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Phase-I study of intravenous modified lipid A
Abstract:
Endotoxin and the lipid-A portion of the molecule have a variety of biological effects, including the induction of necrosis and regression of malignancy. To date extensive clinical trials of endotoxin as a potential therapeutic agent have been shunned due to the toxicity of the material. Several lipid-A analogues have been described which have reduced toxicity and retain antitumor activity. We have investigated in a phase-I trial the clinical toxicity and immunological effects of monophosphoryl lipid A prepared from Salmonella typhimurium and Salmonella minnesota. Patients entered on the study received IV monophosphoryl lipid A twice weekly for a total of 4 weeks. At least three patients were entered sequentially at each of the dose levels of 10, 25, 50, 100, and 250 micrograms/m2 body surface area. One patient was treated at the dose level of 500 micrograms/m2. The major clinical toxicity was fever, chills, and rigor, which occurred in over 50% of the treatments at doses of 250 micrograms/m2. Two instances of bronchospasm occurred in one patient who received 250 micrograms/m2. One patient received 500 micrograms/m2 and became hypotensive. Sequential clinical data showed no evidence of renal or hepatic toxicity. A transient decrease in the WBC and platelets occurred during the first 24 h after therapy. Immune function testing measured T cells, monocyte cytostasis, monocyte suppressor cell activity, and NK activity. These data suggested a shift in monocyte populations with activated cells moving into the tissue. Direct objective antitumor activity or necrosis was not observed in this group of patients. We conclude that monophosphoryl lipid A can be given to patients in a dose of up to 100 micrograms/m2 with acceptable toxicity. Its clinical activity as a single agent in combination with other immunomodulators remains to be demonstrated.
Insights
Monophosphoryl lipid A, a less toxic endotoxin derivative, was tested in a Phase I trial. Doses up to 100 µg/m² showed acceptable toxicity, with fever and chills as primary side effects, but no direct antitumor activity was observed.
Area of Science:
- Immunology
- Pharmacology
- Oncology
Background:
- Endotoxin and its lipid-A component exhibit antitumor properties but are limited by toxicity.
- Lipid-A analogues offer reduced toxicity while retaining anti-cancer potential.
- Monophosphoryl lipid A (MPLA) is a modified lipid-A analogue investigated for therapeutic use.
Purpose of the Study:
- To evaluate the clinical toxicity and immunological effects of MPLA in a Phase I trial.
- To determine the maximum tolerated dose (MTD) of MPLA.
- To explore the immunomodulatory effects of MPLA in cancer patients.
Main Methods:
- Phase I clinical trial administering intravenous MPLA twice weekly for 4 weeks.
- Sequential dose escalation from 10 to 500 µg/m² across multiple patients.
- Monitoring of clinical toxicity, including fever, chills, bronchospasm, and hypotension.
- Assessment of immunological effects, including T cell counts, monocyte function, and natural killer (NK) cell activity.
Main Results:
- The major dose-limiting toxicities were fever, chills, and rigor at doses ≥250 µg/m².
- Bronchospasm and hypotension were observed at higher doses (250-500 µg/m²).
- No significant renal or hepatic toxicity was detected; transient decreases in WBC and platelets occurred.
- Immunological assessments suggested a shift towards activated monocyte populations.
- No direct objective antitumor activity or necrosis was observed.
Conclusions:
- MPLA can be safely administered at doses up to 100 µg/m² with acceptable toxicity.
- Higher doses (≥250 µg/m²) are associated with significant toxicities.
- The clinical efficacy of MPLA as a single agent or in combination with other immunomodulators requires further investigation.