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Lipid A and immunotherapy.

E Ribi, J L Cantrell, K Takayama

    Reviews of Infectious Diseases
    |July 1, 1984
    PubMed
    Summary
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    This study shows that combining 3-deoxy-D-mannooctulosonic acid (KDO) and lipid A from endotoxin with mycobacterial cell wall skeleton (CWS) effectively regresses tumors. This combination also induces systemic tumor immunity in guinea pigs.

    Area of Science:

    • Immunology
    • Biochemistry
    • Oncology

    Background:

    • Endotoxin components, specifically 3-deoxy-D-mannooctulosonic acid (KDO) and lipid A, are investigated for their synergistic effects with mycobacterial cell wall skeleton (CWS).
    • The study focuses on the potential of these components in cancer immunotherapy, particularly for transplantable tumors.

    Purpose of the Study:

    • To evaluate the combined efficacy of specific endotoxin components (KDO and lipid A) and CWS in inducing tumor regression and systemic immunity.
    • To determine the role of phosphorylation and structural variations in lipid A on its adjuvant activity and toxicity.

    Main Methods:

    • Tumor regression was assessed in syngeneic guinea pigs with transplantable line-10 tumors after intralesional injection of combined endotoxin components and CWS.
    • Lipid A was selectively modified by removing KDO (yielding diphosphoryl lipid A) and then the phosphate moiety (yielding monophosphoryl lipid A).

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  • Structural analogs of lipid A were separated chromatographically and compared for their adjuvant activity and toxicity.

    • Main Results:

    • A combination of KDO and lipid A from Re mutant endotoxin synergistically enhanced CWS-mediated regression of line-10 tumors.
    • Even small amounts (50 micrograms) of each component induced rapid tumor regression and systemic immunity.
    • Both toxic diphosphoryl lipid A and nontoxic monophosphoryl lipid A retained the ability to enhance CWS antitumor activity.
    • Structural variations in lipid A, including the degree of O-acylation and fatty acid composition, did not significantly alter antitumor activity.

    Conclusions:

    • The combination of specific endotoxin components and CWS is a potent immunotherapy for hepatocellular carcinoma.
    • Monophosphoryl lipid A, a non-toxic derivative, retains significant adjuvant properties for antitumor activity.
    • Lipid A's structure, particularly the presence of a phosphate group, influences toxicity but not necessarily its capacity to enhance CWS-mediated antitumor effects.