lung, nasopharynx, and thyroid after intravenous (IV) infusion. [3]

L-MTP-PE can bind to TLR4 on monocytes and macrophages, leading to activation of these cells and promoting antitumor activity. [24] Presumably, the antitumor effects of MTP-PE are mediated via release of interleukin (IL)-1β, IL-6, IL-8, nitric oxide (NO), prostaglandin E2 (PGE2) and tumor necrosis factor alpha (TNF-α). [25] The exact mechanism whereby monocyte/macrophage activation and cytokine release results in tumor cell death remains incompletely understood.

MTP-PE administration has been primarily studied in pediatric patients with osteosarcoma, a disease that frequently metastasizes to the lung and a disease in which micrometastases cause treatment failure in almost 40% of patients despite administration of multiagent chemotherapy.

In a phase II trial, MTP-PE prolonged disease-free survival in a group that received 24 weeks of therapy. [3] In addition, peripheral fibrosis, inflammatory cell infiltration, and neovascularization were observed in metastases from recipients of MTP-PE but not in control subjects. Thus, this trial suggested that L-MTP-PE is an active biologic agent that can produce a survival benefit in this patient population. [25]

Further investigation of MTP-PE in patients with osteosarcoma was undertaken in a phase III trial, in which improved survival rates were noted in patients who received ifosfamide-containing cytotoxic drug therapy (ie, cisplatin, methotrexate, doxorubicin [Adriamycin], and ifosfamide) with MTP-PE but were not observed in those receiving MTP-PE without ifosfamide. [25]

Notably, this study was configured with a factorial design, wherein patients were randomized to 1 of 4 arms, with the intent to compare the use of 3 standard drugs versus 4 standard drugs and, in a separate question, to answer whether the addition of MTP-PE improved outcome. Because no benefit was observed when MTP-PE was used in the absence of ifosfamide, which was an unexpected finding, the investigators were not able to conclude a definitive benefit from MTP-PE as a single agent.

To date, MTP-PE has not been approved by the US Food and Drug Administration (FDA) for use in osteosarcoma. At present, therefore, it is not readily available for treatment of patients with this disease.


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