Liposomal MTP-PE: a promising new biologic response modifier.

PURPOSE/OBJECTIVES: To describe liposomal muramyl tripeptide phosphatidylethanolamine (MTP-PE), a new biologic response modifier that stimulates macrophages to a tumoricidal state. DATA SOURCES: Published articles, abstracts, and conference proceedings. DATA SYNTHESIS: Studies show that MTP-PE extends the progression-free interval of relapsed patients with osteosarcoma. Investigators are testing MTP-PE in combination with multiagent chemotherapy regimens to determine if the influences recurrence rates. It can be administered safely in the outpatient setting. Patients with reported side effects respond well to medical and nursing interventions. Efficacy and long-term side effects are unknown. IMPLICATIONS FOR NURSING PRACTICE: Nurses must understand the history, mechanism of action, proper administration, side effects, and psychosocial implications of MTP-PE to effectively plan nursing care. CONCLUSIONS: Promising results of treatment with this new biologic response modifier likely indicate that more and more nurses will be called on to administer it and counsel patients about its effects and side effects.

Efficacy of liposomal muramyl tripeptide (CGP 19835A) in the treatment of relapsed osteosarcoma.

Muramyl tripeptide phosphatidylethanolamine (MTP-PE) is a synthesized lipophilic analogue of muramyl dipeptide. MTP-PE encapsulated in liposomes (L-MTP-PE) allows selective delivery to pulmonary macrophages and circulating monocytes. In vivo administration has resulted in tumor regression in mice with B16 melanoma lung and lymph node metastases and a 40% long-term disease-free survival in dogs with osteosarcoma. Phase I studies have demonstrated that the drug is well tolerated. A Phase II trial using L-MTP-PE was undertaken in relapsed osteosarcoma patients to determine whether L-MTP-PE therapy could improve the progression-free interval in this high-risk group of patients. Patients had histologically proven osteosarcoma and pulmonary metastases that had developed during adjuvant chemotherapy or that were present at diagnosis and had persisted despite chemotherapy. Patients were rendered disease free by surgery. L-MTP-PE, 2 mg/m2, was infused over a 1-hour period twice a week for 12 weeks in 12 patients (Group 1). Sixteen patients (Group 2) received 2 mg/m2 L-MTP-PE twice a week for 12 weeks, then once a week for 12 weeks, for a total of 24 weeks of therapy. Progression-free intervals in each group were calculated from the day of surgery to the day of relapse and compared with the progression-free interval of a historical control group (Group 3) treated postoperatively with chemotherapy at M. D. Anderson Cancer Center between 1980 and 1990. Patients who received 24 weeks of L-MTP-PE therapy had a significant prolongation in time to relapse but those who received 12 weeks of therapy did not. The median time to relapse for group 2 patients was 9.0 months compared with 4.5 months for the control group (Group 3). These data suggest that L-MTP-PE deserves further investigation in a more appropriate adjuvant setting. A nationwide randomized Phase III trial is now underway in newly diagnosed osteosarcoma patients in conjunction with the Children's Cancer Study Group and the Pediatric Oncology Group.

Combination therapy with ifosfamide and liposome-encapsulated muramyl tripeptide: tolerability, toxicity, and immune stimulation.

A phase IIb trial using liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) in combination with ifosfamide (IFX) for patients with relapsed osteosarcoma was undertaken to determine (a) the tolerability of the combination therapy, (b) if L-MTP-PE increased the toxicity of IFX, and (c) whether IFX altered or suppressed the in vivo immune response to L-MTP-PE. Patients had histologically proven osteosarcoma and pulmonary metastases that either developed during adjuvant chemotherapy or were present at diagnosis, persisted despite chemotherapy, and recurred following surgical excision. Stratum A patients were rendered clinically free of disease within 4 weeks of study entry prior to receiving combination therapy. IFX was administered at 1.8 g/m2 for 5 days every 21 days for up to eight cycles. L-MTP-PE was administered twice weekly for 12 weeks, then once weekly for 12 weeks. Once cycle of combination therapy was defined as 5 days of IFX and 3 weeks of L-MTP-PE therapy. Stratum B patients had measurable disease at study entry that was judged to be amenable to surgical resection. Stratum B patients received three cycles of combination therapy prior to surgery to judge clinical and histologic response. Postoperatively, patients received an additional five cycles. A total of nine patients were entered into the protocol: six on stratum A and three on stratum B. Serial blood samples were collected and assayed for cytokine levels (tumor necrosis factor-alpha [TNF alpha], interleukin-6 [IL-6], IL-8, neopterin, C-reactive protein). In addition, peripheral blood monocyte tumoricidal activity was evaluated pre- and post-combination therapy. Complete blood counts with differential and platelet counts were followed weekly. No increase in the toxic side effects of IFX was demonstrated when administered with L-MTP-PE nor were delays in IFX administration due to neutropenia experienced. The toxic side effects of L-MTP-PE were also not increased. Elevations of serum C-reactive protein, plasma neopterin, IL-6, IL-8, and TNF alpha following combination therapy were similar to those observed in patients treated with L-MTP-PE alone. Monocyte-mediated tumoricidal activity was elevated 24 and 72 h following L-MTP-PE and IFX therapy, similar to what has been reported following L-MTP-PE alone. Tumor specimens obtained from stratum B patients showed the histologic characteristics consistent with a "chemotherapy effect," i.e., dead, amorphous, acellular osteoid with cell drop-out.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration of liposomal MTP-PE by the local physician: the role of the research nurse.

Accrual and retention of patients are critical for the successful completion of a research study. In clinical trials involving liposomal muramyl tripeptide phosphatidylethanolamine, time commitment, loss of income, and potential treatment costs were identified as factors that might cause patients to refuse this form of therapy. As a result, the principal investigator, from M.D. Anderson Cancer Center, and representatives from CIBA-GEIGY Corporation entered into an unusual agreement that allowed patients to receive most of the 6-month outpatient treatment course from their local physician. The involvement of local healthcare providers in the care and treatment of study patients presented a unique challenge to the oncology research nurse managing the clinical trials. This article describes how muramyl tripeptide phosphatidylethanolamine therapy was successfully implemented in several communities nationwide and highlights the various roles in which the research nurse served to prepare and support patients and local clinicians throughout the treatment course.

Cytokine production and immune cell activation in melanoma patients treated with liposomal muramyl tripeptide (CGP 19835A lipid).

We conducted a pilot study using liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) preoperatively in patients with stage III or IV resectable melanoma who were at high risk for recurrence. Patients received L-MTP-PE for 1 month before surgery and then 5 months postoperatively. Several immune parameters were monitored during preoperative therapy to search for correlations with clinical (tumor) response. The 18 patients were classified into three groups according to their responses and disease-free intervals: no evidence of disease (NED) at week 24 of therapy, relapse during therapy and progressive disease on therapy noted at the time of surgery. Six of nine patients in the NED group demonstrated increased monocyte tumoricidal activity (MTA) during week 1 of therapy. MTA increased in three of the six patients in the relapse group. MTA did not increase in the three patients who had progressive disease on therapy. Plasma neopterin levels were elevated by 72 h following the first L-MTP-PE dose in all 18 patients. Circulating levels of tumor necrosis factor were elevated in 15 of 16 patients tested, and IL-6 levels were elevated in all 18 patients. Melanoma cells from all three patients with progressive disease at the time of surgery proliferated well in vitro, whereas tumor cells from 10 of the 15 patients in the other two groups did not proliferate. There were no discernible differences among the three groups in the magnitude of IL-2-induced proliferation of tumor infiltrating lymphocytes. However, IL-2-activated TILs from the NED group exhibited cytotoxicity against autologous tumor cells in vitro. In summary, whereas L-MTP-PE stimulated several immunologic responses in all patients, the only two parameters that correlated with clinical status were MTA and the tumor proliferation assay. These two biologic assays could serve to distinguish potential responders from nonresponders early in the course of treatment.