Further studies on the structural requirements of agents for immunotherapy of the guinea pig line-10 tumor

Abstract

In this laboratory and elsewhere, cord factor or some less complex analogue has been found to be an important constituent of agents for suppression and immunotherapy of cancer. In further attempts to delineate structural requirements, we have tested several such analogues, in combination with the optimum quantity (150 µg) of glycolipid from an Re mutant salmonella (Re glycolipid), for ability to produce regression of transplantable one-week-old line-10 tumors in guinea pigs. The synthetic diester, trehalose 6,6-dipalmitate, has been reported to be a useful antibacterial prophylactic and a tumor-suppressive agent, but neither alone nor in combination with Re glycolipid was it effective in therapy of established line-10 tumors, even in doses up to 1500 µg. Trehalose myocolates (cord factor, P3) were also ineffective when given alone, but as little as 15 µg of P3, combined with Re glycolipid and oil droplets, produced a high rate of regression. Some analogues of higher molecular weight were effective but, within the limits of these experiments, only when the fatty acid residues contained side chains at the alpha carbon atom. It was striking that a naturally-occurring 6,6-trehalose diester of a branched chain fatty acid(s) containing the carbon equivalent of two condensed palmitic acid residues was as effective as any of the higher-molecular weight compounds, including the mycolates. Thus, it appears that there may be requirements for a certain molecular size and/or for a particular molecular conformation. Only such a compound, in conjunction with Re glycolipid or other suitable immunogen, has been found to bring about complete cures, including regression of the primary tumor, elimination of metastases in the regional lymph node, and specific systemic immunity to rechallenge with the line-10 tumor.