A post operative immune therapy for cancer has been conducted using the cell-wall skeleton of BCG (BCG-CWS) in patients with lung cancer after surgical resection in the hospital of Osaka Medical Center for Cancer for > 10 years. In a typical study of patients with lung cancer, significant high 5-year survival with good QOL was observed compared to a historical control in the same hospital.31'32 BCG-CWS acts as a potent adjuvant for induction of tumor-specific cytotoxic T lymphocytes (CTL), a potent effector for tumor cells. Thus, the mechanism of this adjuvant for induction of antitumor immunity has been investigated in our research group.
In C57BL/6 mouse B-16 melanoma implanting model, preadministration of the B16 melanoma antigenic peptide and BCG-CWS resulted in suppression of tumor growth.33 Specific CTL against B16 melanoma was induced in parallel with tumor regression.33 The CTL induction as well as retardation of tumor growth was completely diminished in MyD88-deficient mice.33 Hence, the mechanism whereby BCG-CWS and tumor antigen contribute to regression of implanted tumor can be explained as follows: BCG acts as an adjuvant to activate TLR followed by the MyD88 adapter in antigen-presenting dendritic cells leading to up-regulation of antigen-presenting capacity and the levels of co-stimulators. This was true in in vitro dendritic cell stimulation with BCG-CWS both in mouse33 and human.34
Simple subcutaneous administration of BCG-CWS would be effective if the patients are reserving tumor antigen.31 However, in many cases, tumor turned MHC class I-negative and grew again in patients, irrespective of continuous BCG-CWS treatment. This finding is consistent with the fact that BCG-CWS lacks the ability to activate NK cells,4,35 another effector for cancer. Administration of an NK-activating agent additionally to BCG-CWS adjuvant is expected to establish a powerful immune therapy for postoperative patients.
We developed a strategy of tumor immune therapy using BCG-CWS and Spirulina, which is now found to be a strong NK activator.4,6 In transplanted tumor-bearing mice, effective tumor regression was observed if BCG-CWS and Spirulina were simultaneously administered.6 Nearly complete remission could be introduced in about 80% of tumor-bearing mice through oral administration of Spirulina and subcutaneous injection of tumor debris conjugated with BCG-CWS.
The authors mentioned the mechanism whereby tumor was regressed by this combination therapy. According to their previous reports, microbial component acts as a maturation inducer of dendritic cells,30 which play a major role in induction of tumor-specific CTL. CTL targets for high MHC-expressing tumor cell populations.
However, CTL fails to attack low MHC-expressing cells, which can be eliminated by NK cells. Since Spirulina is an efficient NK activator, MHC-negative tumor cells circumventing CTL attack to survive will be killed by Spirulina-mediated NK cells. Hence, this therapy should be adaptable to a variety of tumors. More extensive studies on the tumor-eliminating mechanism by the effector cells are in progress and part of them were presented in the meeting of Princess Takamatsu Cancer Research Meeting held on November 11-13, 2003 in Tokyo.36 In the future, this combined adjuvant immune therapy will be adaptable to human patients with postoperative cancer.
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