摘要:

Ovarian cancer is a leading cause of cancer mortality. Chemotherapy is effective in reducing tumor burden in a majority of patients, however, only approximately 20% of advanced disease patients will ultimately survive tumor free, and further treatment options are needed. Continuing advances in immunology make immunotherapy a promising area for future research. The design of immunotherapy strategies for ovarian cancer requires an understanding of the immune microenvironment of the peritoneal cavity, which is frequently involved with ovarian cancer metastases and is the site of its most devastating effects. Immunotherapy approaches for ovarian cancer include locoregional and systemic cytokine therapies, prophylactic and therapeutic vaccines, and adoptive immunotherapy strategies. This review will summarize previous clinical trials as well as future directions for research. Further progress in T-cell specific immune responses will require the identification of specific ovarian cancer antigens that are processed and presented on the surface of tumor cells in the context of specific HLA molecules. In addition, a more detailed understanding of functional relations between the peritoneal microenvironment and the metastatic process is required.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

After years of banishment from mainstream immunology, the notion that one subset of T cells can exert regulatory effects on other T lymphocytes is back in fashion. Recent work in knockout and transgenic mice has begun to bring molecular definition to our understanding of immunoregulatory CD4+CD25+T cells (Treg/Th3/Tr1). The identification of the glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR, also known as TNFRSF18) expressed on T regulatory cells might afford new therapeutic opportunities. Another possible therapeutic intervention could be the blockade of signaling through the molecular pair of tumor necrosis factor-related activation induced cytokine (TRANCE) and receptor activator of NF-&kgr;B (RANK). Based on the available evidence from experimental mouse tumor models, however, it seems that simply blocking or even eliminating T regulatory function will not be enough to manage established tumors. The challenge for immunotherapists now is to overcome immunosuppression using the knowledge gained through the understanding of T regulatory cell function.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Recent studies have identified a unique population of CD4+CD25+regulatory T cells that is crucial for the prevention of spontaneous autoimmune diseases. Further studies demonstrated that depletion of CD4+CD25+T cells enhances immune responses to nonself antigens. Because immune responses to malignant tumors are weak and ineffective, depletion of regulatory T cells has been reported to result in tumor regression. In the current study, using the weakly immunogenic MCA205 sarcoma and the poorly immunogenic B16/BL6/D5 (D5) melanoma, depletion of CD4+CD25+T cells by the administration of anti-CD25 monoclonal antibodies (mAb), PC61 induced some tumor growth retardation, but all mice eventually succumbed to tumors. In our laboratory, immunotherapy by the transfer of tumor-immune T cells has demonstrated potent antitumor effects. A reliable source of tumor-reactive T cells has been lymph nodes (LN) draining progressive tumors. Therapeutic effector T cells can be generated by in vitro activation of draining LN cells with anti-CD3 mAb followed by culture in interleukin-2. In this system, PC61 mAb depletion of CD4+CD25+T cells before or on day 8 of tumor growth resulted in increased sensitization in the draining LN. The therapeutic efficacy of activated tumor-draining LN cells from mAb depleted mice increased approximately three fold while maintaining specificity when tested in adoptive immunotherapy of established pulmonary metastases. Specific interferon-gamma secretion by LN T cells from mice treated with PC61 mAb 1 day before tumor inoculation increased significantly. However, this increase was not demonstrated with LN T cells from mice treated on day 8 despite their enhanced therapeutic reactivities. Our results indicate that although the antitumor immunity enhanced by the depletion of CD4+CD25+T cells is insufficient to eradicate tumors, it augments the sensitization of immune T cells in the draining LN, thus, facilitating adoptive immunotherapy.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Salmonella typhimuriumgenetically modified at the purI and msbB genes to increase dependence on adenine and decrease stimulation of tumor necrosis factor-&agr; production were injected intravenously into C57BL/6 mice bearing subcutaneous tumor or lung metastases. Decreased tumor growth and prolonged survival were seen in some, but not all of nine transplantable tumors.Salmonellaincreased in number in the tumor and reached levels 10,000 times higher than in the normal liver reservoir of these bacteria. Histologic studies revealedSalmonellagrowth in areas of the tumor although, in all cases, a viable rim of tumor survived and ultimately resulted in progressive tumor growth in all mice. These studies demonstrate thatSalmonellacan localize to transplantable murine tumors and partially inhibit tumor growth; however, additional modifications of the bacteria may be necessary if this approach is to develop into an effective treatment for patients with cancer.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Dendritic cells (DC) are potent antigen-presenting cells that are important for the priming of antitumor cytotoxic T cells. Recent reports suggest that DC may also have direct cytotoxic effector functions against selected tumor-cell lines by mechanisms that are dependent on dendritic cell–tumor cell contact in vitro. The authors report that ex vivo-generated murine DC induce the apoptosis of a panel of syngeneic and allogeneic murine tumors. Apoptosis of the MCA205 fibrosarcoma tumor-cell line by C57BL/6-derived DC was not mediated by Fas/FasL interactions and, in contrast to other studies, DC–tumor cell contact was not required to effect tumor-cell killing by DC. Therefore, the authors postulated that tumor-cell killing was mediated by an apoptotic factor that was secreted by DC. Even though DC did not secrete such apoptotic cytokines as interferon-&agr; or tumor necrosis factor-&agr;, they did secrete nitric oxide, and tumor apoptosis was partially abrogated by the nitric oxide synthase antagonist NG-monomethyl-L-arginine. Therefore, the authors' data demonstrate a novel mechanism for DC-induced tumor-cell apoptosis that does not require DC–tumor cell contact and is partially mediated by nitric oxide.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

We previously reported acid-extracted natural antigenic peptide (F4.2 [YSWMDISCWI]) of a gastric signet ring cell carcinoma HST-2 cells, recognized by HLA-A*31012-restricted autologous cytotoxic T lymphocytes, TcHST-2 line. In this study, the full-length cDNA (1101 bp), termed c98, predicting a protein composed of 170 amino acids was obtained. Because TcHST-2 cells could lyse the HLA-A31 antigen (+) allogeneic tumor cells that were introduced with c98 gene, this gene was suggested to possess antigenicity. Beginning at N-terminal 61 amino acid, the N-terminal six amino acid sequence that is completely identical to F4.2 was present in c98; however, a sequence of four amino acids in C-terminal was not found. Nevertheless, this peptide, c9861–70, seemed to be immunogenic, because cells pulsed with c9861–70peptide were lysed in a dose-dependent manner by TcHST-2 cells. The c98 gene was expressed ubiquitously in tumor cells as well as in normal tissues. However, some tumor cells, including HST-2 cells, expressed this antigen in a high content, and such cells were lysed by TcHST-2 cells in the context of HLA-A31 antigen. However, TcHST-2 cells did not lyse cells that expressed lower amounts of c98 than HST-2 cells. These data suggested that c98-gene product and/or c9861–70peptides could be used as a candidate for tumor vaccines in cancer immunotherapy.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

This report describes a phase I clinical trial using nonmyeloablative, lympho-depleting chemotherapy in combination with adoptive immunotherapy in patients with metastatic melanoma. The chemotherapy-conditioning schedule that induced transient lymphopenia consisted of cyclophosphamide (30 or 60 mg/kg per day for 2 days) followed by fludarabine (25 mg/m2per day for 5 days). Immunotherapy for all patients consisted of in vitro expanded, tumor-reactive, autologous T-cell clones selected for high avidity recognition of melanoma antigens. Cohorts of three to six patients each received either no interleukin (IL)-2, low-dose IL-2 (72,000 IU/kg intravenously three times a day to a maximum of 15 doses), or high-dose IL-2 (720,000 IU/kg intravenously three times a day for a maximum of 12 doses). The toxicities associated with this treatment were transient and included neutropenia and thrombocytopenia that resolved in all patients. High dose intravenous IL-2 was better tolerated by patients after chemotherapy than during previous immunotherapy cycles without chemotherapy. No patient exhibited an objective clinical response to treatment, although five patients demonstrated mixed responses or transient shrinkage of metastatic deposits. This study established a nonmyeloablative-conditioning regimen that could be safely administered in conjunction with adoptive T-cell transfer and IL-2 in patients with metastatic melanoma.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Melanoma differentiation antigens, such as MART-1/MelanA and gp100/PMel17, frequently are observed as targets of tumor infiltrating lymphocytes (TIL) originated from HLA-A*0201-expressing patients with melanoma. Furthermore, particular clinical relevance was attributed to gp100/pMel17 based on the impression that the adoptive transfer of gp100-recognizing TIL was associated with clinical responses in a small group of patients. However, the actual frequency of specific T cells for these melanoma differentiation antigens has never been directly enumerated in ex vivo or in vitro expanded TIL cultures. Here, we enumerated melanoma differentiation antigen-specific T-cell precursor frequency in TIL using tetrameric HLA/epitope complexes, functionally characterizing their responsiveness to cognate epitope by cytokine release assay. T-cell precursor frequencies were enumerated in 11 fresh-tumor preparations and 17 TIL adoptively transferred into patients bearing HLA-A*0201. MART-1 or gp100-specific T cells could be detected respectively in 5 and 2 of the 11 fresh preparations and in 5 and 2 of the 17 adoptively transferred TIL. With one exception, melanoma differentiation antigen-specific T-cell precursor frequency in fresh material and TIL ranged between 5,000 to 21,000/106CD8+T cells. T-cell precursor frequency was not significantly higher in TIL whose administration was associated with clinical response. These data provide direct enumeration of MART-1/MelanA and gp100/pMel17 reactivity ex vivo and in vitro in the context of HLA-A*0201.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The epithelial cell adhesion molecule is strongly expressed in carcinomas of diverse histologic origin and has attracted attention as a target for immunotherapy. We have previously demonstrated that the epithelial cell adhesion molecule-derived human leukocyte antigen-A*0201-restricted nonamer peptide ILYENNVIT184–192can be efficiently recognized by peptide-specific cytotoxic T lymphocytes (CTL). Using this peptide (Ep-2) we could readily expand precursor CTL and demonstrate their cytotoxicity by standard chromium-release assay. We now sought to evaluate the immune reactivity of Ep-2-specific CTL expanded from the peripheral blood mononuclear cells by real-time quantitative polymerase chain reaction assay (LightCycler system) measuring the change in interferon-&ggr; mRNA levels upon stimulation. Cytotoxic T lymphocyte response against the Ep-2 peptide in two patients with epithelial cell adhesion molecule-expressing lung cancer and three healthy donors was compared with the chromium-release assay. In vitro expanded epithelial cell adhesion molecule-specific CTL precursors that exhibited significantly elevated interferon-&ggr; mRNA levels also lysed Ep-2 peptide-pulsed target cells. Our study indicates that quantitative polymerase chain reaction may be a supplement to chromium-release assay for monitoring in vitro expanded CTL precursor reactivity.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Flt3 (fms-like tyrosine kinase 3) ligand, a cytokine that stimulates increases in the number of dendritic cells (DC) in vivo, has been shown to have antitumor activity in murine models via an immune-mediated mechanism. Therefore, we examined the clinical activity of this cytokine in patients with an immunologic-responsive cancer, metastatic renal cell carcinoma. Flt3 ligand (25 &mgr;g/kg subcutaneous) was administered daily for the first 14 days of a 28-day cycle. Although the treatment was well tolerated and was confirmed to induce expansion of lineage (Lin)−/HLA-DR+/CD11c+myeloid DC and Lin−/HLA-DR+/CD123+plasmacytoid DC, no clinical activity was observed. Reasoning that DC expanded by Flt3 ligand might potentiate the clinical activity of low-dose interleukin-2, a second study was conducted of sequential administration of 25 &mgr;g/kg of Flt3 ligand daily for 7 days was followed by 11 x 106IU of subcutaneous interleukin-2 for 4 consecutive days × 4 weeks. In this study, increased numbers of circulating DC were again observed, which was followed by increased numbers of activated T cells, confirming a biologic effect of each cytokine. However, toxicity and clinical efficacy were similar to what has been seen with low-dose interleukin-2 alone, with two minor responses observed. These results demonstrate that Flt3 ligand, although capable of inducing expansion of circulating myeloid and plasmacytoid DC in patients with metastatic renal cell carcinoma, lacks significant clinical activity at the doses and schedules examined.

ISSN:1524-9557    

出版商:OVID    

年代:2002

数据来源: OVID