| 26324768 | Hepatocellular Carcinoma | Inhibit immunity (T cell function) | FOXP3/NFAT interaction is required to repress expression of IL-2, upregulate expression of the Treg markers CTLA4 and CD25, and confer suppressor function to Tregs.
|
| 22584123 | Mesothelioma | Inhibit immunity (T cell function; infiltration) | Blockade of CTLA-4 signaling showed effective anticancer effect, correlating with inhibiting cancer cell repopulation between cycles of chemotherapy and upregulating tumor-infiltrating T lymphocytes, cytokines, and cytolytic enzymes in a murine mesothelioma model.
|
| 27622997 | Melanoma | Inhibit immunity (T cell function); immunotherapy target | Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone.
|
| 29339377 | Melanoma; Prostate carcinoma | Inhibit immunity (infiltration); immunotherapy target | In murine models of melanoma and prostate cancer, the combination of chemotherapy and CTLA-4 blockade induced a shift in the cellular composition of the tumor microenvironment, with infiltrating CD8+ and CD4+ T cells increasing the CD8/Foxp3 T-cell ratio.
|
| 29258739 | Triple-Negative Breast Cancer | Inhibit immunity (T cell function) | Combination Immunotherapy of MUC1 mRNA Nano-vaccine and CTLA-4 Blockade Effectively Inhibits Growth of Triple Negative Breast Cancer. In vivo studies demonstrated that the NP-based mRNA vaccine, targeted to mannose receptors on DCs, could successfully express tumor antigen in the DCs of the lymph node; that the NP vaccine could induce a strong, antigen-specific, in vivo cytotoxic T lymphocyte response against TNBC 4T1 cells; and that combination immunotherapy of the vaccine and anti-CTLA-4 monoclonal antibody could significantly enhance anti-tumor immune response compared to the vaccine or monoclonal antibody alone.
|
| 24658665 | Prostate carcinoma | Immunotherapy target | Promising immunotherapeutic agents include poxvirus vaccines and CTLA-4 inhibitor (ipilimumab).
|
| 24598590 | Melanoma | Inhibit immunity (T cell function); immunotherapy target | Combination therapy with localized NDV and systemic CTLA-4 blockade led to rejection of preestablished distant tumors and protection from tumor rechallenge in poorly immunogenic tumor models, irrespective of tumor cell line sensitivity to NDV-mediated lysis. Therapeutic effect was associated with marked distant tumor infiltration with activated CD8(+) and CD4(+) effector but not regulatory T cells, and was dependent on CD8(+) cells, natural killer cells, and type I interferon.
|
| 24523507 | T-Cell Non-Hodgkin Lymphoma | Inhibit immunity (T cell function); immunotherapy target | Coculture of CTCL cells with normal T lymphocytes consisting of both CD4(+) and CD8(+) populations or the CD4(+) subset alone, transfected with CD152 mRNA, inhibits proliferation of normal T cells in a CD152- and CD80-dependent manner. These data identify a new mechanism of immune evasion in CTCL and suggest that the CD80-CD152 axis may become a therapeutic target in this type of lymphoma.
|
| 24485523 | Melanoma | Immunotherapy target | The potential of combination strategies with these agents has recently been highlighted by clinical observations on CTLA-4+PD-1 combined blockade in melanoma patients.
|
| 18303116 | Prostate carcinoma | Inhibit immunity (T cell function); immunotherapy target | SPAS-1 (stimulator of prostatic adenocarcinoma-specific T cells)/SH3GLB2: A prostate tumor antigen identified by CTLA-4 blockade. Our findings demonstrate that our in vivo CTLA-4 blockade-based T cell expression cloning can identify immunogenic cancer antigens with potential relevance for human immunotherapy.
|
| 18287062 | Melanoma | Inhibit immunity (T cell function); immunotherapy target | Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Here we show that periodic infusions of anti-CTLA-4 antibodies after vaccination with irradiated, autologous tumor cells engineered to secrete GM-CSF (GVAX) generate clinically meaningful antitumor immunity without grade 3 or 4 toxicity in a majority of metastatic melanoma patients. Together, these findings help clarify the immunologic and clinical effects of CTLA-4 antibody blockade in previously vaccinated patients and raise the possibility that selective targeting of antitumor Tregs may constitute a complementary strategy for combination therapy.
|
| 28905118 | Lymphoma | Immunotherapy target | Overall intratumoral or peri-tDLN administration of the novel combination of anti-CTLA4, anti-CD137, and anti-OX40, all agents in the clinic or clinical trials, demonstrates potent systemic anti-tumor effects. This immunotherapeutic combination is promising for future clinical development via both these safe and highly efficacious routes of administration.
|
| 27354469 | B-Cell lymphoma | Inhibit immunity | The therapeutic function of anti-CD20 depends on tumor-specific CD8+?T-cell responses initiated by anti-CD20 through macrophages and DCs. CTLA-4 blockade can synergize with anti-CD20 to overcome adaptive immune response-related resistance in advanced B-cell lymphoma.
|
| 23188506 | Leukemia | Inhibit immunity | Blocking CTLA4 and PD-1 in vivo combined to promote survival of transferred T-cells despite powerful deletional signals that mediate Bim (BCL2L11)-dependent apoptosis. However, this dual blockade was not optimal for stimulating effector function by responding T-cells, which required the additional blockade of LAG3 to induce full expansion and allow the acquisition of robust cytolytic activity.
|
| 23152566 | Prostate carcinoma | Inhibit immunity (T cell function) | hese PAP-specific CD8(+)CTLA-4(+) suppressor T cells expressed IL-35, which was decreased after blockade of CTLA-4, and inhibition of either CTLA-4 or IL-35 reversed PAP-specific suppression of tvDTH response. PAP-specific CD8(+)CTLA-4(+) T cells also suppressed T cell proliferation in an IL-35-dependent, contact-independent fashion.
|
| 19318477 | Melanoma | Inhibit immunity | Ipilimumab is a monoclonal antibody that blocks the immune-inhibitory interaction between CTL antigen 4 (CTLA-4) and its ligands on T cells. Clinical trials in cancer patients with ipilimumab have shown promising antitumor activity, particularly in patients with advanced melanoma. Our results show that Melan-A may be a major target for both the autoimmune and antitumor reactions in patients treated with anti-CTLA-4, and describe for the first time the antigen specificity of CD8-positive T cells that mediate tumor rejection in a patient undergoing treatment with an anti-CTLA-4 antibody.
|
| 28484017 | Melanoma | Inhibit immunity (T cell function); essential for immunotherapy | In particular, the use of function blocking monoclonal antibodies targeting checkpoint inhibitors such as CTLA-4 and PD-1 have proven to be highly effective for the systemic activation of the human immune system to treat a wide range of cancers. Ipilimumab is a fully human antibody targeting CTLA-4 that received FDA approval for the treatment of metastatic melanoma in 2011. This structure reveals that ipilimumab contacts the front β-sheet of CTLA-4 and intersects with the CTLA-4:Β7 recognition surface, indicating that direct steric overlap between ipilimumab and the B7 ligands is a major mechanistic contributor to ipilimumab function.
|
| 23580578 | Lung Carcinoma | Inhibit immunity (T cell function); essential for immunotherapy | Immunomodulatory antibodies directed against cytotoxic T cell-associated antigen 4 (CTLA-4/CD152) and programmed cell death ligand 1 (PDL1/CD274) showed clinical efficacy in patients with lung cancer.
|
| 21173239 | Melanoma | Inhibit immunity (T cell function); essential for immunotherapy | Clinical trials of CTLA-4-blocking antibodies to augment T-cell responses to malignant melanoma are at an advanced stage; however, little is known about the effects of CTLA-4 blockade on memory CD8(+) T-cell responses and the formation and maintenance of long-term CD8(+) T-cell memory. This is followed by an accumulation of memory cells that are capable of producing the effector cytokines IFN-γ and TNF-α.
|
| 19581407 | Melanoma | Inhibit immunity (T cell function); essential for immunotherapy | Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. We conclude that the combination of direct enhancement of T(eff) cell function and concomitant inhibition of T reg cell activity through blockade of CTLA-4 on both cell types is essential for mediating the full therapeutic effects of anti-CTLA-4 antibodies during cancer immunotherapy.
|
| 16778987 | Melanoma | Inhibit immunity (T cell function); essential for immunotherapy | CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. We examined the mechanisms of action of anti-CTLA4 and a GM-CSF-transduced tumor cell vaccine (Gvax) and their impact on the balance of effector T cells (Teffs) and Tregs in an in vivo model of B16/BL6 melanoma. Tumor challenge increased the frequency of Tregs in lymph nodes, and untreated tumors became infiltrated by CD4+Foxp3- and CD4+Foxp3+ T cells but few CD8+ T cells. While Gvax primed the tumor-reactive Teff compartment, inducing activation, tumor infiltration, and a delay in tumor growth, the combination with CTLA4 blockade induced greater infiltration and a striking change in the intratumor balance of Tregs and Teffs that directly correlated with tumor rejection.
|
| 23752227 | B16 Malignant Melanoma | Immunotherapy target | Here, we examine the inhibitory role of indoleamine 2,3-dioxygenase (IDO) on the antitumor efficacy of CTLA-4 blockade. To highlight the therapeutic relevance of these findings, we show that CTLA-4 blockade strongly synergizes with IDO inhibitors to mediate rejection of both IDO-expressing and nonexpressing poorly immunogenic tumors, emphasizing the importance of the inhibitory role of both tumor- and host-derived IDO. This effect was T cell dependent, leading to enhanced infiltration of tumor-specific effector T cells and a marked increase in the effector-to-regulatory T cell ratios in the tumors. Overall, these data demonstrate the immunosuppressive role of IDO in the context of immunotherapies targeting immune checkpoints and provide a strong incentive to clinically explore combination therapies using IDO inhibitors irrespective of IDO expression by the tumor cells.
|
| 23728179 | Central Nervous System Lymphoma | Inhibit immunity (T cell function); immunotherapy target | In tumor-bearing mice, we found that Tregs within the tumor preferentially express the cell surface markers CTLA-4 and OX40. We show that intratumoral coinjection of anti-CTLA-4 and anti-OX40 together with CpG depleted tumor-infiltrating Tregs. This in situ immunomodulation, which was performed with low doses of antibodies in a single tumor, generated a systemic antitumor immune response that eradicated disseminated disease in mice. Further, this treatment modality was effective against established CNS lymphoma with leptomeningeal metastases, sites that are usually considered to be tumor cell sanctuaries in the context of conventional systemic therapy.
|
| 23649004 | Neuroblastoma | Inhibit immunity (T and NK cell function); immunotherapy target | In the Neuro2a model, treatment of established tumor with anti-4-1BB, anti-CD40, or anti-CTLA-4 mAb results in tumor regression and long-term survival in 40% to 60% of mice. This is dependent on natural killer (NK) and CD8(+) T cells and is associated with tumor CD8(+) lymphocyte infiltrate. These data suggest that the combination of antigen and costimulatory mAb may provide effective immunotherapy against neuroblastoma and may be of particular use in the minimal residual disease setting.
|
| 24856586 | Pancreatic Ductal Adenocarcinoma | Immunotherapy target | Although myofibroblast-depleted tumors did not respond to gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival.
|
| 19789309 | Melanoma | Inhibit immunity | Autologous DC were pulsed with MART-1(26-35) peptide and administered with a dose escalation of the CTLA4-blocking antibody tremelimumab. Four patients had an objective tumor response, two partial responses and two complete responses, all melanoma free between 2 and 4 years after study initiation. There was no difference in immune monitoring results between patients with an objective tumor response and those without a response.
|
| 19147765 | Breast Carcinoma | Inhibit immunity | The response to radiotherapy plus 9H10 was markedly enhanced in the absence of iNKT cells, with 50% of iNKT-/- versus 0% of wild-type mice showing complete tumor regression, long-term survival, and resistance to a challenge with 4T1 cells. Administration of the iNKT cell activator alpha-galactosylceramide did not enhance the response of wild-type mice to radiotherapy plus 9H10. Tumor-infiltrating iNKT cells were markedly reduced in wild-type mice treated with radiotherapy plus 9H10.
|
| 19147575 | Prostate Carcinoma | Inhibit immunity | Of the six patients treated at the highest dose level, three had confirmed PSA declines of >50%, including one patient that had a partial response in visceral metastases. Expansion of activated, circulating CD25(+) CD69(+) CD8(+) T cells occurred more frequently at higher doses of treatment and was greater in magnitude than was seen in patients who received the same doses of either ipilimumab or GM-CSF alone.
|
| 19074257 | Melanoma | Inhibit immunity | Fifteen patients were selected on the basis of availability of suitable specimens for immunologic monitoring, and eight of these showed evidence of clinical benefit. Five of the eight patients with evidence of clinical benefit had NY-ESO-1 antibody, whereas none of seven clinical non-responders was seropositive for NY-ESO-1. All five NY-ESO-1 seropositive patients had clearly detectable CD4(+) and CD8(+) T cells against NY-ESO-1 following treatment with ipilimumab. Overall, NY-ESO-1-specific T cell responses increased in frequency and functionality during anti-CTLA-4 treatment, revealing a polyfunctional response pattern of IFN-gamma, MIP-1beta and TNF-alpha.
|
| 25038199 | melanoma | Inhibit immunity (T cell function) | Because α-CTLA-4 Fab fragments had the same effect as the intact antibody, the higher T-cell motility does not seem to be due to CTLA-4 inhibitory signaling but rather to the release of nonproductive stable interactions between tumor-infiltrating T cells and tumor targets or antigen-presenting cells subsequent to CTLA-4 blockade.
|
| 24916470 | adenocarcinoma | Inhibit immunity (infiltration) | We observed substantial therapeutic synergies when combining dolastatins with tumor antigen-specific vaccination or blockade of the PD-1-PD-L1 and CTLA-4 coinhibitory pathways.
|
| 24907635 | Pancreatic Carcinoma | Inhibit immunity (infiltration) | Tremelimumab (CP-675,206) is a fully human monoclonal antibody binding to cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) on T cells that stimulates the immune system by blocking the CTLA4-negative regulatory signal.
|
| 24892807 | T-Cell Non-Hodgkin Lymphoma | Inhibit immunity (infiltration) | These data demonstrate that a CTLA4(apt)-based siRNA delivery strategy allows gene silencing in both tumor-associated T cells and tumor cells and inhibits tumor growth and metastasis.
|
| 29663369 | Squamous Cell Carcinoma | Inhibit immunity (infiltration) | Whereas the population of CD4+ CD73hi /CD8+ CD73hi T cells expressed higher CTLA-4 and PD-1 as compared to untreated controls.
|
| 29657128 | lung adenocarcinoma | Inhibit immunity (infiltration) | TMB should be incorporated in future trials examining PD-(L)1 with CTLA-4 blockade in NSCLC.
|
| 29656892 | melanoma | Inhibit immunity (infiltration) | We validate this gene expression signature in an independent anti-CTLA-4-treated cohort and show its specificity to the CTLA-4 pathway with two independent anti-PD-1-treated cohorts.
|
| 29632721 | B16 Malignant Melanoma | Inhibit immunity (infiltration) | Moreover, immunogenicity of this vaccination platform was enhanced not only by combination with additional adjuvants, but also with antibodies blocking PD-1/PD-L1, CTLA-4 and IL-10, immunosuppressive molecules usually present in the tumor environment and also induced by the vaccine.
|
| 29596939 | melanoma | Inhibit immunity (infiltration) | Two inhibitory molecules, cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), got high attention, as inhibition of CTLA-4 or PD-1 signaling provides the first immune therapy that significantly improves the survival of patients with metastatic solid cancers.
|
| 29581255 | Colon Carcinoma | Inhibit immunity (infiltration) | The VHH H11 lacks an Fc portion, binds monovalently to CTLA-4, and inhibits interactions between CTLA-4 and its ligand by occluding the ligand-binding motif on CTLA-4 as shown crystallographically.
|
| 27873300 | Bladder Carcinoma | Immunotherapy target | Here, we investigated the efficacy of a local low-dose anti-CTLA-4 administration for treatment of subcutaneous or orthotopic murine bladder 49 (MB49) bladder carcinoma in C57BL/6 mice. In addition, p.t. anti-CTLA-4 therapy was potentiated by depletion of regulatory T cells. Our results demonstrate that local anti-CTLA-4 antibody therapy is equally effective as systemic administration, but reduces systemic antibody levels and cytokine release, and enhances the response to anti-PD1 therapy.
|
| 27668655 | Melanoma | Immunotherapy target | Here we show that somatic mutations in SERPINB3 and SERPINB4 are associated with survival after anti-CTLA4 immunotherapy in two independent cohorts of patients with melanoma.
|
| 24055012 | Melanoma | Immunotherapy target | Two distinct approaches have emerged to try to extend survival in patients with metastatic melanoma: immunomodulation with anti-CTLA4 monoclonal antibodies, and targeted therapy with BRAF inhibitors or MEK inhibitors for BRAF-mutated melanoma.
|
| 24004819 | Breast Carcinoma | Inhibit immunity (T cell function) | Enhanced immune surveillance in COX-2(MEC)KO tumors was coincident with increased intratumoral CXCL9, a T cell chemoattractant, and decreased expression of T lymphocyte co-inhibitory receptors CTLA4 and PD-1, as well as PD-L1, the ligand for PD-1.
|
| 23960017 | Hepatocellular Carcinoma | Inhibit immunity (T cell function) | Human CD14+ CTLA-4+ regulatory dendritic cells suppress T-cell response by cytotoxic T-lymphocyte antigen-4-dependent IL-10 and indoleamine-2,3-dioxygenase production in hepatocellular carcinoma. CD14(+) DCs significantly suppress T-cell response in vitro through interleukin (IL)-10 and indoleamine-2,3-dioxygenase (IDO). Unexpectedly, CD14(+) DCs expressed high levels of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1, and CTLA-4 was found to be essential to IL-10 and IDO production. So, we identified a novel human tumor-induced regulatory DC subset, which suppresses antitumor immune response through CTLA-4-dependent IL-10 and IDO production, thus indicating the important role of nonregulatory T-cell-derived CTLA-4 in tumor-immune escape or immunosuppression.
|
| 23913973 | Uveal melanoma | Inhibit immunity (T cell function) | The anticytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab is a standard of care for metastatic melanoma; however, the clinical activity of CTLA-4 inhibition in patients with metastatic uveal melanoma is poorly defined.
|
| 23897981 | Melanoma | Inhibit immunity (T cell function) | Although subject to debate, current models favor a mechanism of activity involving blockade of the inhibitory activity of CTLA-4 on both effector (T eff) and regulatory (T reg) T cells, resulting in enhanced antitumor effector T cell activity capable of inducing tumor regression.
|
| 23871358 | Acute Myeloid Leukemia | Inhibit immunity | We envisage future treatment protocols, in which systemic immune activators, such as vaccines, dendritic cell-based therapies, engineered variants of IL-2, or IL-15, are combined with agents that counter immunosuppression mediated by, e.g., the PD/PDL interaction, CTLA-4, CD200, reactive oxygen species, IDO expression, CXCR4, or the KIR/class I interaction, based on characteristics of the prevailing malignant clone.
|
| 23870385 | Melanoma | Inhibit immunity (T cell function) | The first major advance was the development of selective mitogen-activated protein (MAP) kinase inhibitors (BRAF and MEK inhibitors) and immune checkpoint blockade with a CTLA4 antibody (ipilimumab).
|
| 21480325 | Hepatocellular Carcinoma | Inhibit immunity (T cell function) | Blocking cytotoxic T-lymphocyte antigen-4 (CTLA-4) resulted in unmasking of TAA-specific immune responses by changing cytokine and chemokine profiles of peripheral blood mononuclear cells stimulated by TAA-derived peptides. TAA-specific immunotherapy combined with HCC treatments and anti-CTLA-4 antibody has the possibility to produce stronger tumor-specific immune responses.
|
| 21467163 | Melanoma | Inhibit immunity (T cell function) | Regulatory checkpoints, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), serve to attenuate this signal, thereby preventing autoimmunity. Its key role in regulating the immune system has made CTLA-4 an attractive therapeutic target for cancer, with the development of fully human monoclonal antibodies that have successfully targeted CTLA-4 in clinical trials.
|
| 20156971 | Melanoma | Inhibit immunity (T cell function) | Furthermore, blockade of the coinhibitory receptor CTL-associated antigen 4 (CTLA-4) on the transferred CD4(+) T cells resulted in greater expansion of effector T cells, diminished accumulation of tumor-reactive regulatory T cells, and superior antitumor activity capable of inducing regression of spontaneous mouse melanoma. These findings suggest a novel potential therapeutic role for cytotoxic CD4(+) T cells and CTLA-4 blockade in cancer immunotherapy.
|
| 29361059 | Renal Cell Carcinoma | Inhibit immunity | PD-1, PD-L2, CTLA4 and FOXP3, all of which are implicated in the evasion of an anti-tumor immune response, had a significantly higher expression for samples representing co-detection of productive TcR-α and -β recombination reads.
|
| 29360722 | Melanoma | Inhibit immunity (T cell function) | Part of these advances emerged through the identification of the importance of factors that regulate the immune system, including proteins that negatively modulate T cell-mediated responses termed "immune checkpoints." Indeed, blockade of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint served as a proof of principle that the manipulation of these molecules could induce robust anticancer effects, yet limited to a small percentage of patients.
|
| 29326088 | Melanoma | Immunotherapy target | We used a mouse model of transplantable, orthotopic B16 melanoma to test age effects of treatments with anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies.
|
| 18612161 | Melanoma | Inhibit immunity (T cell function) | Blockade of CTLA4 prevents inhibitory signals that downregulate T-cell activation.
|
| 16094420 | Chronic Lymphocytic Leukemia | Inhibit immunity (T cell function) | Patients with chronic lymphocytic leukemia (CLL) have defects in both cellular and humoral immunity. Since CD152 (CTLA-4) plays a critical role in downregulating T-cell responses, we studied the expression of surface and cytoplasmic CD152 (sCD152 and cCD152, respectively) in freshly isolated T cells from treatment-na?ve patients with CLL.
|
| 16034082 | B16 Malignant Melanoma | Inhibit immunity | The combination of peptide vaccination and treatment with an Ab directed against the inhibitory receptor CTLA-4 enhanced the immune response against TRP-2 peptide, inducing autoimmune depigmentation and further decreasing lung tumor nodules. Furthermore, addition of CTLA-4 blockade increased the frequency of TRP-2-specific, IFN-secreting T cells in spleen and lymph nodes.
|
| 29150430 | Melanoma | Inhibit immunity; immunotherapy target | CTLA4 is a cell surface receptor on T cells that functions as an immune checkpoint molecule to enforce tolerance to cognate antigens. Anti-CTLA4 immunotherapy is highly effective at reactivating T-cell responses against melanoma, which is postulated to be due to targeting CTLA4 on T cells.
|
| 28716895 | Lymphoma | Inhibit immunity | CTLA4 activation resulted in lymphoma cell proliferation and tumor growth, whereas silencing or antibody-blockade of CTLA4 in B-cell lymphoma tumor cells in the absence of T cells inhibits tumor growth.
|
| 28716895 | B-Cell Lymphoma | Inhibit immunity | CTLA4-CD86 ligation recruited and activated the JAK family member Tyk2, resulting in STAT3 activation and expression of genes critical for cancer immunosuppression and tumor growth and survival. CTLA4 activation resulted in lymphoma cell proliferation and tumor growth, whereas silencing or antibody-blockade of CTLA4 in B-cell lymphoma tumor cells in the absence of T cells inhibits tumor growth.
|
| 28027300 | Prostate Carcinoma | Inhibit immunity | Further supporting a role of inflammation-induced immune-suppression in the development of early-onset prostate cancer, we observed significant up-regulation of CTLA4 and IDO1/TDO2 pathways in tumors of the young cohort. Moreover, over-expression of CTLA4 and IDO1 was significantly associated with biochemical recurrence.
|
| 24396833 | Melanoma | Inhibit immunity (T cell function) | Multiple NY-ESO-1 antigen-specific CD4(+) T cell responses with Th1 dominance were induced or enhanced after ipilimumab treatment in peripheral blood in all four patients. NY-ESO-1 antigen-specific CD4(+) T cell lines established from all 4 patients after ipilimumab treatment recognized naturally processed NY-ESO-1 protein in antigen-presenting cells, expressed master transcription factor Eomesodermin (Eomes) and secreted perforin and Granzyme B. Finally, we demonstrated that these NY-ESO-1 antigen-specific CD4(+) T cell lines directly lysed autologous melanoma cell lines expressing NY-ESO-1 in an MHC class II restricted manner.
|
| 24089443 | Melanoma | Inhibit immunity; Immunotherapy target | Immune checkpoint blockade with monoclonal antibodies directed at the inhibitory immune receptors CTLA-4, PD-1, and PD-L1 has emerged as a successful treatment approach for patients with advanced melanoma.
|
| 22028176 | Melanoma | Inhibit immunity | Enhancement of anti-tumor immunity through local modulation of CTLA-4 and GITR by dendritic cells. Using in vitro assays with human DCs, we demonstrated that DCs transfected with mRNA encoding a humanized anti-CTLA-4 mAb and mRNA encoding a soluble human GITR-L fusion protein enhance the induction of anti-tumor CTLs in response to DCs transfected with mRNAs encoding either melanoma or breast cancer antigens.
|
| 20460483 | Colon Carcinoma; Fibrosarcoma | Inhibit immunity (infiltration); Immunotherapy target | Anti-CTLA-4/anti-GITR mAb combination treatment exhibited far stronger antitumor effects compared with either antibody alone. This strong antitumor effect was attributed to (a) increased numbers of CD8+ T cells infiltrating tumor sites in anti-CTLA-4 mAb-treated mice and (b) increased cytokine secretion and Treg resistance of tumor-specific CD8+ T cells with strongly upregulated CD25 expression in anti-GITR mAb-treated mice, indicating distinct quantitative/qualitative changes induced by modulating CTLA-4 and GITR signaling.
|
| 19001145 | Melanoma | Inhibit immunity (T cell function); Immunotherapy target | CD28 provides positive modulatory signals in the early stages of an immune response, while CTLA-4 signaling inhibits T-cell activation, particularly during strong T-cell responses. CTLA-4 blockade using anti-CTLA-4 monoclonal antibody therapy has great appeal because suppression of inhibitory signals results in the generation of an antitumor T-cell response. Both clinical and preclinical data indicate that CTLA-4 blockade results in direct activation of CD4+ and CD8+ effector cells, and anti-CTLA-4 monoclonal antibody therapy has shown promise in a number of cancers, particularly melanoma.
|
| 16204013 | Melanoma | Immunotherapy target | Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade with CP-675,206, a fully human anti-CTLA4 monoclonal antibody, may break peripheral immunologic tolerance leading to effective immune responses to cancer in humans.
|
| 16953240 | Melanoma | Inhibit immunity | Finally, we show that in situ tumour ablation can be efficiently combined with immune modulation by anti-CTLA-4 antibodies or regulatory T-cell depletion. These combination treatments protected mice from the outgrowth of tumour challenges, and led to in vivo enhancement of tumour-specific T-cell numbers, which produced more IFN-gamma upon activation.
|
| 16882704 | Melanoma | Inhibit immunity | We found that genetic removal of CTLA-4 induced activation and acquisition of effector functions in pmel-1 CD8 T cells, resulting in the rapid development of severe autoimmune vitiligo. These effects were abrogated by the removal of the CD4 T-cell population. Therefore, we propose that the lack of CTLA-4 on self/tumor antigen–specific CD8 T cells results in autoimmunity and tumor immunity only in the presence of nonspecific, dysregulated CD4 CTLA-4 / T cells.
|
| 16849577 | Melanoma | Inhibit immunity | This notion is supported by a recent clinical trial involving an anti-CTL antigen-4 (CTLA-4) antibody that showed significant clinical responses but severe autoimmune diseases in melanoma patients
|