Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although tumor-specific T lymphocytes recognize tumor-associated antigens (TAA) present on their cell surface via major histocompatibility complex (MHC) molecules, T cells require other activating signals. These are provided by costimulatory molecules, including B7-1 (CD80), B7-2 (CD86) and intercellular adhesive molecule 1 (ICAM-1; CD54). Transfecting mouse tumor cell lines with the B7 gene can lead to primary tumor rejection and the establishment of protective immunity. However, some studies have shown that the B7 effect upon T-cell-dependent tumor immunity is limited. Therefore, we examined the antitumor effects of recombinant interleukin 12 (IL-12) and genetically engineered glioma cells expressing B7-1 or both B7-1 and ICAM-1. Vaccination of mice with B7-1-expressing tumor cells substantially inhibited the growth of subcutaneously inoculated gliomas but not those located in the brain. Vaccination with B7-1-expressing tumor cells and systemic recombinant IL-12 (rIL-12) was more effective than either B7-1-expressing tumor cells or rIL-12 alone. Our murine brain tumor model also showed that vaccination with tumor cells expressing both B7-1 and ICAM-1 combined with rIL-12 prolonged survival. We have demonstrated the therapeutic potential of vaccination with rIL-12 and tumor cells expressing both B7-1 and ICAM-1 in the control of glioma growth.
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PMID:Induction of effective antitumor immunity in a mouse brain tumor model using B7-1 (CD80) and intercellular adhesive molecule 1 (ICAM-1; CD54) transfection and recombinant interleukin 12. 1041 70

Augmenting immunogenicity by genetically modifying tumor cells to express costimulatory molecules has proven to be a promising therapeutic strategy in murine tumor models and is currently under investigation in human clinical trials for metastatic cancer. However, there are significant technical and logistic problems associated with implementing strategies requiring direct gene modification of primary tumor cells. In an effort to circumvent these problems, we are developing a strategy in which the costimulatory signal required for tumor-specific T lymphocyte activation is provided by a genetically modified human fibroblast (trans-costimulation). We have evaluated the efficiency of CD80- and CD86-mediated trans-costimulation in the activation of human CD8+ and CD4+ T lymphocytes in MHC class I- and class II-restricted lymphoproliferation reactions. Our studies demonstrate that the efficiency of CD80- or CD86-mediated trans-costimulation of purified human CD8+ and CD4+ T lymphocytes is comparable to cis-costimulation under defined conditions. Moreover, a dose-response relationship consistent with the predicted two-hit kinetics of the reaction was evident in trans-costimulation reactions in which the ratio of target cells expressing either signal 1 or signal 2 was varied incrementally from 1:10 to 10:1. Importantly, the level of cell-surface CD86 required for trans-costimulation is equivalent to that constitutively expressed by human peripheral blood monocytes. These results may have significant implications for the clinical implementation of this type of cancer immunotherapy and also raise questions about the possibility of trans-costimulating autoreactive T lymphocytes in vivo.
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PMID:Human fibroblasts transduced with CD80 or CD86 efficiently trans-costimulate CD4+ and CD8+ T lymphocytes in HLA-restricted reactions: implications for immune augmentation cancer therapy and autoimmunity. 1047 93

The generation of fused cells between dendritic cells (DC) and tumor cells is a very effective approach for tumor antigen presentation in cancer immunotherapy. However, the application of this approach in clinical studies is limited by the need for established tumor cell lines and the time-consuming procedures for selecting and expanding the fused cells. In the current study, the authors report a rapid, novel approach to produce fused cells between DCs and primary tumor cells from patients with malignant melanoma. Peripheral blood DCs and a primary tumor cell culture were generated from the same patients, labeled with fluorescent green and red dyes, respectively, and fused. The fused cells were isolated by fluorescence-activated cell sorting. Because the fused cells do not need to be expanded, these cell hybrids have been named instant dendritomas. Fluorescence-activated cell sorting analysis showed that instant dendritomas express the key molecules for antigen presentation (HLA-A, B, C; HLA-DR; CD80; and CD86). In vitro studies have shown that instant dendritomas effectively activated autologous CD8+ T lymphocytes to proliferate and secret interferon-gamma. More importantly, the activated CD8+ T lymphocytes effectively lysed the patients' primary tumor cells. This approach represents a practical clinical strategy for cancer immunotherapy.
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PMID:A rapid, novel strategy to induce tumor cell-specific cytotoxic T lymphocyte responses using instant dentritomas. 1126 78

SUMMARY: The generation of fused cells between dendritic cells (DC) and tumor cells is a very effective approach for tumor antigen presentation in cancer immunotherapy. However, the application of this approach in clinical studies is limited by the need for established tumor cell lines and the time-consuming procedures for selecting and expanding the fused cells. In the current study, the authors report a rapid, novel approach to produce fused cells between DCs and primary tumor cells from patients with malignant melanoma. Peripheral blood DCs and a primary tumor cell culture were generated from the same patients, labeled with fluorescent green and red dyes, respectively, and fused. The fused cells were isolated by fluorescence-activated cell sorting. Because the fused cells do not need to be expanded, these cell hybrids have been named instant dendritomas. Fluorescence-activated cell sorting analysis showed that instant dendritomas express the key molecules for antigen presentation (HLA-A, B, C; HLA-DR; CD80; and CD86). In vitro studies have shown that instant dendritomas effectively activated autologous CD8+ T lymphocytes to proliferate and secret interferon-gamma. More importantly, the activated CD8+ T lymphocytes effectively lysed the patients' primary tumor cells. This approach represents a practical clinical strategy for cancer immunotherapy.
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PMID:A Rapid, Novel Strategy to Induce Tumor Cell-Specific Cytotoxic T Lymphocyte Responses Using Instant Dendritomas. 1144 68

Intraoperative lymphatic mapping and sentinel lymphadenectomy (LM/SL) provides a unique opportunity for assessing potential immunologic interactions between the primary tumor and regional lymph node basin. We performed LM/SL in 24 patients with early-stage melanoma and resected an additional nonsentinel node (non-SN) in each case. Sentinel nodes (SNs) and non-SNs were evaluated by routine pathologic analysis, and a portion of each node was processed for expression of three dendritic markers of activation (CD80, CD86, CD40) and their corresponding T-cell receptors (CTLA-4 and CD28). Twenty (83%) patients had matched SNs and non-SNs. A total of 26 nodal pairs were obtained because one patient had three pairs and two other patients each had two pairs. Reverse transcriptase-polymerase chain reaction (RT-PCR) analyses of paired SNs and non-SNs demonstrated a marked reduction in semiquantitative expression of CD80 (77%), CD86 (77%), and CD40 (85%), as well as CTLA-4 (88%) and CD28 (85%) in SNs. The diminished expression appeared to be unrelated to B-cell (CD20) and T-cell (CD2) expression. A quantitative reduction in dendritic cell markers in SNs may be important in the immunologic interaction between the primary site and regional lymph node basin and may also provide useful criteria for identifying SNs.
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PMID:Surgical and molecular approaches to the sentinel lymph nodes. 1159 94

Intraoperative lymphatic mapping and sentinel lymphadenectomy has become an increasingly popular technique for staging the regional lymph nodes in early-stage melanoma. This operative technique allows for detailed pathologic analysis of the first (or sentinel) lymph node in direct connection with the primary tumor, and provides a unique opportunity for assessing potential immunologic interactions between the primary tumor and regional lymph node basin. We performed lymphatic mapping and sentinel lymphadenectomy on 25 patients with early-stage melanoma and resected an additional nonsentinel node in each case. Sentinel and nonsentinel nodes were evaluated by routine pathologic analysis. A portion of each node was processed for expression of the dendritic markers of activation CD80, CD86, and CD40, and their corresponding T-cell receptors CTLA-4 and CD28. Of 25 patients undergoing lymphatic mapping and sentinel lymphadenectomy, 20 (80%) had matched sentinel and nonsentinel nodes. A total of 26 matched lymph node sets were obtained: three pairs from one patient and two from an additional two patients. Reverse transcription polymerase chain reaction analyses of corresponding sections of the sentinel and nonsentinel nodes demonstrated a marked reduction in semiquantitative expression of CD80 (77%), CD86 (77%), and CD40 (85%), as well as CTLA-4 (88%) and CD28 (85%) in sentinel as compared to nonsentinel nodes. The diminished expression of the dendritic cell markers appeared to be unrelated to the B-cell (CD20) and T-cell (CD2) expression. Lymphatic mapping and sentinel lymphadenectomy allows for detailed pathologic and molecular characterization of sentinel nodes. Our results suggest a quantitative reduction in dendritic cell markers in sentinel as compared to nonsentinel nodes, which may be important in the immunologic interaction between the primary site and regional lymph node basin and may also serve as useful criteria for identifying sentinel nodes.
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PMID:Dendritic cell function in sentinel nodes. 1182 80

Our aim was to evaluate whether the number of circulating lymphocytes expressing costimulatory molecules can be associated with melanoma prognosis. We determined the concentration of peripheral blood lymphocytes, which expressed the CD80/CD86 or CD28/CTLA-4 molecules, in 38 patients with cutaneous melanoma and 27 controls. The number of each cell subset was compared between patients and controls, as well as between groups of patients stratified according to Breslow thickness of the primary tumor (< or = 2 mm vs > 2 mm) or to survival after 3 years. The concentration of circulating lymphocytes expressing the CD80/CD86 molecules was not significantly different between patients and controls. There was a lower number of CD3(+)CD8(+)CD28(+) cells, as well as a higher CD3(+)CD8(+)/CD3(+)CD8(+)CD28(+) cell ratio, in melanoma patients than in controls. Melanoma patients with thinner tumors and those surviving revealed an increase of CD19(+)CD80(+) and CD19(+)CD80(+)CD86(+) cells, as well as a higher concentration of CD3(+)CD4(+)CD28(+) cells. CD80(+) B cells and a low CD8 suppressor/cytolytic cell ratio correlate with a good prognosis in melanoma. Our findings support our conclusion that CD80(+) B cells may be important antigen presenting cells that can contribute to an antimelanoma immune response and are candidates to be monitored in melanoma patients.
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PMID:Changes in the number of CD80(+), CD86(+), and CD28(+) peripheral blood lymphocytes have prognostic value in melanoma patients. 1287 58

Administration of soluble human interleukin-12 (hIL-12) has been shown to induce a potent anti-tumor response. However, the use of soluble hIL-12 is hindered by its cytotoxicity when systemically administered and the difficulty of transferring multiple genes into primary tumor cells. In this study, we developed a membrane-anchored hIL-12 and expressed it on tumor membrane vesicles to deliver and confine IL-12 to the vaccination site. We constructed a glycolipid-anchored hIL-12 (GPI-hIL-12) by fusing the coding region of p35 and p40 subunits of hIL-12 with the GPI-signal sequence of CD59 at the C-terminal ends. The two subunits were processed correctly and expressed as a GPI-anchored disulfide-linked heterodimeric protein on the cell surface. GPI-hIL-12 cells induced proliferation of activated T cells and augmentation of allogeneic T cell generation in an MLR assay. Purified GPI-hIL-12 was efficiently intercalated onto isolated tumor cell membrane vesicles prepared from various human tumor cell lines. Further, the incorporation of GPI-hIL-12 onto tumor membrane vesicles induced proliferation of T cells and the release of IFN-gamma by activated T cells. Notably, GPI-hIL-12 enhanced the proliferative response initiated by CD80, a principal costimulatory molecule for T cell activation. These studies suggest that tumor membrane vesicles modified with GPI-anchored cytokines can be used to create potent immunogenic tumor vaccines for use in human immunotherapy. Since protein transfer can be used to modify tumor membrane vesicles obtained from surgical specimens, this approach offers a useful alternative to gene therapy as a means of developing cancer vaccines.
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PMID:Human tumor membrane vesicles modified to express glycolipid-anchored IL-12 by protein transfer induce T cell proliferation in vitro: a potential approach for local delivery of cytokines during vaccination. 1637 65

Vaccination with autologous tumor cells genetically modified to express costimulatory molecules has shown utility for cancer immunotherapy in preclinical and limited clinical settings. Given the complicated nature of gene therapy, a practical alternative approach has been designed that relies on modification of the cell membrane with biotin and its "decoration" with a chimeric protein composed of the functional portion of human CD80 and core streptavidin (CD80-SA). We tested whether primary tumor cells resected from cancer patients can be decorated with CD80-SA and whether such cells serve as antigen-presenting cells (APCs) to generate autologous T cell responses ex vivo. Tumors and peripheral blood lymphocytes (PBLs) were collected from 14 lung, 9 colon, and 2 breast "treatment-naive" cancer patients presenting various clinical stages of the disease. Tumors were mechanically processed, irradiated, decorated with CD80-SA or control streptavidin (SA) protein, and used as APCs in ex vivo autologous T cell-proliferative and cytotoxicity assays. All tumor samples were modified with CD80-SA, albeit with various degrees of decoration ranging from 21.8 to 100%. CD80- SA-decorated cells generated significant proliferative responses in autologous T cells from 9 of 16 evaluable patients (p < 0.05). Proliferative responses were CD80-SA specific and heterogeneous, with stimulation indices ranging from 0.25 to 45. In 15 of 15 evaluable patients, CD80-SA-specific cytotoxic T cell responses against autologous tumors were generated, 11 of which were significant, with specific killing ranging from 5 to 70%. Taken together, these data demonstrate that primary tumor cells can be effectively decorated with CD80-SA and that such cells serve as APCs to induce autologous antitumor T cell responses.
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PMID:Primary tumor cells resected from cancer patients and decorated with a novel form of CD80 protein serve as effective antigen-presenting cells for the induction of autologous T cell immune responses ex vivo. 1654 82

Dendritic cells (DC) engineered in vitro by DNA encoding OVAhsp70 and IL-15 up-regulated their expressions of CD80, CD86, CCR7 and IL-15Ralpha and promoted their productions of IL-6, IL-12 and TNF-alpha. Transcriptional IL-15-directed in vivo DC targeting DNA vaccine encoding OVAhsp70 elicited long-lasting Th1 and CTL responses and anti-B16OVA activity. CD8T cell-mediated primary tumor protection was abrogated by DC or CD4T cell depletion during the induction phase of immune responses. However, CD4T cell depletion during immunization did not impair CD8T cell-dependent long-lasting tumor protection. Furthermore, in vivo DC-derived IL-15 exerted the enhancements of cellular and humoral immune responses and antitumor immunity elicited by OVAhsp70 DNA vaccine. Importantly, the potency of this novel DNA vaccine strategy was proven using a self/tumor Ag (TRP2) in a clinically relevant B16 melanoma model. These findings have implications for developing next generation DNA vaccines against cancers and infectious diseases in both healthy and CD4 deficient individuals.
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PMID:Transcriptional IL-15-directed in vivo DC targeting DNA vaccine. 1972 34


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