A prospective trial of adjuvant therapy for high-risk uveal melanoma: assessing 5-year survival outcomes.

Background/aims: Survival after diagnosis of metastasis from uveal melanoma is poor. Identifying individuals at high risk for metastasis and developing adjuvant therapy to prevent clinically apparent metastasis could improve survival. We conducted an adjuvant trial of sequential, low-dose dacarbazine (DTIC) and interferon-alpha-2b (IFN-α-2b) in patients with cytogenetic high-risk uveal melanoma.

Expression of natural killer cell regulatory microRNA by uveal melanoma cancer stem cells.

Natural killer (NK) cells are implicated in the control of metastasis in uveal melanoma, a process that has been ascribed to its cancer stem cell subpopulation. NK cell activation is regulated by specific microRNA (miR). The NK cell sensitivity and regulatory miR production of uveal melanoma cancer stem cells was examined.

Association of tumor and plasma microRNA expression with tumor monosomy-3 in patients with uveal melanoma.

Background: Epigenetic events mediated by methylation and histone modifications have been associated with the development of metastasis in patients with uveal melanoma. The role of epigenetic events mediated by microRNA (miR) is less clear. Tumor and plasma miR expression was examined in patients with primary uveal melanoma with tumor monosomy-3, a predictor of metastasis.

Spontaneous cellular and humoral tumor antigen responses in patients with uveal melanoma.

Antigens that may be involved in the immune response to uveal melanoma have not been identified. Cellular and humoral responses to melanoma differentiation antigens, as well as to BRCA1-associated protein 1 (BAP1) and α-enolase, alterations of which are associated with metastatic disease, were examined in patients with uveal melanoma. Blood was collected from 66 patients with primary and 13 patients with metastatic uveal melanoma.

Circulating immune cell and microRNA in patients with uveal melanoma developing metastatic disease.

Background: The immune response has been implicated in the control of uveal melanoma progression. Epigenetic mechanisms mediated by specific microRNAs (miRs) regulate immune responses.

Methods: Blood was drawn from six patients with uveal melanoma followed from diagnosis, at which time there was no clinical or radiographic evidence of metastasis, until metastasis manifested.

Elevated blood β-2 microglobulin is associated with tumor monosomy-3 in patients with primary uveal melanoma.

Prognostic blood biomarkers for patients with uveal melanoma have not been identified. Tumor monosomy-3 is strongly associated with the development of metastatic disease. Tumor expression of human leukocyte antigen class I molecules and insulin-like growth factor (IGF)-1 receptor has also been associated with the development of metastatic disease.

Differential immunologic and microRNA effects of 2 dosing regimens of recombinant human granulocyte/macrophage colony stimulating factor.

Recombinant human (rh) granulocyte/macrophage colony stimulating factor (GM-CSF) has demonstrated antitumor immunologic activity in prostate and other cancers. Dosing has been empiric, and biomarkers of effect have not been established. Eight patients with biochemical relapse of prostate cancer were randomized into group A, in which they received rhGM-CSF at 250 µg/m days 1-14 of a 28-day cycle, and 8 were randomized into group B, in which they received 250 µg 3 times a week continuously.

Differential effects of low-dose decitabine on immune effector and suppressor responses in melanoma-bearing mice.

Background: Low doses of the demethylating agent decitabine have been shown to enhance the sensitivity of tumors to immune effector cells and molecules through upregulation of tumor antigen presentation and apoptotic pathways. Effects on host immune effector and suppressor responses have not been well characterized.

Methods: Mice bearing B16 melanoma were treated with low-dose decitabine, cytokine, interleukin-2 (IL-2), toll-like receptor 9 agonist ODN1826, and/or a viral vectored vaccine targeting the melanoma antigen Trp2.

Epigenetic regulation by decitabine of melanoma differentiation in vitro and in vivo.

Apoptosis genes, such as TP53 and p16/CDKN2A, that mediate responses to cytotoxic chemotherapy, are frequently nonfunctional in melanoma. Differentiation may be an alternative to apoptosis for inducing melanoma cell cycle exit. Epigenetic mechanisms regulate differentiation, and DNA methylation alterations are associated with the abnormal differentiation of melanoma cells.

Effects of interleukin-1 receptor antagonist on tumor stroma in experimental uveal melanoma.

Purpose: In contrast to many malignancies showing evidence that interleukin-1 (IL-1) promotes progression through effects on tumor vascularity and myeloid suppressor cell populations, in uveal melanoma there is evidence that IL-1 can inhibit progression.

Methods: The effects of the IL-1 receptor antagonist IL-1ra against the aggressive/invasive MUM2B and the nonaggressive/noninvasive OCM1 uveal melanoma models were examined in vitro and in vivo in mouse xenografts. Vascularity and myeloid suppressor cell populations and their regulators were assessed.

Regulation of the activity of an adeno-associated virus vector cancer vaccine administered with synthetic Toll-like receptor agonists.

Recombinant adeno-associated virus (rAAV) is being tested as a vaccine vector, but the cellular immune responses elicited in animal tumor models have not been completely protective. The adjuvant effects of the TLR7 agonist, imiquimod, and the TLR9 agonist, ODN1826, were tested with rAAV expressing the melanoma antigen, Trp2. Mice immunized with rAAV-TRP2 and either TLR agonist alone generated T-helper-1 antitumor immune responses.

Effects of interleukin-1 receptor antagonist and chemotherapy on host-tumor interactions in established melanoma.

Background: Interleukin-1 (IL-1) has been implicated in the vascular and immune suppressor cell responses that promote tumor progression. IL-1, however, has also been shown to inhibit tumor progression by promoting antitumor immune responses and by enhancing the activity of chemotherapy.

Materials And Methods: The effects of IL-1 receptor antagonist (IL-1Ra), alone and combined with temozolomide and docetaxel chemotherapy, were examined in vitro and in vivo against microscopic and macroscopic mouse B16 melanoma.

Differential effects of imatinib mesylate against uveal melanoma in vitro and in vivo.

Uveal melanoma is refractory to chemotherapy. The receptor tyrosine kinase inhibitor, imatinib mesylate, has demonstrated antiproliferative effects against uveal melanoma cells in vitro. The effects of imatinib mesylate, alone and combined with the alklyating agent, temozolomide, were examined in vivo as well as in vitro.

Anti-GD3 monoclonal antibody effects on lymphocytes and antibody-dependent cellular cytotoxicity.

Purpose: Antibodies targeting GD3 gangliosides highly expressed on melanomas mediate immune effector functions in vitro and inhibit animal model melanoma tumor growth in vivo. Because GD3 is expressed also on a subpopulation of human lymphocytes, we characterized the in vitro immune effects of murine R24 and a chimeric anti-GD3 antibody (KW-2871).

Design: Anti-GD3 complement-mediated (CMC) and antibody-dependent cellular cytotoxicity (ADCC) were tested against cell line Mel-624.

Innate anti-breast cancer immunity of apoptosis-resistant human gammadelta-T cells.

We previously identified a CD2-initiated signaling pathway which inhibits activation-induced cell death in mitogen-stimulated human gammadelta-T cells permitting the large-scale expansion of these cells. Here we report the innate anti-tumor activity of expanded human gammadelta-T cells against human breast cancer cells. Apoptosis-resistant human gammadelta-T cells which were expanded in vitro from cultured human peripheral blood mononuclear cells displayed lytic activity against breast cancer cell lines MDA-MB-231, MCF-7 and T-47D, but failed to kill normal human skin fibroblasts and normal human liver cells.

Phase I study of a plasmid DNA vaccine encoding MART-1 in patients with resected melanoma at risk for relapse.

Immunization with plasmid DNA represents an attractive method for increasing cellular immune responses against cancer antigens. The safety and immunologic response of a plasmid encoding the MART-1 melanocyte differentiation antigen was evaluated in 12 patients with resected melanoma at risk for relapse. As a control, patients were also administered a plasmid encoding hepatitis B surface antigen (HBsAg).

High efficiency transduction of dendritic cells by adenoviral vectors targeted to DC-SIGN.

Dendritic cells (DCs) are a central element in the development of antigen-specific immune responses. The lack of a specific and efficient technique for the in vivo delivery of antigens to DCs remains a major obstacle limiting a vaccine's ability to induce an effective immune response. The efficacy of adenoviral (Ad) vectors in this regard can be enhanced through alterations in vector tropism such that DC-targeted transduction is achieved.

Antitumor activity of the intratumoral injection of fowlpox vectors expressing a triad of costimulatory molecules and granulocyte/macrophage colony stimulating factor in mesothelioma.

Deficiency in costimulatory molecule expression has been implicated in the ability of tumors to escape immune effectors. The activity of the intratumoral administration of recombinant fowlpox vectors expressing a triad of costimulatory molecules (rF-TRICOM) was evaluated in the asbestos-induced AB12 and AC29 mouse models of mesothelioma. Mesothelioma cell infected with rF-TRICOM expressed high levels of the costimulatory molecules.

Augmentation of antitumor activity of a recombinant adeno-associated virus carcinoembryonic antigen vaccine with plasmid adjuvant.

Recombinant adeno-associated virus 2 (rAAV) vectors have been successfully used for sustained expression of therapeutic genes. The potential of using rAAV as a cancer vaccine vector and the impact of a bacterial plasmid adjuvant on this activity were investigated. C57BL/6 mice received a single intramuscular injection of rAAV expressing the human tumor-associated antigen, carcinoembryonic antigen (CEA).

Targeting of adenovirus via genetic modification of the viral capsid combined with a protein bridge.

A potential barrier to the development of genetically targeted adenovirus (Ad) vectors for cell-specific delivery of gene therapeutics lies in the fact that several types of targeting protein ligands require posttranslational modifications, such as the formation of disulfide bonds, which are not available to Ad capsid proteins due to their nuclear localization during assembly of the virion. To overcome this problem, we developed a new targeting strategy, which combines genetic modifications of the Ad capsid with a protein bridge approach, resulting in a vector-ligand targeting complex. The components of the complex associate by virtue of genetic modifications to both the Ad capsid and the targeting ligand.

Genetically targeted adenovirus vector directed to CD40-expressing cells.

The success of gene therapy depends on the specificity of transgene delivery by therapeutic vectors. The present study describes the use of an adenovirus (Ad) fiber replacement strategy for genetic targeting of the virus to human CD40, which is expressed by a variety of diseased tissues. The tropism of the virus was modified by the incorporation into its capsid of a protein chimera comprising structural domains of three different proteins: the Ad serotype 5 fiber, phage T4 fibritin, and the human CD40 ligand (CD40L).

Infusion of unpulsed dendritic cells derived from granulocyte/macrophage colony-stimulating factor-mobilized peripheral blood CD34+ cells and monocytes in patients with advanced carcinoma.

Dendritic cells are potent antigen-presenting cells that are reduced in number and function in cancer patients. The infusion of dendritic cells pulsed with tumor-associated antigens has demonstrated antitumor immunologic activity. The effects of dendritic cells derived from granulocyte/macrophage colony-stimulating factor (GM-CSF)-mobilized peripheral blood CD34(+) cell and monocyte precursors when administered without antigen pulsing was examined.