Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD40 is a receptor at the surface of B lymphocytes with important functions in the immune response. CD40 has also been found on a variety of carcinoma and melanoma cell lines where it has been suggested to serve as a possible receptor for mitogenic signals. We studied the expression and distribution of CD40 in paraffin sections of 71 uniformly treated malignant melanomas (MMs) with a long clinical follow-up using well known monoclonal antibodies. For comparison, 71 benign nevi were also studied. Common acquired nevi occasionally expressed CD40 in nests or single cells at the dermo-epidermal junction; no immunoreactivity was observed in the dermal part of acquired nevi, and all Spitz' nevi were entirely negative. One-third of large congenital nevi expressed CD40 in small clusters of heavily pigmented, epithelioid cells, corresponding to so-called proliferative nodules. In 41 of 71 MMs, CD40 was expressed in single or clustered neoplastic melanocytes; 9 cases showed CD40 expression only in the radial growth phase, and in 32 cases, the vertical growth phase showed CD40 expression. The same staining pattern was obtained with other anti-CD40 monoclonal antibodies, directed to different epitopes of the CD40 molecule. In 29 of 32 MMs showing CD40 in the vertical growth phase, expression of the CD40 ligand (CD40L) was studied; in 13 of these 29, CD40L was found in the same tumor areas that expressed CD40. Analysis of 28 metastases from 24 MM patients showed in the majority of cases a similar, scattered or nodular staining pattern as observed in the primary tumor. Patients expressing CD40 in the vertical growth phase of their MM did not differ significantly from CD40-negative patients with respect to any of the known prognostic parameters but showed a significantly shorter tumor-free survival. Patients with CD40+ CD40L+ MM tended to have a shorter tumor-free survival than those lacking CD40L. We conclude that CD40 represents a novel prognostic parameter in primary cutaneous MM. The co-localization of CD40 and CD40L suggests an autocrine growth loop in the vertical growth phase of MM.
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PMID:CD40 is a prognostic marker in primary cutaneous malignant melanoma. 895 30

This study focuses on the specific CD4+ T cell requirement for optimal induction of cytotoxicity against MHC class II negative autologous tumors (AuTu) collected from patients with various types of cancer at advanced stages. CD4+ T cells were induced in cultures of cancer patients' malignant effusion-associated mononuclear cells with irradiated AuTu (mixed lymphocyte tumor cultures (MLTC)) in the presence of recombinant IL-2 and recombinant IL-7. Tumor-specific CD4+ T cells did not directly recognize the AuTu cells, but there was an MHC class II-restricted cross-priming by autologous dendritic cells (DCs), used as APC. CD8+ CTL, also induced during the MLTC, lysed specifically AuTu cells or DCs pulsed with AuTu peptide extracts (acid wash extracts (AWE)) in an MHC class I-restricted manner. Removal of CD4+ T cells or DCs from the MLTC drastically reduced the CD8+ CTL-mediated cytotoxic response against the AuTu. AWE-pulsed DCs preincubated with autologous CD4+ T cells were able, in the absence of CD4+ T cells, to stimulate CD8+ T cells to lyse autologous tumor targets. Such activated CD8+ T cells produced IL-2, IFN-gamma, TNF-alpha, and GM-CSF. The process of the activation of AWE-pulsed DCs by CD4+ T cells could be inhibited with anti-CD40 ligand mAb. Moreover, the role of CD4+ T cells in activating AWE-pulsed DCs was undertaken by anti-CD40 mAb. Our data demonstrate for the first time in patients with metastatic cancer the essential role of CD4+ Th cell-activated DCs for optimal CD8+ T cell-mediated killing of autologous tumors and provide the basis for the design of novel protocols in cellular adoptive immunotherapy of cancer, utilizing synthetic peptides capable of inducing T cell help in vivo.
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PMID:Tumor-specific CD4+ T lymphocytes from cancer patients are required for optimal induction of cytotoxic T cells against the autologous tumor. 1072 53

We have directly compared the efficacy of two immunotherapeutic strategies for the treatment of cancer: "vaccination" of tumor-bearing mice with genetically modified dendritic cells (DCs), and vaccination with genetically modified tumor cells. Using several different preexisting tumor models that make use of B16F10 melanoma cells expressing a target tumor antigen (human melanoma-associated gene [MAGE]-1), we found that vaccination with bone marrow-derived DCs engineered to express MAGE-1 via adenoviral-mediated gene transfer led to a dramatic decrease in the number of metastases in a lung metastasis model, and led to prolonged survival and some long-term cures in a subcutaneous preexisting tumor model. In contrast, vaccination with granulocyte/macrophage colony-stimulating factor (GM-CSF)-transduced tumor cells, previously shown to induce potent antitumor immunity in standard tumor challenge assays, led to a decreased therapeutic effect in the metastasis model and no effect in the subcutaneous tumor model. Further engineering of DCs to express either GM-CSF, tumor necrosis factor alpha, or CD40 ligand via retroviral-mediated gene transfer, led to a significantly increased therapeutic effect in the subcutaneous tumor model. The immunological mechanism, as shown for GM-CSF-transduced DCs, involves MAGE-1-specific CD4(+) and CD8(+) T cells. Expression of GM-CSF by DCs led to enhanced cytotoxic T lymphocyte activity, potentially mediated by increased numbers of DCs in draining lymph nodes. Our results suggest that clinical studies involving the vaccination with genetically modified DCs may be warranted.
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PMID:Comparative analysis of genetically modified dendritic cells and tumor cells as therapeutic cancer vaccines. 1081 63

The induction of tumor-protective immunity against malignancies remains a major challenge in cancer immunotherapy. A novel, humanized anti-ganglioside-GD(2)-IL-2 immunocytokine (hu14.18-IL-2) induced CD8(+) T cells to eradicate established pulmonary metastases of B78-D14 murine melanoma, in a process that required help by CD4(+) T cells and was mediated by the CD40/CD40 ligand (CD40L) interaction. The anti-tumor effect was diminished in mice deficient in CD4(+) T-cells. Three lines of evidence show that CD4(+) T-cell help was mediated by CD40/CD40L interaction but not by endogenous IL-2 production. First, the hu14.18-IL-2-induced anti-tumor response is partially abrogated in C57BL/6J CD40L knockout (KO) mice in contrast to C57BL/6J IL-2 KO animals, in which the immunocytokine was completely effective. Second, partial abrogation of the anti-tumor effect is induced with anti-CD40L antibodies to the same extent as with CD4(+) T-cell depletion. Third, a complete anti-tumor response induced by hu14.18-IL-2 can be reconstituted in C57BL/6J CD40L KO mice by simultaneous stimulation with an anti-CD40 mAb. These results suggest that help provided by CD4(+) T cells via CD40/CD40L interactions in our tumor model is crucial for effective immunotherapy with an IL-2 immunocytokine.
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PMID:Melanoma immunotherapy by targeted IL-2 depends on CD4(+) T-cell help mediated by CD40/CD40L interaction. 1084 21

CD40 ligand (CD40L) is essential for the initiation of antigen-specific T-cell responses. This study is based on the hypothesis that dendritic cells (DCs) genetically modified ex vivo to express CD40L will enhance in vivo presentation of tumor antigen to the cellular immune system with consequent induction of antitumor immunity to suppress tumor growth. To examine this concept, subcutaneous murine tumors were injected with bone marrow-derived DCs that had been modified in vitro with an adenovirus (Ad) vector expressing murine CD40L (AdmCD40L). In B16 (H-2(b), melanoma) and CT26 (H-2(d), colon cancer) murine models, intratumoral injection of 2 x 10(6) AdmCD40L-modified DCs (CD40L-DCs) to established (day 8) subcutaneous tumors resulted in sustained tumor regression and survival advantage. This antitumor effect was sustained when the number of CD40L-DCs were reduced 10-fold to 2 x 10(5). Analysis of spleens from CD40L-DC-treated animals demonstrated that CD40L-DCs injected into the subcutaneous CT26 flank tumors migrated to the spleen, resulting in activation of immune-relevant processes. Consistent with this concept, intratumoral administration of CD40L-DCs elicited tumor-specific cytotoxic T-lymphocyte responses, and the transfer of spleen cells from CD40L-DC-treated mice efficiently protected naive mice against a subsequent tumor challenge. In a distant 2-tumor model of metastatic disease, an untreated B16 tumor in the right flank regressed in parallel with a left B16 tumor treated with direct injection of CD40L-DCs. These results support the concept that genetic modification of DCs with a recombinant CD40L adenovirus vector may be a useful strategy for directly activating DCs for cancer immunotherapy.
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PMID:Dendritic cells modified to express CD40 ligand elicit therapeutic immunity against preexisting murine tumors. 1089 36

Mice transgenic for the human MUC1 carcinoma-associated antigen (MUC1.Tg) are tolerant to immunization with MUC1 antigen. Recent studies, however, have demonstrated that immunization of MUC1.Tg mice with fusions of MUC1-positive tumour and dendritic cells (FC/MUC1) reverses MUC1 unresponsiveness and results in rejection of established MUC1-positive pulmonary metastases. Here we demonstrate that lymph node cells from MUC1.Tg mice immunized with the FC/MUC1 fusion cells proliferate in response to MUC1 antigen by a mechanism dependent on the function of CD4, major histocompatibility complex (MHC) class II, B7-1, B7-2, CD28, CD40 and CD40 ligand. The findings demonstrate that stimulation of lymph node cells with MUC1 results in selection of MUC1-specific CD8+ T cells. We show that the CD8+ T cells exhibit MUC1-specific cytotoxic T lymphocyte (CTL) activity by recognition of MUC1 peptides presented in the context of MHC class I molecules Kb and Db. The MUC1-specific CD8+ T cells also exhibit antitumour activity against MUC1-positive metastases, but with no apparent reactivity against normal tissues. These results indicate that immunization of MUC1.Tg mice with FC/MUC1 reverses immunological unresponsiveness to MUC1 by presentation of MUC1 peptides in the presence of costimulatory signals and generates MHC-restricted MUC1-specific CD8+ T cells.
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PMID:Selection and characterization of MUC1-specific CD8+ T cells from MUC1 transgenic mice immunized with dendritic-carcinoma fusion cells. 1110 34

All of these studies taken together highlight key areas that must be addressed in the future in order for the field to continue to move forward. These issues are many, including but not limited to method of delivery of dendritic cells to patients, maturation status of the dendritic cells, and methods of monitoring responses to these vaccines. Each of these requires some comment. Different strategies of immunization were used in these studies. DCs were injected at various times and in various locations, including intradermally/subcutaneously, intranodally, and intravenously. Investigation of the pattern of spread of subcutaneously injected fluorescently labeled DCs in the chimpanzee was studied at the University of Pittsburgh. Although rodent DCs had previously been shown to remain at the site of injection, these immature primate DCs migrated to draining lymph nodes and interact appropriately with T cells for as long as 5 days after administration. Data not shown in the same study reveal that intravenously administered DCs were undetectable in draining lymph nodes. Two groups have undertaken evaluation of route of administration of DCs in humans. The first of these examined migration of immature, indium-111-labeled dendritic cells after RNA-loading in metastatic cancer patients [44]. The DCs were injected either intravenously, subcutaneously, and intradermally. Only DCs injected intradermally were cleared from the injection site with migration to regional lymph nodes. The immunologic significance of these findings is unclear, however. Another study examined this issue by studying prostatic acid phosphatase (PAP) protein-loaded mature DCs injected intravenously, intradermally, and intralymphatically in prostate cancer patients [45]. Regardless of route of administration, T cell responses were induced as measured by proliferation when PBMCs in vitro were stimulated with the PAP protein. Cytokine analysis of the patients revealed that the majority of patients undergoing either intralymphatic or intradermal injection had increases in measurable interferon-gamma but that none of the intravenously-injected patients did. The intralymphatic and intradermal routes thus seem to lead to stronger Th1 responses. But no data was presented regarding the numbers of PAP precursors induced by vaccination nor their specificity/cytotoxicity. Another issue in DC administration that should also affect route of administration is maturation status of the dendritic cells. Many of the studies used immature dendritic cells to immunize patients whereas others used mature cells. A number of studies have demonstrated that maturation signals such as inflammatory cytokines and CD40 ligation lead to down-regulation of antigen processing and up-regulation of the chemokine receptor CCR7, which leads to homing to lymph nodes [46] as well as the MHC molecules, costimulatory molecules, and maturation markers [8,47,48]. In addition, different maturation agents and sequences of addition of these maturation agents may lead to differences in functions of dendritic cells [48-51]. Others have found that injection of immature DCs pulsed with influenza matrix peptide and KLH, and lead to greater numbers of influenza-specific T cells, but these cells had reduced interferon-gamma production and lacked killer activity [52]. Perhaps the most impressive results in a clinical trial, however, were gained by injecting similar cells loaded with melanoma peptides [21]. In addition, sequence of loading and maturation may be important in creating vaccines. One study using CEA peptides and CEA RNA found that optimal T cell presentation occurs when peptides are loaded after maturation with CD40 ligand and when RNA is transfected before maturation with CD40 ligand [53]. As all of these studies reveal, more investigation into the role of DC maturation as well as its timing and sequence is needed. Finally, a multitude of methods to detect response to vaccination have been attempted in all of the above studies. Many use DTH responses, but these may measure CD4 T cells instead of CD8 T cells. The availability of tetramers allows easier quantification of CTL precursors, but they provide no assessment of the function of these T cells. Enzyme-linked immunospot assays allow identification and quantification of numbers of cells producing cytokines such as interferon-gamma when encountering target antigens, but cytokine production may not correlate with tumor cell killing. Chromium release assays or flow cytometric assays for molecules such as perforin may be used to validate killing, but inability of many tumors to grow in vitro precludes direct assessment of tumor cell killing via this method. Other responses in human subjects may also be measured. Some of the cited studies yielded clinical responses that could be measured via physical examination or radiologic study. This is the exception rather than the rule, however. Others have monitored the decrease in serum tumor markers such as PSA or CEA. But these may not correlate directly with tumor burden. Indirect calculation of tumor burden by using quantitative PCR to estimate the number of circulating tumor cells in peripheral blood may be promising in this regard. Despite the lack of consensus as to what constitutes an effective response, most would agree that monitoring of these patients should include measures of both immunologic response and clinical tumor effect. All of this leads to the conclusion that DC-based cancer vaccines have progressed a great deal but that much work still needs to be done. Only rigorous bench top experimentation followed by careful patient selection and vaccine administration, and then by meticulous patient monitoring, will lead to advances in the field.
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PMID:Dendritic cell gene therapy. 1248 60

Efficient T cell priming by GM-CSF and CD40 ligand double-transduced C26 murine colon carcinoma is not sufficient to cure metastases in a therapeutic setting. To determine whether a cellular vaccine that interacts directly with both APC and T cells in vivo might be superior, we generated C26 carcinoma cells transduced with the T cell costimulatory molecule OX40 ligand (OX40L) either alone (C26/OX40L) or together with GM-CSF (C26/GM/OX40L), which is known to activate APC. Mice injected with C26/OX40L cells displayed only a delay in tumor growth, while the C26/GM/OX40L tumor regressed in 85% of mice. Tumor rejection required granulocytes, CD4+, CD8+ T cells, and APC-mediated CD40-CD40 ligand cosignaling, but not IFN-gamma or IL-12 as shown using subset-depleted and knockout (KO) mice. CD40KO mice primed with C26/GM/OX40L cells failed to mount a CTL response, and T cells infiltrating the C26/GM/OX40L tumor were OX40 negative, suggesting an impairment in APC-T cell cross-talk in CD40KO mice. Indeed, CD4+ T cell-depleted mice failed to mount any CTL activity against the C26 tumor, while treatment with agonistic mAb to CD40, which acts on APC, bypassed the requirement for CD4+ T cells and restored CTL activation. C26/GM/OX40L cells cured 83% of mice bearing lung metastases, whereas C26/OX40L or C26/GM vaccination cured only 28 and 16% of mice, respectively. These results indicate the synergistic activity of OX40L and GM-CSF in a therapeutic setting.
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PMID:OX40 ligand-transduced tumor cell vaccine synergizes with GM-CSF and requires CD40-Apc signaling to boost the host T cell antitumor response. 1249 88

Understanding the whole process of dendritic cell (DC) activation might help in the development of more efficient immunotherapeutic strategies for tumor patients. Part of this process is cytokine secretion, which has important effects on innate and adaptive immune response. Here, we cultured circulating monocytes for five days with interleukin-4 and GM-CSF followed by two-day culture with or without CD40 ligand and LPS to create a mature DC (mDC) and an immature DC (iDC) phenotype, respectively, characterized by differential expression of co-stimulatory molecules (CD80, CD83). We then compared the cytokine expression profile of the mDC and iDC using two protein platform arrays. Twelve supernatants from mDC paired with 12 from iDC were compared. The mDC protein expression profile showed significant increases in 16 out of 34 factors tested, including TNFalpha, IL-10, IL-12, IFNgamma, MIP1alpha, MIP1beta, IL-8, MDC, RANTES, and IL-6, which play a crucial role in the regulation of the innate immune response as well as the recruitment and activation of adaptive immune effectors. Interestingly, some of the cytokines expressed during maturation were also found in the gene expression profile identified in tumor metastases following IL-2 therapy using cDNA arrays. This finding suggests a possible role for resident DC maturation as a mediator of systemic IL-2 effects. Most important, the array of cytokines secreted during DC maturation may be considered an important component during adoptive transfer. Further characterization of the kinetics and persistence of their secretion should be undertaken in the future.
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PMID:Cytokine and chemokine expression profiles of maturing dendritic cells using multiprotein platform arrays. 1468 83

Effective targeting of vectors to tumor cells that have metastasized to multiple different tissue sites remains a major challenge for gene therapy. Tumor-specific cytotoxic T lymphocytes (CTLs) have been shown in animal models and in humans to be able to cross tissue barriers and traffic to tumor cells. However, their capacity to eliminate malignancy has been limited by tumor immune evasion strategies. We now use a model of Epstein-Barr virus-mediated malignancy to show that human CTLs themselves may be modified to release therapeutic vectors following engagement of their antigen-specific receptors and that these vectors will effectively transduce and destroy tumor targets. We generated EBV-specific CTLs that were transgenic for the adenoviral E1 gene under the control of the cell activation-dependent CD40 ligand (CD40L) promoter. Following transduction with E1-deficient adenoviral vectors, these CTLs produced infectious virus when exposed to HLA-matched EBV-expressing targets, but not on exposure to major histocompatibility complex (MHC)-mismatched or otherwise irrelevant cells. This approach provides a means of delivering oncolytic/therapeutic vectors not only to locally accessible macroscopic tumors as is presently the case, but also to disseminated metastatic disease, while avoiding the risks associated with systemic administration of large doses of adenoviral vectors.
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PMID:Targeted delivery of adenoviral vectors by cytotoxic T cells. 1516 64


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