Stimulation of Host Response Against Metastatic Tumors by Liposome-Encapsulated Immunomodulators

  • George Poste
  • Corazon Bucana
  • Isaiah J. Fidler
Part of the NATO Advanced Study Institutes Series book series (NSSA, volume 47)


The metastatic spread of malignant tumors to form metastases at other sites in the body remains the principal cause of failure in the treatment of neoplastic disease1. Several factors are responsible for this unfortunate situation. First, metastases are frequently too small to be detected at the time the primary tumor is removed. Second, widespread dissemination of metastases often takes place before symptoms of metastatic disease occur. Third, the anatomic location of many metastatic lesions renders them inaccessible to surgical removal and/or limits the effective dose of therapeutic agents that reach metastases. The final, and most formidable, problem concerns emergence of metastatic lesions that are resistant to conventional therapy. Recent work suggests that metastases arise from non-random spread of specialized subpopulations of cells within the primary tumor and that the responsiveness of these metastatic subpopulations to therapy may not only differ from that of non-metastatic tumor cells in the primary tumor but may also vary significantly between the tumor cell subpopulations present in individual metastases within the same patient (review, 2). The depressing implication of this marked heterogeneity in the response of malignant cells to chemotherapy and other therapeutic modalities is that the only successful approach to the therapy of metastases will be one that circumvents the problem of cellular diversity between tumor cells in primary and metastatic lesions, and between different metastatic foci.


Alveolar Macrophage None None Tumoricidal Activity Muramyl Dipeptide Alveolar Macro 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    G. Poste and I.J. Fidler, The pathogenesis of cancer metastases, Nature, 283: 139 (1980).PubMedCrossRefGoogle Scholar
  2. 2.
    I.J. Fidler and M.L. Kripke, Biological variability within murine neoplasms, Antibiot. Chemother. 28: 123 (1980).Google Scholar
  3. 3.
    I.J. Fidler, Recognition and destruction of target cells by tumoricidal macrophages, Isr. J. Med. Sci. 14: 177 (1978).PubMedGoogle Scholar
  4. 4.
    R.S. Kerbel, Implications of immunological heterogeneity of tumours, Nature 280: 358 (1979).PubMedCrossRefGoogle Scholar
  5. 5.
    E. Den Otter, F.J. Dullens Hub, H. Van Lovern and E. Pels, Antitumor effects of macrophages injected into animals: a review, in: “The Macrophage and Cancer,” K. James, B. McBride and A. Stuart, eds., Econoprint, Edinburgh, (1977).Google Scholar
  6. 6.
    I.J. Fidler, Inhibition of pulmonary metastasis by intravenous injection of specifically activated macrophages, Cancer Res. 34: 1074 (1977).Google Scholar
  7. 7.
    L.A. Liotta, C. Gattozzi, J. Kleinerman and G. Saidel, Reduction of tumor-cell entry into vessels by BCG-activated macrophages, Brit. J. Cancer 36: 639 (1977).PubMedCrossRefGoogle Scholar
  8. 8.
    I.J. Fidler and G. Poste, Macrophage destruction of micro-metastases, in: “Manual of Macrophage Methodology,” H.B. Herscowitz, H.J. Holden, J.A. Bellanti and A. Ghaffar, eds., Marcel Dekker, New York (1981).Google Scholar
  9. 9.
    I.J. Fidler, Z. Barnes, W.E. Fogler, R. Kirsh, P. Bugelski and G. Poste, Evidence for the involvement of macrophages in the eradication of established metastases following intravenous injection of liposomes containing macrophage activators, Cancer Res. - submitted.Google Scholar
  10. 10.
    S.W. Russell, G.Y. Gillespie and J.L. Pace, Evidence for mononuclear phagocytes in solid neoplasms and appraisal of the nonspecific cytotoxic capabilities, in: “In Situ Expression of Tumor Immunity,” I. P. Witz and M.G. Hanna, eds., Plenum, New York (1980).Google Scholar
  11. 11.
    A.C. Allison, Mode of action of immunological adjuvants, J. Reticuloendothel. Soc. 26: 619 (1979).PubMedGoogle Scholar
  12. 12.
    I.J. Fidler and A. Raz, The induction of tumoricidal capacities in mouse and rat macrophages by lymphokines, in: “Lymphokines,” E. Pick, ed., Vol. 3, Academic Press, New York, (1981).Google Scholar
  13. 13.
    B.W. Papermaster, O.A. Holterman, E. Klein, I. Djerassi, D. Rosner, T. Dao and J.J. Costanzi, Preliminary observations on tumor regressions induced by local administration of a lymphoid-cell culture supernatant fraction in patients with cutaneous metastatic lesions, Clin. Immunol. Immunopathol. 5: 31 (1976).PubMedCrossRefGoogle Scholar
  14. 14.
    S.B. Slavin, J.S. Youngner, J. Nishio and R. Neta, Brief communication: tumor suppression by a lymphokine released into the circulation of mice with delayed hypersensitivity, J. Nat. Cancer Inst. 55: 1233 (1975).Google Scholar
  15. 15.
    N.E. Adelman, M.G. Hammond, S. Cohen and H.F. Dvorak, Lymphokines as inflammatory mediators, in: “Biology of the Lymphokines,” S. Cohen, E. Pick and J.J. Oppenheim, eds., Academic Press, New York (1979).Google Scholar
  16. 16.
    G. Poste and R. Kirsh, Rapid decay of tumoricidal activity and loss of responsiveness to lymphokines in inflammatory macrophages, Cancer Res. 39: 2582 (1979).PubMedGoogle Scholar
  17. 17.
    L. Chedid, F. Audibert and A.G. Johnson, Biological activities of muramyl dipeptide, a synthetic glycopeptide analogous to bacterial immunoregulating agents, Progr. Allergy 25: 63 (1978).Google Scholar
  18. 18.
    G. Gregoriadis and A.C. Allison, eds., in: “Liposomes in Biology and Medicine,” Wiley Interscience, New York (1980).Google Scholar
  19. 19.
    T.D. Heath, R.T. Fraley and D. Papahadjopoulos, Antibody targeting of liposomes - cell specificity obtained by conjugation of F(AB)2 to vesicle surface, Science, 210: 539 (1980).PubMedCrossRefGoogle Scholar
  20. 20.
    L.D. Leserman, J.N. Weinstein, R. Blumenthal and W.D. Terry, Receptor mediated endocytosis of antibody-opsonized liposomes by tumor cells, Proc. Nat. Acad. Sci. USA, 77: 4089 (1980).PubMedCrossRefGoogle Scholar
  21. 21.
    G. Gregoriadis and D. Neerunjun, Homing of liposomes to target cells, Biochem. Biophys, Res. Commun. 65: 537 (1975).CrossRefGoogle Scholar
  22. 22.
    G. Poste, R. Kirsh and I.J. Fidler, Cell surface receptors for lymphokines. I. The possible role of glycolipids as receptors for macrophage migration inhibitory factor (MIF) and macrophage activation factor (MAF), Cell Innnunol. 44: 71 (1979).CrossRefGoogle Scholar
  23. 23.
    G. Poste, R. Kirsh, W.E. Fogler and I.J. Fidler, Activation of tumoricidal properties in mouse macrophages by lymphokines encapsulated in liposomes, Cancer Res. 39: 881 (1979).PubMedGoogle Scholar
  24. 24.
    I.J. Fidler, S. Sone, W.E. Fogler and Z. Barnes, Eradication of spontaneous metastases and activation of alveolar macrophages by intravenous injection of liposomes containing muramyl dipeptide, Proc. Nat. Acad. Sci. USA, 78: 1680 (1981).PubMedCrossRefGoogle Scholar
  25. 25.
    I.J. Fidler, A. Raz, W.E. Fogler, R. Kirsh, P. Bugelski and G. Poste, Design of liposomes to improve delivery of macrophage-augmenting agents to alveolar macrophages, Cancer Res. 40: 4460 (1980).PubMedGoogle Scholar
  26. 26.
    I.J. Fidler, I.R. Hart, A. Raz, W.E. Fogler, R. Kirsh and G. Poste, Activation of tumoricidal properties in macrophages by liposome-encapsulated lymphokines: in vivo studies, in: “Liposomes and Immunobiology,” B.H. Tom and H. Six, eds., Elsevier, New York (1980).Google Scholar
  27. 27.
    S. Sone, G. Poste and I.J. Fidler, Rat alveolar macrophages are susceptible to activation by free and liposome-encapsulated lymphokines, J. Immunol. 124: 2197 (1980).PubMedGoogle Scholar
  28. 28.
    G. Poste, C. Bucana, A. Raz, R. Kirsh, P. Bugelski and I.J. Fidler, The behaviour of intravenously inoculated liposomes in the microcirculation: implications for liposome targeting and drug delivery, Cancer Res. - submitted.Google Scholar
  29. 29.
    G.P. Velo and W.G. Spector, The origin and turnover of alveolar macrophages in experimental pneumonia, J. Pathol. 109: 7 (1973).PubMedCrossRefGoogle Scholar
  30. 30.
    E.D. Thomas, R.E. Ramberg, G.E. Sale, R.S. Sparkes and D.W. Golde, Direct evidence for a bone marrow origin of the alveolar macrophage in man, Science, 192: 1016 (1976).PubMedCrossRefGoogle Scholar
  31. 31.
    K.J. Johnson, P.A. Ward, G. Striker and R. Kunkel, A study of the origin of pulmonary macrophages using the Chediak-Higashi marker, Am. J. Pathol. 101: 365 (1980).PubMedGoogle Scholar
  32. 32.
    A. Blusse van Ould Alblas and R. Van Furth, Origin, kinetics and characteristics of pulmonary macrophages in the normal steady state, J. Exp. Med. 149: 1504 (1979).CrossRefGoogle Scholar
  33. 33.
    I.R. Hart, Selection and characterization of an invasive variant of the B16 melanoma, Am. J. Pathol. 97: 587 (1979).PubMedGoogle Scholar
  34. 34.
    I.J. Fidler, Therapy of spontaneous metastases by intravenous injection of liposomes containing lymphokines, Science 208: 1469 (1980).PubMedCrossRefGoogle Scholar
  35. 35.
    M. Parant, Biological properties of a new synthetic adjuvant, muramyl dipeptide (MDP), Semin. Immunopathol. 2: 101 (1979).Google Scholar
  36. 36.
    D.P. Griswold, Jr., Consideration of subcutaneously implanted B16 melanoma as a screening model for potential anticancer agents, Cancer Chemotherap. Rep. 3: 315 (1972).Google Scholar
  37. 37.
    M. Aalto, M. Potila and E. Kulonen, The effect of silica-treated macrophages on the synthesis of collagen and other proteins in vitro, Exp. Cell Res. 97: 193 (1976).PubMedCrossRefGoogle Scholar
  38. 38.
    C.F. Brosnan, M.B. Bornstein and B.R. Bloom, The effects of macrophage depletion on the clinical and pathological expression of experimental allergic encephalomyelitis, J. Immunol. 126: 614 (1981).PubMedGoogle Scholar
  39. 39.
    P.J. Cantanzaro, H.J. Schwartz and R.C. Graham, Jr., Spectrum and possible mechanism of carrageenan cytotoxicity, Am. J. Pathol. 64: 387 (1971).Google Scholar
  40. 40.
    D.G. Hopper, M.V. Pimm and R.W. Baldwin, Silica abrogation of mycobacterial adjuvant contact suppression of tumor growth in rats and athymic mice, Cancer Immunol. Immunother. 1: 143 (1976).CrossRefGoogle Scholar
  41. 41.
    R. Keller, Promotion of tumor growth in vivo by anti-macrophage agents, J. Nat. Cancer Inst. 57: 1355 (1976).PubMedGoogle Scholar
  42. 42.
    M.H. Levy and E.F. Wheelock, Effects of intravenous silica on immune and non-immune functions of the murine host, J. Immunol. 115: 41 (1975).PubMedGoogle Scholar
  43. 43.
    A.W. Thomson, N. Cruickshank and E.F. Fowler, Fc receptor-bearing and phagocytic cells in syngeneic tumors of corynebacterium-parvum treated and carrageenan treated mice, Brit. J. Cancer 39: 598 (1979).PubMedCrossRefGoogle Scholar
  44. 44.
    S.D. Miller and A. Zarkower, Alterations of murine immunological responses after silica dust inhalation, J. Immunol. 113: 1533 (1974).PubMedGoogle Scholar
  45. 45.
    E. Lotzova, C. parvum-mediated suppression of the phenomenon of natural killing and its analysis, in: “Natural Cell-Mediated Immunity Against Tumors,” R.B. Herberman, ed., Plenum, New York (1980).Google Scholar
  46. 46.
    G. Poste, unpublished observations.Google Scholar
  47. 47.
    I.J. Fidler, J. Immunol. - in press (1981).Google Scholar
  48. 48.
    S. Sone and I.J. Fidler, In vitro activation of tumoricidal properties in rat alveolar macrophages by synthetic muramyl dipeptide encapsulated in liposomes, Cell Immunol. 57: 42 (1981).PubMedCrossRefGoogle Scholar
  49. 49.
    I.R. Hart, W.E. Fogler, G. Poste and I.J. Fidler, Toxicity studies of liposome-encapsulated imetunomodulators administered intravenously to dogs and mice, Cancer Immunol Immunother. 10: 157 (1981).CrossRefGoogle Scholar
  50. 50.
    S.A. Eccles, Macrophages and cancer, in: “Immunological Aspects of Cancer,” J.E. Castro, ed., Univ. Park Press, Baltimore (1978).Google Scholar
  51. 51.
    M.J. Berendt and R.J. North, T-cell mediated suppression of anti-tumor immunity. An explanation for progressive growth of an immunogenic tumor, J. Exp. Med. 151: 69 (1980).PubMedCrossRefGoogle Scholar
  52. 52.
    L.P. Ruco and M.S. Meltzer, Macrophage activation for tumor cytotoxicity: increased lymphokine responsiveness of peritoneal macrophages during acute inflammation, J. Immunol. 120: 1054 (1978).PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1982

Authors and Affiliations

  • George Poste
    • 1
    • 2
  • Corazon Bucana
    • 3
  • Isaiah J. Fidler
    • 3
  1. 1.Smith Kline and French LaboratoriesPhiladelphiaUSA
  2. 2.Department of Pathology and Laboratory MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  3. 3.Cancer Metastasis and Treatment LaboratoryNCI-Frederick Cancer Research CenterFrederickUSA

Personalised recommendations