3/30/09

Dendritic cells vaccine therapy

"The potential to harness the effectiveness and specificity of the immune system underlies the growing interest in cancer immunotherapy. One such approach uses bone marrow-derived dendritic cells (DCs), phenotypically distinct and very potent antigen-presenting cells, to present tumour-associated antigens (TAAgs) and, thereby, generate tumour-specific immunity.

Many observations have led to clinical trials designed to investigate the immunological and clinical effects of Ag-pulsed DCs administered as a therapeutic vaccine to patients with cancer.

Although current DC-based vaccination methods are cumbersome and complex, promising preliminary results from clinical trials in patients with malignant lymphoma, melanoma, and prostate cancer suggest that immuno-therapeutic strategies, that take advantage of the unique properties of DCs, may ultimately prove both efficacious and widely applicable treatment in patients with cancer. "
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Dendritic Cell Therapy is something to learn all you can about.. remember to gather all the information you can from many different sources and use your intuition, Make your own decision based on what you, yourself have gathered and learned.
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The interaction between tumour cells and the host immune system are complex, involving a multitude of cell types and mediators. Immune system has the potential to eliminate neoplastic cells, as evidenced by rare but well documented instances of spontaneous remissions (with no or inadequate treatment) in renal cell carcinoma and melanoma. Also, chronically and severely immunosuppressed individuals (transplantation recipients, congenital immune deficiency states and AIDS patients) exhibit an increased incidence of putative virallyinduced neoplasms; presence of AIDS-associated tumours correlate with the degree of immunosuppression.

Induction of effective tumour immunity can be viewed as a three-step process that includes:
appropriate presentation of tumour-associated antigens (TAAgs),
selection and activation of TAAg-specific T cells as well as non-Ag-specific effectors and
homing of TAAg-specific T cells to the tumour site and effective elimination of malignant cells expressing the TAAgs. Cancers may escape immune surveillance due to changes in and modulation of these various processes.
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The establishment of an effective anti-tumour response is a complex process. Initially, peptides associated with malignant cells must be located and recognised by T cells circulating in the blood stream and permeating tissues. Most solid cancers express small amounts of TAAgs, which may also be cryptic and not readily available for recognition by rare T cell clones, through a low affinity T cell receptor (TCR) complex. Moreover, tumour cells tend to lack co-stimulatory molecules that drive clonal expansion of T cells, the production of key regulatory cytokines, and development into tumour cell specific cytotoxic T lymphocytes (CTLs).
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Eliciting an effective anti-cancer response and removal of malignant cells is a complex biological process.
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Escape from immune surveillance is believed to be a fundamental biological feature of malignant disease in man, which contributes to uncontrolled tumour growth, eventually leading to death of the host. Defects in immune response in patients with a variety of tumours have been well documented. These defects have been ascribed mostly to suppressor cell function. Some authors have shown defective function of macrophages in malignant disease. In recent studies, it has been shown that a distinct subset of IA+ epidermal APCs appear capable of inducing tolerance to tumour Ags and that activated macrophages may induce structural abnormalities of the TCR-CD3 complex.

Future clinical trials with dendritic cells pulsed with tumor epitopes derived from newly identified tumor-associated peptides, RNA, lystates, and apoptotic bodies. Dendritic cells might also be genetically modified with cDNA encoding.

Some studies in humans with solid cancers have investigated DC trafficking in peripheral blood. It was showed that DCs in the peripheral blood of patients with head and neck cancer were significantly immunosuppressed. There was also an increased intratumoural presence of the immunosuppressive CD34+ progenitor cells. Patients with head and neck squamous cell carcinoma also had increased levels of the immunosuppressive peripheral blood CD34+ cells.
Defects in response to tetanus toxoid and influenza virus were observed in patients with advanced breast cancer. Dendritic cells isolated from patients with breast cancer demonstrated a significantly decreased ability to stimulate control allogeneic T cells. Data suggest that reduced DC function could be a major cause for the observed defect in cellular immunity documented in the patients with breast cancer.

Patients whose melanoma were responding (rM) to chemotherapy had DCs which were five times more potent inducers of allogeneic T cell proliferation than those patients whose tumours were progressing (pM). Phenotypic analysis showed a marked depression of CD86 expression on DCs in the latter patients. Culture supernatants from pM showed production of a TH2-type cytokine profile (IL-10), whereas a TH1-type cytokine profile (IL-2, IL-12 and interferon-gamma (IFN-gamma) was found predominantly in patients whose melanomas had responded to treatment.There is evidence that shows that dendritic cell function was inhibited by soluble factors present in melanoma cell cultures.

DCs from patients with hepatocellular carcinoma had significantly lower capacity to stimulate allogeneic T cell proliferation, compared with DCs isolated from patients with liver cirrhosis and normal controls. In patients with hepatocellular carcinoma, DCs expressed significantly lower levels of HLA-DR and induction of IL-12 production. On the other hand, DCs from such donors produced significantly higher levels of nitric oxide and tumour necrosis factor-alpha (TNF-alpha) compared with DCs from donors with liver cirrhosis and normal controls. These results confirm a defect of DC maturation in patients with established hepatocellular carcinoma and probably during carcinogenesis and tumour induction.

Dendritic cell progenitors give rise to myeloid ( monocytes and CD11c+DCs ) and lymphoid (CD11c-plasmacytoid DCs) precursors. Uponinteraction with inflamed endothelium, monocytes differentiate into CD11+blood DCs which give rise to langerhans cells, interstitial DCs, and macrophages. Differentiation of plasmacytoid DCs from CD34+progenitors can be blocked by Id2 and Id3 overexpression, suggesting their lymphoid origin.

DENDRITIC CELLS AND ANTI-CANCER THERAPY
Dendritic cells are potentially good candidates for immune-based therapies for a variety of reasons. In particular, the following aspects are important---

Their ability to migrate through tissues and infiltrate into tumours, where they encounter TAAgs which they capture, digest, and re-express for effective induction of a CMI response;
Their capacity to activate native T cells in regional lymph nodes and theirdifferentiation into CTLs, specifically able to interact with cancer cells and lead to tumour cell damage and death;and

Their role as APCs and capacity to process and present a spectrum of different Ags simultaneously that allows for the induction of a broad repertoire of anti-tumour immune responses to occur.

The ability of DCs to generate anti-tumour immune responses in vivo has been documented in a number of animal tumour models.Most of these experiments have involved in vitro isolation of DCs, followed by loading of the DCs with tumour Ags and injection of the Ag-bearing DCs into syngeneic animals as a cancer vaccine. Dendritic cells loaded with tumour lysates, tumour Ag-derived peptides, synthetic MHC class I-restricted peptides and whole proteins, have all been demonstrated to generate tumour-specific immune responses and anti-tumour activities. Furthermore, Ag-loaded DCs can be used therapeutically to induce regression of preexisting tumours. Dendritic cells loaded with appropriate TAAgs can induce either protection or rejection of malignant cells in various animal models.

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