The original concept that immune systems could recognize and control cancer was first postulated by Ehrlich and later embodied in cancer immuno-surveillance hypothesis of Burnet and Thomas in the 1950's and 60's. Their hypothesis was largely abandoned a decade or so later because of the absence of solid evidence to support this idea. Fortunately, cancer immuno-surveillance has continued to be vigorously debated and experimentally tested, and now as we enter the 21^st century, mounting evidence in humans and mice supports the involvement of immunity in tumor initiation, growth and metastasis. The concept that the immune system detects stressed, transformed and frankly malignant cells underpins much of the excitement currently surrounding new immuno-therapeutic options in cancer treatment. Paradoxically, while strong evidence exists that immuno-surveillance systems operate at early stages of tumorigenesis, established tumors primarily induce immune tolerance. To avoid immunity, tumors must develop mechanisms that inhibit the generation and detection of pro-inflammatory danger signals. In this review, we will define the cancer immuno-surveillance hypothesis, summarize the historical circumstances that led to its conception and debate, and discuss more recent convincing experimental evidence that supports this and other emerging concepts about the cancer : immunity interface.

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Surgical or radiotherapy-mediated eradication of tumors gives the best opportunity for cure, if the tumor is restricted to the primary sites. Chemotherapy is employed for disseminated disease but frequently fails to give clinical benefit. Thus, with our ever expanding understanding of the regulatory mechanisms of cytokine- and/or chemokine-mediated immune reactions to tumor, these molecules have become good candidates for cancer therapy. Unfortunately, most cytokines and chemokines have very short half-lives and their systemic delivery of pharmacological doses frequently results in severe adverse effects. These circumstances prompted many investigators to evaluate the genetic delivery of cytokines and chemokines for the treatment of cancer. Here, current status of clinical and pre-clinical studies of cytokine and chemokines will be discussed, particularly focusing on those with clinical relevance.

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The identification of tumor antigens recognized by cytotoxic T-lymphocytes and subsequent clinical trials using peptide immunization have shown tumor regression in advanced malignant melanoma patients. However, efficacious therapies for epithelial cancers, and certainly bone and soft tissue sarcomas, seemed to have been significantly delayed. For the development of a peptide-based immunotherapy for epithelial cancer and sarcomas, we have identified novel antigens recognized by CTLs using autologous pairs of tumor cell line-CTLs, or reversed immunological approach. Recently we started the phase I clinical trials of peptide-based immunotherapy. In this review, we described the recent study to establish a peptide-based immunotherapy for epithelial cancers, bone and soft-tissue sarcomas.

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CD4⁺ Th cells, in particular IFN-γ-producing Th1 cells, play a critical role in the activation and maintenance of CD8⁺ Tc1 cells that are essential for tumor eradication. Recent identification of MHC class II binding peptides derived from tumor antigens theoretically made possible to tumor-specific CD4⁺ T cells in addition to CD8⁺ T cells induced by MHC class I binding tumor antigen peptides. However, the generation of tumor-specific T cells is still a practically challenging and time-consuming procedure. This fact makes difficult the application of tumor-specific T cells to adoptive immunotherapy of cancer patients. Recently, novel methods have been developed to prepare tumor-specific T cells from nonspecifically activated T cells by gene transfer. Specifically, two types of genes were shown to be successful when they were introduced into nonspecific-T cells to generate genetically engineered tumor-specific T cells. One is the TCR α and β chain genes obtained from tumor-specific T cells, and the other is the chimeric immunoglobulin-T cell receptor (cIgTCR) gene which contains a single chain variable fragment from antitumor monoclonal antibody. In this review, we overviewed these methods briefly, and showed our recent results generating genetically engineered tumor-specific Th1 cells successfully by both these methods. In both mouse and human systems, non-specifically activated Th1 cells transduced with TCR genes specific for tumor antigen-derived peptide showed potent antitumor activity against tumor cells when they recognized tumor antigen peptide presented on MHC molecules. On the other hand, Th1 cells transduced with a cIgTCR gene specific for carcinoembryonic antigen, CEA, were shown to be reactive with cell surface CEA in an MHC independent manner. Taken together, these results strongly suggest that it is possible to prepare tumor-specific human Th1 cells by gene transfer technique that is applicable to adoptive tumor immunotherapy for cancer patients.

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Purpose: Previous studies showed that HLA-B40 and -B51 antigens were associated with the response to immunotherapy using protein-bound polysaccharide (PSK) and chemotherapy, respectively, in gastric cancer. We evaluated whether a putative HLA antigen correlated with the response to therapy, and associated with secondary malignancies. Patients and Methods: 413 patients with 302 gastric, 57 colon and 52 rectal cancers, and 2 synchronous gastric and colon cancers who underwent resection of the tumors from DEC-1990 to AUG-1993. They were examined 53 HLA antigens by using the micro-cytotoxicity assay and were randomized to immunotherapy or chemotherapy according to status of the positive or negative HLA -B40 and -B51 antigen and followed for secondary malignancy. Results: Three hundred two gastric cancers followed to be 12 secondary malignancies and 109 colorectal cancers 3. HLA-B40 and -B51 antigens were not significantly associated with the response to therapy. Patients in stage 1A gastric cancer without HLA-40 antigen who received chemotherapy and those with this antigen who received immunotherapy all lived. HLA-Cw3 positive patients with gastric cancer showed significantly higher incidence of secondary malignancies. Patients with heterozygous at HLA-A and -C, and those with homozygous at HLA-DQ also showed significantly higher incidence of secondary malignancies than those with homozygous at HLA-A and -C, and those with heterozygous at HLA-DQ. Conclusion: This study failed to confirm that HLA-B40 and -B51 antigens significantly associated with response to therapy, but we have discovered that HLA-Cw3 antigen was susceptible to subsequent malignancies in gastric cancer.

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This study investigated quality of life (QOL) in patients with advanced non-small-cell lung cancer in an early phase of chemotherapy in a randomized phase III trial. QOL assessments for four domains (functional, physical, mental, and psychosocial) and global QOL were self-administered every week during chemotherapy by 77 and 84 patients who received cisplatin plus irinotecan or cisplatin plus vindesine, respectively, with the schedules repeated every 4 weeks. Mean QOL scores at each week in the first and second courses of chemotherapy (weeks 1 to 8) were estimated for either treatment group and compared between groups using a longitudinal data analysis. The impact of non-hematological adverse events on QOL was examined using a general linear model. The maximum decrease in QOL scores (except for the psychosocial domain) was observed at weeks 1 and 5 for both groups, and recovery from the lapses was suggested before initiation of the next treatment course. There were statistically significant differences in QOL scores during the first course, favoring cisplatin plus vindesine for the physical domain. Nausea/vomiting was significantly related to deterioration in the three domains (except the psychosocial domain) and to global QOL for the first and second courses of either treatment group. These results comprehensively illustrate QOL in cancer patients during the early phase of chemotherapy and suggest that control of nausea/vomiting may be critical for the maintenance of QOL in cancer patients during chemotherapy.

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To elucidate the process of metastasis in submucosal gastric cancer (SM-GC), we examined the immunohistochemical expression of matrix metalloproteinases (MMPs: MMP-2, MMP-7, and MMP-9) and tissue inhibitors of metalloproteinases (TIMPs: TIMP-1, and TIMP-2) in 66 cases of SM-GC, and compared them with clinicopathological findings of the cases. The positive rates for MMP-2, MMP-7, MMP-9, TIMP-1, and TIMP-2 were 42.4%, 33.3%, 9.1%, 0%, and 48.5%, respectively. There was a significant correlation between MMP-7 positive rate and the degree of tumor invasion. Moreover, only MMP-7 positive rate was significantly higher in cases with lymphatic invasion, vascular vessel invasion, and lymph nodes metastasis than in cases without them. MMP-2 positive rate was significantly higher in cases with massive submucosal invasion (sm₂) and intestinal-type carcinoma. There were no significant correlations between clinicopathological findings and positive rates for MMP-9, TIMP-1, and TIMP-2. In logistic regression, MMP-7 immunoreactivity was found to be an independent risk factor of lymphatic invasion, vascular vessel invasion, and lymph nodes metastasis. These data suggest that MMP-7 is an important factor implicated in local invasion and metastasis, and would be a useful marker for predicting aggressive behavior of SM-GC.

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Current treatment of osteosarcoma is associated with poor prognosis, especially due to the increased risk of developing other cancers with chemotherapy. Therefore, new safe effective treatment strategies are needed. This prompted us to investigate the synergistic effect of a nutrient mixture (NS) of lysine, proline, arginine, ascorbic acid, and epigallocatechin gallate on the growth of human osteosarcoma xenografts in athymic nude mice. We also investigated the effect of NS on human osteosarcoma cell line MNNG-HOS in vitro by measuring: cytotoxicity, modulation of MMP-2 and -9, cancer cell invasive potential, and angiogenesis. After one-week of isolation, 5-6 week old athymic male nude mice (n=12) were inoculated with 3x10⁶ osteosarcoma cells MNNG-HOS. After injection, the mice were randomly divided into two subgroups; group A was fed a regular diet and group B was fed a regular diet supplemented with 0.5% of the nutrient mixture. Four weeks later, the mice were sacrificed, and their tumors were excised, weighed, and processed for histology. Cell proliferation was evaluated by MTT assay, MMP expression by gelatinase zymography, and invasion through Matrigel. Cells were also treated with phorbol 12-myristate 13-acetate (PMA) to study enhanced MMP expression. Results showed that the nutrient mixture (NS) inhibited the growth and reduced the size of tumors in nude mice. Furthermore, the mitotic index was decreased in the supplemented group (4-5) in contrast to the control group (12-15). The invasion of osteosarcoma MNNG-HOS cells through Matrigel was significantly reduced in a dose-dependent fashion, with 100% inhibition of invasion of MNNG cells at 50 μg/ml concentration of the nutrient mixture. No significant anti-proliferative effect by NS was seen with MNNG cells. Zymography showed dose-dependent inhibition of MMP secretion by MNNG in the presence of NS. Nutrient synergy strongly suppressed the growth of tumors without any adverse effects in nude mice, suggesting the nutrient combination has potential as an anticancer agent. In vitro studies demonstrated inhibition of cancer cell invasion and secretion of MMPs -critical parameters for cancer control and prevention.

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Introduction: Matrix metalloproteinases (MMPs) have received much attention in recent years for their role in various malignancies, and have been implicated in tumor invasion, metastasis and angiogenesis. Certain MMPs, such as MMP-2 and MMP-9, have shown a special propensity for promoting cancer. Development of MMP inhibitors has been a recent approach to controlling cancer and blocking metastasis. Objective: We investigated the effect of EGCG individually and in combination with lysine, proline, and ascorbic acid (LPA), in vitro, on human fibrosarcoma cells HT-1080, by measuring: cytotoxicity, modulation of MMP-2 and MMP-9, and invasive potential. Fibrosarcoma cell line was chosen for this study as it expresses both MMP-2 and MMP-9. Methods: Cytotoxicity was evaluated based on cell proliferation by MTT assay and MMP expression in condition media by gelatinase zymography. Invasion was evaluated through Matrigel. Results: Treatment of fibrosarcoma cells with EGCG independently showed dose-dependent cytotoxicity that was enhanced when EGCG was combined with LPA, with a maximum toxic effect of 45% at 50 μg/ml EGCG + LPA. Zymography showed dose dependent inhibition of MMP-2 and MMP-9 expression by EGCG, also enhanced at each concentration when combined with LPA, with virtual total inhibition of MMP-2 at LPA + EGCG 20 μg/ml and MMP-9 at LPA + EGCG 50 μg/ml concentration. The invasion of fibrosarcoma cells through Matrigel was significantly reduced (63%) with LPA + EGCG 20 μg/ml and totally inhibited with LPA + EGCG 50 μg/ml. Conclusion: Our results suggest that the synergistic effect of lysine, proline, and EGCG, is an effective, yet safe agent for adjunctive therapeutic use in the treatment of fibrosarcoma, by inhibiting cell proliferation, MMP expression, and matrigel invasion.

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