Since macrophages can infiltrate tumor tissue or have a tendency to be recruited to the tumor site, this suggests a new approach to cancer immuno-therapy. Macrophages are known to have antitumor activity and are thought to have the potential to mediate tumor cytotoxicity and to stimulate antitumor effects of other immune-related cells. However, in the majority of human cancers, cancer cells can escape these macrophage-associated defense mechanisms. The possible mechanisms by which cancer cells escape macrophage-associated antitumor activity include [106-108]: (1) cancer cells do not express specific surface antigens that can be recognized by macrophages; (2) TAMs are modified by the tumor microenvironment, loose their cytotoxicity toward cancer cells, and are even redirected to protumorigenesis pathways; (3) after interaction with cancer cells, TAMs become suppressive for tumor-specific T- and NK-cell cytotoxicity.
Although there is evidence that the antitumor activity of TAMs can be suppressed and their protumorigenesis activity stimulated by the tumor microenvironment in the majority of human cancers, there is still a lot of potential to enhance antitumor activity by stimulation or activation of TAMs. A number of basic and clinical studies (including clinical trials) using activated macrophages in the immunotherapy of human cancers have been reported (reviewed in Ref. ).
One approach is to activate macrophages using biological response modifiers, such as muramyl tripeptide phosphatidylethanolamine (MTP-PE), GM-CSF, M-CSF, or IFN-7, both in vivo (injection of patients with biological response modifiers) or in vitro (adoptive transfer of macrophages treated with biological response modifiers). Asano et al.  showed that liposomal MTP-PE increased cytokine expression in monocytes and prolonged relapse-free survival time in osteosarcoma patients with lung metastasis in a Phase II clinical study. GM-CSF therapy in patients with lymphoma, breast cancer, or neuroblastoma was shown to increase antibody-dependent cytotoxicity and endogenous TNF-a levels , but produced no clinical response (regression of tumor) in Phase I and II studies . In terms of adoptive cellular immunotherapy, although biological responses, including increases in cytokine levels, have been shown, clinical responses have been almost absent [112-114].
The second approach is to use gene transfer to induce and enhance the antitumor effect of TAMs. Recently, genetic modification of tumor cells with cytokines, adhesion molecules, or MHC molecules has resulted in activation of immune cells, induction of immune responses, and facilitation of cancer cell recognition and killing. Dranoff et al.  showed that transfection of the GM-CSF gene into murine melanoma cells initiated an eVective and long-lasting anti-tumor response. Sanda et al.  also showed that vaccination with prostate cancer cells transfected with GM-CSF resulted in a significant increase in tumor-free survival of mice inoculated with the tumor. Morita et al.  showed that transfection of M-CSF into Lewis lung carcinoma cells prolonged the survival of mice injected with the transfected carcinoma cells compared to those injected with nontransfected cells and prevented lung metastasis. Dong et al.  showed that inoculation of mice with human prostate cancer cells transfected with IFN-^ inhibited tumor growth and lymph node metastases. In animal studies, increased TAM infiltration of the tumor and inhibition of angiogenesis were found to correlate with GM-CSF production. In addition to these animal studies, several human clinical trials of gene therapy have been recently performed [119-122]. Treatment of patients with renal cell carcinoma with irradiated autologous GM-CSF transfected renal cell carcinoma cells resulted in a decrease in lung metastasis . Vaccination with irradiated autologous melanoma cells transfected with the GM-CSF gene also resulted in extensive cancer cell destruction in melanoma patients . Furthermore, using the tendency of TAMs to accumulate around the tumor nest, several investigators have started to transfect macrophages with genes encoding colony stimulation factor-1 (CSF-1), INF-7, tumor antigens, antiangiogenic agents, and prodrug activation enzymes to enhance tumoricidal eVects [123-126]. The results showed that these macrophages can eVectively deliver gene therapy to the tumor mass but the clinical response remains to be determined. In conclusion, although a number of animal or human studies have demonstrated that gene therapy can enhance the tumoricidal effect of TAMs or other immune-related cells, further clinical trials are required to elucidate its effectiveness in human cancer.
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