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Phase-I study of intravenous modified lipid A

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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 μg/m2 body surface area. One patient was treated at the dose level of 500 μg/m2. The major clinical toxicity was fever, chills, and rigor, which occurred in over 50% of the treatments at doses of 250 μg/m2. Two instances of bronchospasm occurred in one patient who received 250 μg/m2. One patient received 500 μg/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 μg/m2 with acceptable toxicity. Its clinical activity as a single agent in combination with other immunomodulators remains to be demonstrated.

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  1. 1.

    Coley WB (1911) A report of recent cases of inoperable sarcoma treated with mixed toxins of Erysipelas and Bacillus prodigious. Surg Gynecol Obstet 13:174–190

  2. 2.

    Duran-Reynals F (1935) Reaction of spontaneous mouse carcinomas to blood-carried bacterial toxins. Proc Soc Exp Biol Med 32:1517–1521

  3. 3.

    Fidler IJ, Sone S, Fogler WE, Barnes ZL (1981) Eradication of spontaneous metastasis and activation of alveolar macrophages by intravenous injection of liposomes containing muramyl dipeptide. Proc Natl Acad Sci USA 78:1680–1684

  4. 4.

    Freedman HH, Sultzer BA, Kleinberg W (1961) Detoxification of bacterial endotoxin with retention of ability to stimulate non-specific resistance to infection. Proc Soc Exp Biol Med 136:819–823

  5. 5.

    Gratia A, Linz R (1931) Le phénomène de Schwartzman dans le sarcome du cobaye. CR Soc Biol (Paris) 108:427–428

  6. 6.

    Jensen PJ, Koren HS (1980) Heterogeneity within the population of NK and K cells. J Immunol 124:395–398

  7. 7.

    Kotani S, Takada H, Tsumimoto M, Ogawa T, Mori Y, Sakuta M, Kawasaki A, Inage M, Kosumoto S, Shiba T, Kasai N (1983) Immunobiological activities of synthetic lipid A analogs and related compounds as compared to those of bacterial lipopolysaccharide, re-glycolipid, lipid A and muramyl dipeptide. Infect Immun 41:758–773

  8. 8.

    Luderitz O, Galanos C, Lehmann V, Nurminen M, Rietschel ET, Rosenfelder G, Simon M, Westphal O (1973) Lipid A: Chemical structure and biological Activity. J Infect Dis 128:517–529

  9. 9.

    Masahiro N, Raetz CRH (1981) Characterization of two membrane-associated glycolipids from an Escherichia coli mutant deficient in phosphatidylglycerol. J Biol Chem 256:10690–10696

  10. 10.

    Mihich E, Westphal O, Luderitz O, Neter E (1961) The tumor nectrotizing effect of Lipid A component of Escherichia coli endotoxin. Proc Soc Exp Biol Med 107:816–819

  11. 11.

    Miller TR, Nicholson JT (1971) End results in reticulum cell sarcoma of bone treated by bacterial toxin therapy alone or combined with surgery and/or radiotherapy (47 cases) or concurrent infection (5 cases). Cancer 27:524–547

  12. 12.

    Nauts HC (1975) Beneficial effects of immunotherapy (bacterial toxins) on sarcoma of the soft tissues, other than lymphosarcoma. Cancer Research Institute, New York

  13. 13.

    North RJ (1981) Bacterial endotoxins as an immunotherapeutic agent — Basic data on mechanisms of action. In: Hersh EM, et al. (eds) Augmenting agents in cancer therapy. Raven Press, New York, pp 113–124

  14. 14.

    Nowotny A, Golub S, Brian K (1971) Fate and effect of endotoxin derivatives in tumor-bearing mice. Proc Soc Exp Biol Med 136:66–69

  15. 15.

    Quan PC, Burtin P (1976) Demonstration of non-specific suppressor cells in peripheral lymphocytes of cancer patients. Cancer Res 38:288–296

  16. 16.

    Raz A, Fogler WE, Fidler IJ (1979) The effects of experimental conditions on the expression of in vitro-mediated tumor cytotoxicity mediated by murine macrophages. Cancer Immunol Immunother 7:157–163

  17. 17.

    Ribi E, Amano K, Cantrell J, Schwartzman S, Parker R, Takayma K (1982) Immunotherapy and antitumor activity of non-toxic Lipid A. Cancer Immunol Immunother 12:91–96

  18. 18.

    Rick PD, Fung LWM, Ho C, Osborn MJ (1977) Lipid A mutants of Salmonella typhimurium. J Biol Chem 252:4904–4912

  19. 19.

    Schwartzman G (1937) The phenomenon of local tissue reactivity. Harper (Hoeber), New York

  20. 20.

    Shear MJ, Turner FC (1943a) Chemical treatment of tumors; reactions of mice with primary subcutaneous tumors to injections of hemorrhage-producing bacterial polysaccharide. J Natl Cancer Inst 4:81

  21. 21.

    Shear MJ, Turner FC (1943b) Chemical treatment of tumors; isolations of hemorrhagic-producing fraction from Serratia marcescens Bacillus prodigiosus culture filtrate. J Natl Cancer Inst 4:461–476

  22. 22.

    Sone S, Pallac A, Fidler IJ (1980) Direct activation of tumorcidal properties in rat alveolar macrophages by Nocardia rubra cell wall skeleton. Cancer Immunol Immunother 9:227–232

  23. 23.

    Takayama K, Ribi E, Cantrell JL (1981) Isolation of non-toxic Lipid A fraction containing tumor regression activity. Cancer Res 41:2654–2657

  24. 24.

    Vosika GJ, Schmidtke JR, Goldman A, Parker R, Ribi E, Gray GR (1979) Phase I–II study of intralesional immunotherapy with oil-attached Mycobacterium smegmatis cell wall skeleton and trehalose dimycolate. Cancer Immunol Immunother 6:135–142

  25. 25.

    Vosika GJ, Schmidtke JR, Goldman A, Ribi E, Parker R, Gray GR (1979) Intralesional immunotherapy of malignant melanoma with mycobacterium smegmatis cell wall skeleton combined with trehalose dimycolate. Cancer 44:495–503

  26. 26.

    Vosika GJ, Thies J (1979) Effect of indomethacin on blastogensis of lymphocytes from cancer patients: Differentiation of patient types. Clin Immunol Immunopathol 13:30–38

  27. 27.

    Westphal O, Westphal U, Sommer T (1977) History of pyrogenic research. In: Schlesinger D (ed) Microbiology 1977. The American Society of Microbiology, Washington, pp 221–238

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Correspondence to Gerald J. Vosika.

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Vosika, G.J., Barr, C. & Gilbertson, D. Phase-I study of intravenous modified lipid A. Cancer Immunol Immunother 18, 107–112 (1984). https://doi.org/10.1007/BF00205743

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  • Dose Level
  • Antitumor Activity
  • Body Surface Area
  • Suppressor Cell
  • Direct Objective