Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The B7-1 molecule expressed on antigen presenting cells is an important costimulatory molecule for T cell activation. It has been demonstrated that murine B7-1 can enhance host immunity and lead to tumor rejection via its costimulatory function. Here, we investigate how transfection of B7-1 into line 1, a poorly immunogenic murine lung carcinoma, affects the generation and function of different immune effector cells. Line 1 cells expressing B7-1 form tumors that grow at a slower rate than the parental line 1. Our studies have shown that tumor infiltrating lymphocytes present within the B7-1 expressing tumors are primarily composed of nonspecific killer cells with no specific cytotoxic T cells present. To determine if increased nonspecific killer cells could inhibit the tumor growth of line 1 in the presence of B7-1, we examined the cytotoxicity of natural killer (NK) cells and lymphokine-activated killer (LAK) cells on the B7-1-transfected line 1 and the parental line 1. We found that B7-1 augments the NK- but not LAK-mediated killing against line 1 as measured in an in vitro 51Cr-release cytotoxicity assay. This enhancement could be blocked by CTLA-4 Ig. In vivo depletion of NK cells led to growth of the B7-1-transfected line 1 at the same rate as the parental line 1. These results suggest that in addition to its costimulatory role for T cell activation B7-1 could be an accessory molecule that intensifies NK-mediated cytotoxicity. This novel finding may provide a mechanism for the effect of B7-1 on tumors of low immunogenicity.
 ...
PMID:B7-1 enhances natural killer cell-mediated cytotoxicity and inhibits tumor growth of a poorly immunogenic murine carcinoma. 755 86

Direct antigen presentation of tumor-associated antigens by tumor cells to T lymphocytes may induce clonal anergy as a mechanism of escape from immune surveillance. B7-1 is a costimulatory molecule for the activation of both CD4+ and CD8+ T lymphocytes that prevents the induction of clonal anergy. Thus, the transfer of B7-1 genes into tumor cells can induce protective immunity and lead to tumor rejection of some tumors in model systems of in vivo tumor growth; however, there is no information on whether stable expression of B7-1 can affect the in vivo growth of squamous cell carcinoma, a common skin cancer. Here, we study how the stable cell surface expression of high levels of B7-1 by Pam 212, a murine squamous cell carcinoma, affects tumor cell-lymphocyte interactions (lymphocyte proliferation and cytotoxicity). Consistent with its costimulatory role, we demonstrate that B7-1 can efficiently induce dendritic epidermal T-cell proliferation in three different dendritic epidermal T-cell cell lines. In addition, B7-1 enhances dendritic epidermal T-cell cytolytic activity against Pam 212 cells in an in vitro 51Cr-release assay, which was blocked by CTLA-4/Ig fusion protein. In contrast to dendritic epidermal T cells, the expression of B7-1 does not alter Pam 212 interactions with either cytotoxic T-lymphocytes, natural killer, or lymphokine-activated killer cells. B7-1 expression by Pam 212 cells did not alter its ability to grow tumors in vivo, as their rate of tumor growth was the same as vector-transfected Pam 212 cells, which were B7-1 negative. Our studies indicate that B7-1 gene transfer into Pam 212 does not alter its tumorigenicity, because it does not alter tumor cell-lymphocyte interactions with cytotoxic T lymphocytes, natural killer cells, and lymphokine-activated killer cells. Further studies of B7-1 modified Pam 212 and dendritic epidermal T cells will clarify whether T-cell receptor-gamma/delta-bearing T lymphocytes can play a role in immunotherapy of Pam 212 squamous cell carcinoma.
 ...
PMID:Expression of B7-1 by Pam 212 squamous cell carcinoma enhances tumor cell interactions with dendritic epidermal cells but does not affect in vivo tumor growth. 940 12

A promising approach to cancer immunotherapy is immunization with modified tumor cells carrying cytokine or immunomodulatory genes. Cytokine genes (tumor necrosis factor-alpha, interleukin 2, interferon gamma) and costimulatory molecule, B7-1, were incorporated into canarypox virus, ALVAC, which does not replicate in infected mammalian cells, and highly attenuated vaccinia virus, NYVAC. We examined the effect of local cytokine production on the growth of the mouse prostate tumor, RM-1, and the mouse bladder tumor, MBT-2. The vectors expressed the high levels of cytokines and B7-1 and the tumor growth of infected cells was significantly inhibited. The mice immunized with irradiated MBT-2 cells infected with ALVAC-interleukin 2 were protected against the subsequent challenge of parental tumor cells. We conclude that poxvirus vectors are useful for gene delivery in immunotherapy studies because of their infection efficiency, their capability of high gene product expression, their safety, and their case of handling.
 ...
PMID:[Poxvirus vectors for gene transfer]. 943 32

The aim of the study was the induction of an antitumor immune response by genetic modification of tumor cells. This was done by transfecting the costimulatory molecule B7.1 into a murine tumor cell line SCCVII/SF in order to increase T cell recognition and to install an immunologic memory. One cohort of immunocompetent mice C3 H/HeN were injected with B7.1 expressing tumor cells, while the control group received parental B7.1 negative tumor cells. In a second step those immunized mice were rechallenged by parental tumor cells and tumor growth was compared to a new control group. Transfection with B7.1 prohibits outgrowth of the SCCVII cell line. Animals that have been vaccinated in this way are partially immune towards a secondary exposition to B7.1 negative tumor cells. Outgrowth of this recurrent tumor is slowed down. Such an immunization builds up an immunologic memory. Vaccination with B7.1 expressing tumor cells lead to a partial protective tumor immunity in the SCCVII-C3 H/HeN mouse model.
 ...
PMID:[Induction of antitumor immune response in the mouse model after vaccination with B7.1 expressing tumor cells]. 1008 Jan 27

Early reports suggest that the costimulatory molecule CD86 (B7-2) has sporadic efficacy in tumor immunity, whereas changes in cancer immunity mediated by the MHC class II transactivator (CIITA) have not been extensively investigated. CIITA activates MHC class II expression in most cells; however, in the Line 1 lung carcinoma model system, CIITA activates MHC class I and well as class II. Here we show that CD86 is very effective in inducing a primary immune response against Line 1. Tumor cells expressing CD86 grew in only 50% of the mice injected with live cells, and those mice that developed tumors did so with significantly delayed kinetics. Furthermore, irradiated CD86-expressing Line 1 cells served as an effective tumor vaccine, demonstrating that CD86 is effective in inducing tumor immunity in the Line 1 system. These data suggest that if CIITA and CD86 cooperate, enhanced tumor immunity could be achieved. CIITA alone was mildly beneficial in slowing primary tumor growth but only when expressed at low levels. Clones expressing high levels of class II MHC grew as fast as or faster than parental tumor, and CIITA expression in a tumor vaccine assay lacked efficacy. When CIITA and CD86 were coexpressed, there was no cooperative immune protection from tumor growth. Cells that coexpress both genes also failed as a cancer vaccine, suggesting a negative role for CIITA in this lung carcinoma. These data suggest that human cancer vaccine trials utilizing CIITA gene therapy alone or in combination with CD86 should be approached with caution.
 ...
PMID:Combination gene therapy with CD86 and the MHC class II transactivator in the control of lung tumor growth. 1035 84

Transfection of the costimulatory molecule B7-1 (CD80) into murine tumors can increase antitumor immunity and eradicate tumor growth. The purpose of this study was to test autologous lymphocyte responses against freshly resected human cancers infected in vitro with an adenovirus vector expressing the B7-1 molecule (AdB7). Resected tumors (sarcomas, adenocarcinomas, melanomas, and multiple myelomas) were disaggregated into single-cell suspensions and divided into three groups: (a) native, noninfected tumor cells (TM); (b) AdB7-infected, B7-1(+) tumor cells (TMB7); and (c) control Addl70.3-infected, B7-1(-) tumor cells (TMAd). B7-1 expression was verified by flow cytometry. Autologous peripheral blood lymphocytes from these patients were tested for proliferative and cytotoxic activity against the three tumor groups. There was an increased lymphocyte-proliferative response against B7-1(+) tumor cells, particularly in the presence of interleukin-12 (IL-12) or low-dose IL-2. B7-1(+) tumor cells were also killed more efficiently than B7-1(-) tumor cells in natural killer cell-mediated cytotoxicity assays, and this was most significant when lymphocytes had been pretreated with IL-12. Human natural killer cells were found to express CD28, a receptor for B7-1. The high efficiency of AdB7-mediated gene transfer and the augmented B7-1-mediated lymphocyte responses suggest that AdB7 vectors may be effective in human cancer immunotherapy.
 ...
PMID:Autologous lymphocyte responses to adenovirus-B7-1-transduced human cancer cells. 1035 5

The generation of cytotoxic effector T cells requires delivery of two signals, one derived from a specific antigenic epitope and one from a costimulatory molecule. A phase I clinical trial was conducted with a non-replicating canarypoxvirus (ALVAC) constructed to express both human carcinoembryonic antigen (CEA) and the B7.1 costimulatory molecule. This was the first study in cancer patients to determine if the delivery of costimulation with a tumor vaccine was feasible and improved immune responses. Three cohorts of six patients, each with advanced CEA-expressing adenocarcinomas, were treated with increasing doses of an ALVAC-CEA-B7.1 vaccine (4.5 x 10(6), 4.5 x 10(7), and 4.5 x 10(8) plaque-forming units, PFU). Patients were vaccinated by intramuscular injection every 4 weeks for 3 months and monitored for side-effects, tumor growth and anti-CEA immune responses. ALVAC-CEA-B7.1 at doses up to 4.5 x 10(8) PFU was given without evidence of significant toxicity or autoimmune reactions. Three patients experienced clinically stable disease that correlated with increasing CEA-specific precursor T cells, as shown by in vitro interferon-gamma enzyme-linked immunoassay spot tests (ELISPOT). These three patients underwent repeated vaccination resulting in augmented CEA-specific T cell responses. This study represents the first use of costimulation to enhance antitumor vaccines in cancer patients. This approach resulted in CEA-specific immunity associated with stable diseases in three patients. This study also demonstrated that CEA-specific T cell responses could be sustained by repeated vaccinations. Although the number of patients was small, the addition of B7.1 to virus-based vaccines may improve immunological and stable diseases to vaccination against tumor-associated antigens with tolerable toxicity.
 ...
PMID:Phase I clinical trial of a recombinant canarypoxvirus (ALVAC) vaccine expressing human carcinoembryonic antigen and the B7.1 co-stimulatory molecule. 1109 17

In the present study, TNF-alpha gene-transduced B78 melanoma cells (B78/TNF) were used as a vaccine and combined with interleukin (IL)-12 in the treatment of B78 melanoma-bearing mice. The combined administration of genetically modified melanoma cells and IL-12 induced specific protective antitumor immunity resulting in a decreased rate of the tumor take following a rechallenge with parental B78 cells. When used therapeutically, intratumoral injections of irradiated B78/TNF melanoma cells and IL-12 exerted strong antitumor effects and led to complete regression of established tumors in 50% of mice. Injections of irradiated B78/TNF cells alone did not influence tumor development and IL-12 itself significantly delayed tumor growth but without curative effect. FACS analysis of parental B78 melanoma cells and its B78/TNF genetically modified variant showed that a proportion of cells of both cell lines expressed 87-1 (CD80) costimulatory molecule and that the expression of this molecule was increased during incubation with IFN-gamma. Moreover, IFN-gamma markedly augmented expression of major histocompatibility class (MHC) class I and II molecules on B78/TNF cells that were primarily MHC class I and II negative with no substantial effect on MHC-negative parental B78 melanoma. IFN-gamma also synergized in cytostatic/cytotoxic effects with TNF-alpha against B78 melanoma in vitro. Lymphocyte depletion studies in vivo showed reduction of the antitumor response in mice treated with anti - NK monoclonal antibodies (mAbs) as well as in mice treated with anti-CD4+ anti-CD8 mAbs. The results suggest that, when used therapeutically, IL-12 and a vaccine containing TNF-alpha gene-transduced tumor cells may reciprocally augment their overall antitumor effectiveness by facilitating development of systemic antitumor immunity and by stimulating local effector mechanisms of the tumor destruction.
 ...
PMID:Antitumor effects of the combination therapy with TNF-alpha gene-modified tumor cells and interleukin 12 in a melanoma model in mice. 1122 37

IL-12 gene therapy results in tumor regression in some, but not all, murine models. We hypothesized that expression of B7.1 on the tumor cell surface was necessary for IL-12-mediated tumor regression. In addition, we hypothesized that all cells must express B7.1 for this to be effective. To evaluate this hypothesis, tumor nodules were established in mice with either wild-type B16 melanoma or with B16 melanoma modified to express B7.1. IL-12 cDNA was transferred to the tumor by particle-mediated gene transfer. All tumors modified to express B7.1 regressed completely after IL-12 cDNA treatment. When the percent of B7.1-transfected B16 cells was decreased to 50%, no animals survived after treatment. Animals rendered tumor-free were then challenged with wild-type B16. Fifty percent of mice was protected from this tumor challenge. Expression of CD28 (the stimulatory B7.1 ligand) was significantly increased in both CD8(+) T cells and natural killer cell populations of mice rejecting tumor challenge compared to mice with tumor growth. These results suggest that the costimulatory molecule B7.1 is required for initial tumor sensitivity to IL-12 gene therapy and that protection from subsequent challenge with B7.1 (-) tumor is mediated by CD28(+) immune effector cells.
 ...
PMID:B7.1 expression eliminates tumor resistance to IL-12 gene therapy. 1126 27

We demonstrate that a mouse-human chimeric anti-ganglioside GD2-interleukin (IL)-2 fusion protein (ch14.18-IL2) substantially amplifies tumor-protective immunity against murine melanoma induced by an autologous oral DNA vaccine containing the murine ubiquitin gene fused to murine melanoma peptide epitopes gp100(25-35) and TRP-2(181-188). This combination therapy led to the complete rejection of a lethal challenge with B78D14 murine melanoma cells in six of eight mice and a marked suppression of s.c. tumor growth in the two remaining animals. The tumor-protective immunity was mediated by MHC class I antigen- restricted CD8(+) T cells together with CD4(+) T cell help, which was required only for tumor cell killing in the effector phase of the immune response. A single oral vaccination with the DNA vaccine, which was carried by attenuated Salmonella typhimurium, was equally as effective as three such vaccinations applied at 2-week intervals. The immunological mechanisms involved in this antitumor effect were suggested by a decisively increased secretion of tumor necrosis factor alpha TNFTnTNa and IFN-gamma from CD4(+) and CD8(+) T cells and a markedly up-regulated expression on CD8(+) T cells of high-affinity IL-2 receptor alpha chain (CD25), costimulatory molecule CD28, and adhesion molecule lymphocyte function-associated antigen-2 (LFA-2/CD2). Additionally, the combination therapy induced increased expression of costimulatory molecules B7.1 and CD48 on murine antigen-presenting cells. Taken together, our results suggest that IL-2 targeted to the tumor microenvironment by a specific antibody-IL-2 fusion protein is a potent enhancer of tumor-protective immunity induced by an oral DNA vaccine that may ultimately enhance the chances of success in its clinical application.
 ...
PMID:Targeted interleukin 2 therapy enhances protective immunity induced by an autologous oral DNA vaccine against murine melanoma. 1150 70


1 2 3 4 5 6 7 Next >>