Muramyl Tripeptide Phosphatidylethanolamine Research Articles

Activation of the Intracellular Pattern Recognition Receptor NOD2 Promotes Acute Myeloid Leukemia (AML) Cell Apoptosis and Provides a Survival Advantage in an Animal Model of AML.

TLRs, a family of membrane-bound pattern recognition receptors found on innate immune cells, have been well studied in the context of cancer therapy. Activation of these receptors has been shown to induce inflammatory anticancer events, including differentiation and apoptosis, across a wide variety of malignancies. In contrast, intracellular pattern recognition receptors such as NOD-like receptors have been minimally studied. NOD2 is a member of the NOD-like receptor family that initiates inflammatory signaling in response to the bacterial motif muramyl dipeptide. In this study, we examined the influence of NOD2 in human acute myeloid leukemia (AML) cells, demonstrating that IFN-γ treatment upregulated the expression of NOD2 signaling pathway members SLC15A3 and SLC15A4, downstream signaling kinase RIPK2, and the NOD2 receptor itself. This priming allowed for effective induction of caspase-1-dependent cell death upon treatment with muramyl tripeptide phosphatidylethanolamine (MTP-PE), a synthetic ligand for NOD2. Furthermore, the combination of MTP-PE and IFN-γ on AML blasts generated an inflammatory cytokine profile and activated NK cells. In a murine model of AML, dual treatment with MTP-PE and IFN-γ led to a significant increase in mature CD27- CD11b+ NK cells as well as a significant reduction in disease burden and extended survival. These results suggest that NOD2 activation, primed by IFN-γ, may provide a novel therapeutic option for AML.

Combination therapy of liposome-entrapped muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) against syngeneic tumors in mice

Combination therapy of liposome-entrapped muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) against syngeneic tumors in mice

Orphan designation: Muramyl tripeptide phosphatidyl ethanolamine, Treatment of osteosarcoma

Orphan designation: Muramyl tripeptide phosphatidyl ethanolamine, Treatment of osteosarcoma

Osteogenic Sarcoma: Systemic Chemotherapy Options for Localized Disease.

Treatment for osteosarcoma, the most common malignant tumor of bone in children and adolescents, has not changed in decades. Treatment is multimodal, employing neoadjuvant chemotherapy followed by aggressive and complete surgical resection to achieve negative margins and a prolonged course of adjuvant chemotherapy. The primary tumor is usually successfully managed via surgery, but micrometastases are likely present in most patients at diagnosis. Death is the result of tumor recurrence in the lungs or more rarely in other bones despite aggressive treatment regimens and is likely attributable to innate resistance to chemotherapy. Better therapies are desperately needed. The three most active agents-high-dose methotrexate, doxorubicin, and cisplatin-commonly referred to as "MAP," form the backbone of therapy. After 2cycles of MAP, surgical resection is performed of all sites of disease if possible. Histologic response following neoadjuvant chemotherapy is prognostic in non-metastatic osteosarcoma, but augmentation of adjuvant therapy for poor responders with additional agents (ifosfamide, etoposide) has not improved outcome. Inclusion of immunotherapy into treatment regimens is promising. Specifically, liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE), a macrophage and monocyte activator, improved 10-year overall survival for patients with localized disease, with a similar pattern of response in patients with metastatic disease. L-MTP-PE (mifamurtide) is approved and in widespread use in Europe and elsewhere but has not been approved for use by the Federal Drug Administration in the USA. Identifying novel targeted therapies to improve outcomes for patients with osteosarcoma remains an area of active research.

Monocytes, Macrophages, and Osteoclasts in Osteosarcoma.

Macrophages appear to have a fundamental role in the pathogenesis of osteosarcoma. These highly diverse plastic cells are subdivided into classical or inflammatory macrophages known as M1 and alternative macrophages, which decrease inflammation and are reparative, called M2. Although primary and metastatic osteosarcomas are infiltrated with M2 macrophages, targeting the M1 macrophages with the immune adjuvant muramyl tripeptide phosphatidyl ethanolamine (MTP-PE) has been the greatest recent therapeutic advance in osteosarcoma. This discrepancy between the presence of M2 and activation of M1 macrophages is intriguing and is likely explained either by the plasticity of M1 and M2 macrophages or nonclassical patrolling monocytes (PMos). To date, MTP-PE has been approved in combination with chemotherapy for nonmetastatic osteosarcoma, but its use in metastatic tumors has not been investigated. In this review, we focus on macrophages, monocytes, and osteoclasts, their role in osteosarcoma, and the potential for targeting these cells in this disease.

Immunotherapy for Bone and Soft Tissue Sarcomas.

Although multimodal therapies including surgery, chemotherapy, and radiotherapy have improved clinical outcomes of patients with bone and soft tissue sarcomas, the prognosis of patients has plateaued over these 20 years. Immunotherapies have shown the effectiveness for several types of advanced tumors. Immunotherapies, such as cytokine therapies, vaccinations, and adoptive cell transfers, have also been investigated for bone and soft tissue sarcomas. Cytokine therapies with interleukin-2 or interferons have limited efficacy because of their cytotoxicities. Liposomal muramyl tripeptide phosphatidylethanolamine (L-MTP-PE), an activator of the innate immune system, has been approved as adjuvant therapeutics in combination with conventional chemotherapy in Europe, which has improved the 5-year overall survival of patients. Vaccinations and transfer of T cells transduced to express chimeric antigen receptors have shown some efficacy for sarcomas. Ipilimumab and nivolumab are monoclonal antibodies designed to inhibit immune checkpoint mechanisms. These antibodies have recently been shown to be effective for patients with melanoma and also investigated for patients with sarcomas. In this review, we provide an overview of various trials of immunotherapies for bone and soft tissue sarcomas, and discuss their potential as adjuvant therapies in combination with conventional therapies.

Muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) in the treatment of osteosarcoma.

Bacille Calmette-Guerin (BCG) has been used for decades as an immune stimulant to treat cancer. Early work by Fidler and Kleinerman identified muramyl dipeptide (MDP) as a critical component of the BCG cell wall which retained most of the immunostimulatory properties of the native BCG. Addition of a peptide to MDP resulted in muramyl tripeptide (MTP) which allowed incorporation into liposomal membranes. The resulting pharmaceutical, liposomal muramyl tripeptide phosphatidyl ethanolamine (L-MTP-PE or mifamurtide) showed activity in preclinical models of human cancers. Phase I studies documented the safety of the compound for human administration. These trials did not reach a maximally tolerated dose (MTD), and the dose chosen for phase II trials was a biologically optimized dose, not an MTD. Phase II studies showed decreased risk of further recurrence in patients who received mifamurtide after surgical ablation of metastatic osteosarcoma. A phase III prospective randomized trial demonstrated a statistically significant reduction in the risk of death from osteosarcoma when MTP was added to systemic chemotherapy for the treatment of localized osteosarcoma. The same trial allowed treatment of patients who presented with initially metastatic disease. While the overall and event-free survival was improved in patients with metastatic osteosarcoma who received L-MTP-PE, the sample size was small and the improvement did not achieve conventional statistical significance. From 2008 to 2012, patients with metastatic and recurrent osteosarcoma were given L-MTP-PE in an expanded access trial, and the results suggest a decreased risk of subsequent recurrence and death with the inclusion of L-MTP-PE in the treatment strategy for these high-risk patients.

Treating pediatric osteosarcoma: recent clinical trial evidence

Pediatric osteosarcoma is most commonly diagnosed during adolescence and young adulthood and requires treatment with surgical intervention and intensive chemotherapy. While the exact molecular mechanism leading to osteosarcoma has yet to be elucidated, some syndromes and genetic conditions have been associated with development of the disease. Treatment of osteosarcoma has always included surgical intervention with amputation being most common prior to the introduction of multi-agent chemotherapy. The introduction of multi-agent chemotherapy along with improved surgical techniques have allowed increasing use of limb-salvage surgery. Current investigations including the use of modern chemotherapy show no detectable survival difference between amputation and limb salvage surgery. Standard neo-adjuvant and adjuvant regimens using a combination of doxorubicin, cisplatin and methotrexate, with or without ifosfamide have become the standard in the medical management of osteosarcoma. Other newer agents, such as HER2 receptor monoclonal antibody and muramyl tripeptide phosphatidylethanolamine have also been investigated and are included in this review.

Abstract 3980: The immunomodulatory agent L-MTP-PE induces activation and expansion of human γδ T cells capable of lysing osteosarcoma cells.

Abstract The outcome of patients with metastatic osteosarcoma remains poor despite aggressive multimodality therapy. Liposomal Muramyl Tripeptide Phosphatidyl Ethanolamine (L-MTP-PE) is a non-specific immune modulator that activates monocytes and macrophages and has shown antitumor activity in osteosarcoma. The mechanism of action of L-MTP-PE remains unresolved. Here we investigated the effects of the agent on lymphocyte subpopulations. Whole peripheral blood from 9 healthy donors were stimulated with L-MTP-PE for 24 hours. Compared to non-stimulated controls, a proliferative response of CD3+ lymphocytes was found (1.77±0.06 fold expansion, p=<0.001). The strongest effect was observed on the γδ TCR+ CD3+ T cell subpopulation which expanded 5.0±1.0 fold. To further evaluate the effects of L-MTP-PE on γδ T cell proliferation, mononuclear cells were isolated from peripheral blood of 5 healthy donors and cultured in the presence of L-MTP-PE. On day 11, γδ T cells had expanded 4.6±0.6 fold compared to medium-controls. Addition of interleukin-2 (IL-2) to the cultures increased expansion of γδ T cells up to 9.8±1.6. In comparison, the known γδ T-cell stimulatory aminobisphosphonate agent zoledronic acid (ZA) combined with IL-2 induced 25.8±7.2-fold expansion. γδ T cell stimulation by ZA was previously shown to involve inhibition of the mevalonate pathway enzyme farnesyl diphosphate synthase and subsequent increase of isopentyl pyrophosphate levels. To explore the mechanism of γδ T cell expansion by L-MTP-PE, coincubation experiments were repeated in the presence of the HMG-CoA reductase inhibitor mevastatin. Addition of mevastatin resulted in a 5.1±1.8-fold reduction of L-MTP-PE induced γδ T cell expansion, confirming a critical role of the mevalonate pathway in γδ T cell expansion and thus a mechanism comparable to ZA. To explore the in vitro antitumor activity of L-MTP-PE activated γδ T cells, 24 hour coincubation experiments were performed with the osteosarcoma cell lines HOS and SAOS on day 6 of cultures. In a flow-cytometry based cytotoxicity assay, substantial cytolysis of osteosarcoma cells from both cell lines was observed after coincubation with both L-MTP-PE- and L-MTP-PE/IL-2-stimulated γδ T cells. At an effector-to-target-ratio of 1:1, L-MTP-PE-stimulated γδ T cells reduced viable cell counts of HOS and SAOS to 41.4±2.7% and 54.0±7.6%, respectively, and L-MTP-PE/IL-2-stimulated γδ T cells decreased cell counts to 33.7±2.0% and 23.0±0.9%. In comparison, ZA/IL-2-stimulated γδ T cells resulted in reduced viability to 46.2±1.0% (HOS) and 38.9±3.8% (SAOS). We conclude that L-MTP-PE induces effective in vitro expansion of γδ T cells via a mechanisms involving the mevalonate pathway, in a manner similar to aminobisphosphonate agents. L-MTP-PE-activated γδ T cells have the potential to lyse osteosarcoma cells and may thus be involved in the antitumor effects of this agents. Citation Format: Sibylle Mellinghoff, Bianca Altvater, Uta Dirksen, Heribert Juergens, Claudia Rossig, Martina Ahlmann. The immunomodulatory agent L-MTP-PE induces activation and expansion of human γδ T cells capable of lysing osteosarcoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3980. doi:10.1158/1538-7445.AM2013-3980

1518TiP - Observational, Noninterventional Surveillance Study of Patients with High-Grade Osteosarcoma who are Candidates for Liposomal Mifamurtide Treatment

ABSTRACT Background Although surgery is the mainstay of osteosarcoma treatment, it is generally not curative and prognosis is poor. Survival rates improved with the introduction of adjuvant and neoadjuvant chemotherapy but have remained largely unchanged since the 1980s. Mifamurtide is a liposomal formulation of muramyl tripeptide phosphatidyl ethanolamine, which stimulates macrophages and monocytes, resulting in tumoricidal effects. In a phase 3 trial in 678 patients with newly diagnosed high-grade osteosarcoma, mifamurtide given post-resection in combination with chemotherapy improved 6-year overall survival probability to 77% vs. 66% with chemotherapy alone (p = 0.03; mifamurtide assessment report [www.ema.europa.eu]). The most common grade 3/4 adverse events (AEs) were cytopenias, stomatitis and infections, with no difference between the treatment arms for most toxicities reported (www.ema.europa.eu). Methods This phase 4 study will assess osteosarcoma patients who are candidates for mifamurtide therapy at European centres. (EudraCT: 2009-017204-89;NCT01194284). Eligible patients are aged 2–30 years, with a confirmed diagnosis of high-grade osteosarcoma. Approximately 150 patients are planned to be entered, and recruited over a 2-year period. Patients will receive the standard schedule of 2 mg/m2 IV mifamurtide, administered twice weekly for 12 weeks then once weekly for 24 weeks (total 36 weeks). The primary objectives are to assess the short- (during treatment) and long-term (≤5 years from last mifamurtide dose or until death) safety profile of mifamurtide, including evaluation of AEs of special interest (defined as important identified and potential risks) to take into account the risk of recurrence and comorbidities with chemotherapy. Secondary objectives include assessment of disease status, disease-free survival and overall survival. Disclosure C. Oliva: Employment: Takeda. Y. Liu: Employment: Millennium. All other authors have declared no conflicts of interest.

1508P - Mifamurtide (L-MTP-PE) for Metastatic and Recurrent Osteosarcoma (OS): Survival and Safety Profile from a Patient Access Study

ABSTRACT Introduction and research objectives Liposomal muramyl tripeptide phosphatidyl ethanolamine (L-MTP-PE; mifamurtide) is approved for treatment of non-metastatic osteosarcoma (OS) in Europe, Israel, and Mexico. The primary objective of MTP-OS-403 was to collect information regarding the safety and tolerability of MTP in patients with high-risk OS. The open label access study called for L-MTP-PE 2mg/m2 twice /week x 24 doses, then weekly (total doses= 48 in 9 months). OS patients could receive MTP as a single agent or with appropriate chemotherapy. Results As of April 2012, 202 patients were registered at 8 participating centers. Most had metastases at initial presentation or recurrent OS. Median age was 16 yr. Time from initial diagnosis to L-MTP-PE treatment was 29 +/- 23 months (median 24 mo). Although >88% had metastases, 27% had been resected to no evidence of disease (NED) before study entry. The most common Infusion related AE (IRAE) within 24 hours of infusion were chills (37%), fever (25%), nausea (21%), headache (19%), and fatigue (15%). The most common AE (grade 3-4) other than IRAE were chemotherapy-related and included thrombocytopenia (22%), neutropenia (19%), leukopenia (18%), febrile neutropenia (16%), lymphopenia (15%), and anaemia (15%). At MDACC, there was 1 episode of pleural effusion and one episode of pericardial effusion that were possibly L-MTP-PE related. The median number of L-MTP-PE doses given was 34 (mean 30.1 +/- 17.5); 32% of these high risk OS patients received 48 doses. As of April 2012 45% (90/202) of these high risk OS patients continue to be followed for survival. Conclusion The safety profile of L-MTP-PE in high-risk OS patients is consistent with the known toxicity of the product. The infusion related AEs were generally mild to moderate. Since survival benefit in high-grade OS from MTP may be related to disease burden (i.e. achieving NED status using local control measures such as surgery and/or radiotherapy), L-MTP-PE may be more effective when used in the adjuvant setting. A randomized multi-institutional clinical trial in OS patients presenting with metastases at diagnosis should be considered. Disclosure C. Oliva: Cristina Oliva is a Takeda employee. Y. Liu: I am a Millennium employee. All other authors have declared no conflicts of interest.

New treatment options for nonmetastatic osteosarcoma: focus on mifamurtide in adolescents

New treatment options for nonmetastatic osteosarcoma: focus on mifamurtide in adolescents Winston W Huh, Daniela Egas-Bejar, Peter M AndersonDivision of Pediatrics, The Children's Cancer Hospital of the University of Texas MD Anderson Cancer Center, Houston, TX, USAAbstract: New treatments are needed to improve the clinical outcome for patients with osteosarcoma. Liposomal muramyl tripeptide phosphatidylethanolamine (mifamurtide) is a synthetic peptidoglycan component packaged in multilamellar liposomes. Mifamurtide has been demonstrated to induce recruitment and activation of macrophages and monocytes of the host innate immune system, which leads to antitumoricidal activity. Early clinical trials have demonstrated the safety and tolerability of mifamurtide combined with chemotherapy, and one major study has demonstrated an overall survival benefit in patients with newly diagnosed nonmetastatic osteosarcoma. This review summarizes the mechanism of action, clinical results, and the optimal biologic dose, and raises potential questions for future development of mifamurtide.Keywords: osteosarcoma, childhood cancer, adolescent, sarcoma, immunotherapy, bone

Mifamurtide for the treatment of nonmetastatic osteosarcoma

Introduction: The standard treatment for osteosarcoma requires both macroscopic surgical wide resection and postoperative multi-drug chemotherapy in neoadjuvant and adjuvant settings. However, the 5-year event-free survival has remained at a plateau of 60 – 70% of patients with nonmetastatic osteosarcoma for more than 30 years.Areas covered: Mifamurtide (liposomal muramyl tripeptide phosphatidylethanolamine; L-MTP-PE) is a new agent. L-MTP-PE is a nonspecific immunomodulator, which is a synthetic analog of a component of bacterial cell walls. L-MTP-PE activates macrophages and monocytes as a potent activator of immune response in addition to standard chemotherapy. It also improves the overall survival from 70 to 78% and results in a one-third reduction in the risk of death from osteosarcoma. This review summarizes the most recent findings about L-MTP-PE and its therapeutic application for nonmetastatic osteosarcoma.Expert opinion: Recently, L-MTP-PE has been approved in Europe for the treatment of nonmetastatic osteosarcoma with chemotherapy. L-MTP-PE in combination with traditional treatment is expected to go mainstream and to be beneficial for patients with osteosarcoma. Information about potential benefit regarding mifamurtide use in the neoadjuvant setting (i.e., before surgery) and/or usefulness of L-MTP-PE in metastatic in relapsed and metastatic osteosarcoma requires analysis of expanded access and/or future clinical trials of L-MTP-PE in high-burden and low-burden situations.

Mifamurtide

Mifamurtide (liposomal muramyl tripeptide phosphatidyl ethanolamine; Mepact) is an immunomodulator with antitumor effects that appear to be mediated via activation of monocytes and macrophages. In the EU, mifamurtide is indicated in children, adolescents, and young adults for the treatment of high-grade, resectable, non-metastatic osteosarcoma after macroscopically complete surgical resection; it is administered by intravenous infusion in conjunction with postoperative multiagent chemotherapy. In the US, mifamurtide is currently an investigational agent that holds orphan drug status for the treatment of osteosarcoma. In a large, randomized, open-label, multicenter, phase III trial, the addition of adjuvant (postoperative) mifamurtide to three- or four-drug combination chemotherapy (doxorubicin, cisplatin, and high-dose methotrexate with, or without, ifosfamide) was associated with a statistically significant improvement in overall survival in patients with newly diagnosed, high-grade, non-metastatic, resectable osteosarcoma. The pattern of outcome was generally similar in a small cohort of patients with metastatic disease who were enrolled in this trial. Mifamurtide is generally well tolerated; adverse events attributed to administration of the drug include chills, fever, headache, nausea, and myalgias. Based on the available data, mifamurtide can be considered for inclusion in treatment protocols for localized osteosarcoma.

Past, Present and Future of Therapies in Pediatric Sarcomas

Limited progress has been made over the past 30 years in improving the outcome of patients with high-risk pediatric sarcomas. The 5-year overall survival rate remains at 20% or less with metastatic sarcomas. Therefore, current and future research is focused on the identification and development of molecular or biological agents targeting the pathogenic pathways in sarcomas, either alone or in combination with conventional chemotherapy. To this end, the most promising activity has been seen with IGF-1 receptor antibodies and mTOR inhibitors. Other agents of interest are oncolytic viruses, epigenetic modulators (e.g., histone deacetylase inhibitors), immune modulators (e.g., muramyl tripeptide phosphatidylethanolamine) and other biological agents (e.g., trabectedin). In addition to the development of novel drugs, the other major area of recent focus is developing immune therapies, such as dendritic cell vaccines and adoptive immunotherapy for treating pediatric sarcomas. This article discusses the successes, the failures and the future direction of these therapies.

Mifamurtide in osteosarcoma - A practical review

Mifamurtide, also known as liposomal muramyl tripeptide phosphatidyl ethanolamine (L-MTP-PE), has been approved for the treatment of osteosarcoma in Europe. Mifamurtide's rational drug design employs MTP-PE for macrophage activation in a multilamellar liposome drug carrier, containing the synthetic phospholipids 1-palmitoyl-2-oleoyl phosphatidyl choline (POPC) and 1,2-dioleoyl phosphatidyl serine (OOPS). Although the drug is not cytotoxic towards normal or tumor cells in vitro, immune activation against osteosarcoma lung metastases in vivo accounts for mifamurtide's antiosteosarcoma effects. Phosphatidyl serine-containing lipids signal macrophage cells that have "flipped phosphatidyl serine" to the outer membrane after apoptosis (e.g., after damage of tumor cells from chemotherapy); thus, both mifamurtide's active and inactive ingredients target immune cells in the lungs. Mifamurtide administration has resulted in 8% and 13% improvement in 6- and 5-year overall survivals, when added to chemotherapy in nonmetastatic and metastatic patients with osteosarcoma, respectively. The short-term toxicities of mifamurtide (fever, headache, flu-like symptoms and rigors) are reduced or eliminated using ibuprofen (200 mg) as premedication for the first infusion; an algorithm for pre- and postmedication is presented. To date, no long-term side effects of mifamurtide have been reported. Compassionate access programs based in two major cancer centers (MD Anderson and Memorial Sloan-Kettering), have recently provided this potentially life-saving drug in North America. The experience with mifamurtide provides an outstanding example of successful cooperation among regulatory bodies and agencies, the pharmaceutical industry and pediatric oncologists to improve cancer care and outcomes for children and young people with a rare sarcoma.

Addition of muramyl tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma

The addition of liposomal muramyl tripeptide phosphatidylethanolamine (MTP-PE) to chemotherapy has been shown to improve overall survival in patients with nonmetastatic osteosarcoma (OS). The authors report the results of addition of liposomal MTP-PE to chemotherapy for patients with metastatic OS. Intergroup-0133 was a prospective randomized phase 3 trial for the treatment of newly diagnosed patients with OS. The authors compared 3-drug chemotherapy with cisplatin, doxorubicin, and high-dose methotrexate (Regimen A) to the same 3 drugs with the addition of ifosfamide (Regimen B). The addition of liposomal MTP-PE to chemotherapy was evaluated. Five-year event-free survival (EFS) for patients who received liposomal MTP-PE (n = 46) was 42% versus 26% for those who did not (n = 45) (relative risk for liposomal MTP-PE, 0.72; P = .23; 95% confidence interval [CI], 0.42-1.2). The 5-year overall survival for patients who received MTP-PE versus no MTP-PE was 53% and 40%, respectively (relative risk for liposomal MTP-PE, 0.72; P = 0.27; 95% CI, 0.40-1.3). The comparison of Regimen A with Regimen B did not suggest a difference for EFS (35% vs 34%, respectively; relative risk for Regimen B, 1.07; P = .79; 95% CI, 0.62-1.8) or overall survival (52% vs 43%, respectively; relative risk for Regimen B, 1.1, P = .75; 95% CI, 0.61-2.0). When the metastatic cohort was considered in isolation, the addition of liposomal MTP-PE to chemotherapy did not achieve a statistically significant improvement in outcome. However, the pattern of outcome is similar to the pattern in nonmetastatic patients.

Well-defined and potent liposomal hepatitis B vaccines adjuvanted with lipophilic MDP derivatives

The characterization of immunological cascades of the innate immune system activated by invariant molecular structures termed as pathogen-associated molecular patterns recognized by pattern recognition receptors of macrophages and dendritic cells, have allowed the elucidation of the mechanisms underlying the immunomodulatory properties of adjuvants. Thus, adjuvant-active lipophilic analogues of N-acetyl muramyl dipeptide (MDP) were incorporated in liposomal hepatitis B surface antigen (HBsAg) formulations. The immunoreactivity of the formulations was evaluated by measuring anti-HBs, immunoglobulin G (IgG), and isotype antibody titer and compared with alum-adsorbed HBsAg formulation. The formulations were also evaluated for cell-mediated immune response by HBsAg-specific proliferation of splenocytes and simultaneous estimation of cytokines (interleukin-4 [IL-4], interferon-γ [IFN-γ]). Results indicate that the serum IgG and anti-HBs titer obtained after intramuscular administration of liposomal muramyl tripeptide–phosphatidylethanolamine (MTP-PE) and liposomal N-acetylmuramyl-l-alanyl-d-isoglutamine–glycerol dipalmitate (MDP-GDP) antigenic formulations were significantly higher. The incorporation of MTP-PE on the liposomal HBsAg increased the stimulation index (SI) four to five times as compared to plain HBsAg solution, and it also induced significantly higher Th1 cellular immune response with a predominant IFN-γ level. So it is the novel effective and potentially safe approach in which liposomes act as delivery vehicles for hepatitis B viral antigen to antigen-presenting cells and is ornamented with a biological response modifier that could activate these target cells to enhance the antigen presentation to T lymphocytes. From the Clinical Editor In this study, adjuvant-active lipophilic analogues on N-acetyl muramyl dipeptide (MDP) were incorporated in liposomal hepatitis B surface antigen (HBsAg) formulations. The immunoreactivity of the formulations was evaluated and found effective, leading to a potentially enhanced immune response against the delivered antigen.

Novel bone cancer drugs: investigational agents and control paradigms for primary bone sarcomas (Ewing's sarcoma and osteosarcoma)

Background: New investigational agents and chemotherapy regimens including cyclophosphamide + topotecan, temozolomide + irinotecan, and anti-IGF-1R antibodies in Ewing's sarcoma (ES) and liposomal muramyltripeptide phosphatidylethanolamine (L-MTP-PE), aerosol therapy, and bone-specific agents in osteosarcoma (OS) may improve survival and/or quality of life on ‘continuation’ therapy. Objective: Review of investigational approaches and control paradigms for recurrent or metastatic primary bone tumors. Methods: Analyze temozolomide + irinotecan data and review in the context of other newer approaches including antiangiogenesis, anti-IGF-1R antibodies and bisphosphonates for ES. Review some current state-of-the-art approaches for OS including L-MTP-PE, anti-IGF-1R inhibition, aerosol therapies and bone specific agents. Results/conclusion: L-MTP-PE with chemotherapy in OS has been shown to improve survival; compassionate access is available for recurrence and/or metastases. Aerosol therapy (granulocyte–macrophage colony stimulating factor, cisplatin, gemcitabine) for lung metastases is a promising approach to reduce systemic toxicity. The bone-specific agents including denosumab (anti-receptor activator of NF-κB ligand antibody) and bisphosphonates may have benefit against giant cell tumor, ES and OS. Anti-IGF-1R antibody SCH717454 has preclinical activity in OS but best effectiveness will most likely be in combination with chemotherapy earlier in therapy. Both temozolomide + irinotecan and cyclophosphamide + topotecan combinations are very active in ES and are likely to be tested with anti-IGF-1R antibodies against ES.

Imunomodulative effect of liposomized muramyltripeptide phosphatidylethanolamine (L-MTP-PE) on mice with alveolar echinococcosis and treated with albendazole

The effect of liposomized muramyltripeptide phosphatidylethanolamine (L-MTP-PE) administered separately or with anthelmintic albendazole (ABZ) on cellular immunity of mice with alveolar echinococcosis was studied. The proliferative activity of splenic T and B lymphocytes was the most stimulated after combined L-MTP-PE + ABZ therapy [from weeks 8 to 14 post-infection (p.i.)] that also induced a long-term development of protective Th1 response (the highest serum concentration of IFN-gamma from weeks 8 to 18 p.i.). On the contrary, Th2 response (cytokine IL-5) in infected mice treated with L-MTP-PE was inhibited since week 8 p.i., but a significant long-term decrease in IL-5 concentration was found after combined L-MTP-PE+ABZ therapy until the end of the experiment (until week 26 p.i.). L-MTP-PE stimulated the production of superoxide anion (O2-) by peritoneal macrophages from weeks 8 to 12 p.i., but the highest O2- production was accordingly recorded after therapy L-MTP-PE+ABZ from weeks 8 to 18 p.i. Stimulation of cellular immunity of mice with alveolar echinococcis with L-MTP-PE and an interaction with ABZ's anti-parasitic effect resulted in the greatest and long-term reduction of growth of Echinococcus multilocularis cysts in the host from week 10 p.i. until the end of the experiment.