Rabu, 3 Oktober 2012

Terapi sel dendritik


 

http://cancer.stanford.edu/research/immunology/dendritic.html

Dendritic cells (DCs) represent unique antigen-producing cells capable of sensitizing T cells to both new and recall antigens. In fact, these cells are the most potent antigen-producing cells. The goal of DC based cancer immunotherapy is to use the cells to prime specific antitumor immunity through the generation of effector cells that attack and lyse tumors.

DCs as Cancer Vaccines


The first attempt to use DCs as cancer vaccines in humans was made by Edgar Engleman and Ronald Levy (Program 6) here at Stanford, who isolated DCs from patients with non-Hodgkin's lymphoma who had failed conventional chemotherapy, loaded the cells with immunoglobulin idiotype obtained from the patient's tumor, and reinjected the antigen-loaded cells back into the patients. Remarkably, most of the treated patients developed T cell mediated immune responses to their tumor-specific antigen and of the first six patients, two had complete remissions.

Since then, a larger number of patients with non-Hodgkin's lymphoma have been treated at Stanford with idiotype-pulsed DCs and the efficacy confirmed. In addition, pilot clinical trials of antigen-pulsed DCs have been conducted at Stanford in various types of cancer, including prostate cancer, colorectal cancer, multiple myeloma, and non-small cell lung cancer. These studies, and other studies carried out elsewhere, show that antigen-loaded DC vaccinations represent a safe and promising form of immunotherapy for a wide range of malignancies.

DC Loading and Activation

However, the current approaches are far from optimal in that many patients treated with DC vaccines have failed to respond. Moreover, ex vivo manipulation of DCs is time consuming and costly, requires the use of numerous cytokines and exposes the patient to increased risk of infection. To avoid manipulation of DCs in vitro and increase the potency of DC vaccination, Dr. Engleman's group has been working on approaches to load and activate DCs in vivo.

By administering a DC growth factor, Fms like tyrosine kinase 3 Ligand ( Flt3L ), to tumor bearing mice, followed by subcutaneous injection of oligodeoxynucleotides containing unmethylated CG motifs (CpG) together with a defined tumor Ag, they were able to induce significant anti-tumor responses in mice challenged with B16 melanoma.

The induction of a strong and durable immune response was dependent on the accumulation in skin of high numbers of Flt3L -mobilized DCs which facilitated their loading and activation with a local injection of a mixture of tumor antigen and CpG. These results suggested that access of DCs to tumor antigens, as well as the ability of these cells to mature, are critical for the induction of an efficient immune response.

Uptake of Tumor Antigens

More recently the Engleman lab has attempted to increase the uptake of tumor antigens by DCs, in vivo, by directing circulating DCs to tumors rather than delivering exogenous tumor antigens to Flt3L mobilized DCs. CCL20/macrophage inflammatory protein-3 a (MIP-3 chemokine, a potent chemo-attractant for a subset of DCs in both humans and mice, was used alone or in combination with CpG to activate tumoral DCs in mice.

Expression of CCL20 in the tumo r site attracted large numbers of circulating DCs into the tumor mass, and in the case of CT26 (colorectal) tumors led to complete tumor regression. Intratumoral CpG injections, in addition to CCL20, were required to induce therapeutic immunity against B16 melanoma tumors.

In this model CpG overcame tumor mediated inhibition of DC activation and enabled tumoral DCs to cross present tumor antigens to naïve CD8 T cells. CpG activation of tumoral DCs alone was not sufficient to induce tumor regression in either tumor model, nor was systemic delivery of Flt3 ligand, which dramatically increased the number of circulating DCs but not the number of tumoral DCs.

These results indicate that the number of tumoral DCs as well as the tumor milieu determines the ability of tumor bearing hosts to mount an effective anti-tumor immune response. The results also suggest that DCs can be manipulated in vivo without delivery of defined tumor antigens to induce a specific T cell mediated anti-tumor response and provide the basis for the use of chemokines in DC-targeted clinical strategies.

Intratumoral Injections of Naïve DCs

An additional approach under investigation by the Engleman lab involves intratumoral injections of naïve DCs into tumors that have been treated with either radiofrequency ablation or photodynamic therapy. The latter therapies are effective locally but not systemically, and importantly, in tumor bearing mice the combination of either treatment with intratumoral DCs can be curative.

These observations formed the basis of two recently approved INDs for clinical trials that are being undertaken by Drs. Engleman, George Fisher (Program 9), and Wenru Song (Program 6) for the treatment of pancreatic cancer and metastatic colorectal cancer, respectively.

 

Ruj daripada : http://dendritic.info/


Dendritic Cell (DC) therapy represents a new and promising immunotherapeutic approach for treatment of advanced cancer as well as for prevention of cancer. As Dr. Harmon Eyre, the VP of Research at the AMA commented: “Patients’ responses are far out of proportion to anything that any current therapy could do”. For decades, cancer researchers have been interested in immunologic treatments against cancer but with little progress. However, recent advances lead to successful implementation of Dendritic Cell therapy with reports of complete responses even in stage IV cancer patients who have failed all other therapies. Dendritic Cell (DC) Therapy or so-called Dendritic Cell vaccine is a newly emerging and potent form of immune therapy used to treat cancer. To learn more about vaccine and Dendritic Cell therapy for cancer, please read the following:

The National Cancer Institute has a very concise primer on Treating and Preventing Cancer with Vaccines on their site.

Dendritic cells and immunity against cancerby K. Palucka, H. Ueno1, J. Fay, and J. Banchereau of Baylor Institute for Immunology Research and Sammons Cancer Center, Baylor University Medical Center,Dallas, TX; and Department of Gene and Cell Medicine and Department of Medicine, Immunology Institute, Mount SinaiSchool ofMedicine, New York,NY,USA as published in Journal of Internal Medicine.

Volume 269, Issue 1, 2010.

Dendritic Cells (I): Biological functions” and “Dendritic Cells (II) Role and therapeutic implications in cancer by S. Satthaporn and O. Eremin of the U. of Nottingham and Lincoln County Hospital, UK as published in J. of the Royal College Surgeons, Edinb.
46:9-20 and 159-167, 2001.

Clinical Applications of Dendritic Cell Cancer Vaccinesby Dr. Joseph Barr of the U. of Pittsburgh Cancer Institute, Pittsburgh, PA USA in The Oncologist 4(2): 140-144, 1999.

Also, a slide show / lecture presentation by Dr. Michael Morse on Current Status of Dendritic-Cell Vaccines” is available on the Medscape site from WebMD as part of an educational session on “Therapeutic Cancer Vaccines: Targeting the Future of Cancer Treatment” but requires registration to enter the site.

There is also a youtube video presentation on “Using Dendritic Cells to Create Cancer Vaccinesby Professor Edgar Engleman of Standford University.

Abstracts of recent reviews on Pubmed include articles by IG Schmidt-Wolf et al. on “Dendritic Cell, the immunotherapeutic cell for cancer”, TL Whiteside and C Odous from U. of Pittsburgh Cancer Institute on Dendritic cell biology and cancer therapy”, EM Hersh et al. onClinical Applications of dendritic cell vaccination in the treatment of cancer

Also, please refer to our Research Archives for many related abstracts on the therapy.

Also see the FAQ  http://dendritic.info/faq/

FAQ
















What are dendritic cells, and why are they useful?


Dendritic cells are in every person’s bloodstream and is a blood cell. They normally function as an immune cell but are present in very small numbers, somewhat like an elite force. Their usual function is to identify a foreign substance, including cancer cells, and process the bits of such foreign substances and then jumpstart the the immune response by bringing the foreign substance to the attention of the rest of the immune system (mostly T lymphocyte cells). The activated immune system is then able to circulate throughout the body and destroy the cancer cells.

What kind of cancers can be treated with Dendritic Cell therapy?


Theroretically all cancers can be treated, but experience tells us that certain cancers such as melanoma and kidney cancer should respond best. To date, therapeutic benefit has been documented in B cell lymphoma, myeloma, melanoma, prostate cancer, colon cancer, ovarian cancer, breast cancer, and renal cell cancer amongst others. If interested, patients should seek professional advice on specific cancer and DC therapy and carefully weigh their treatment options. There are currently active trials using DC therapy in melanoma and kidney cancer.

At what cancer stage should a patient consider Dendritic Cell therapy?


A patient can consider Dendritic Cell therapy when all other options have been exhausted, or if the disease is stable and the patient is not on any chemo or radiation therapies concurrently, or if the patient is free of disease but at risk for recurrence and is seeking to potentially reduce the likelihood of cancer reoccurrence. In general, patient should generally seek professional advice on specific cancers and carefully weigh treatment options before proceeding with specific therapy.

Can leukemias/lymphomas be treated with Dendritic Cell therapy?


Research is now progressing in these areas, but patients should seek professional advice on specific cancers and carefully consider their treatment. (See review)

Can childhood tumors be treated with Dendritic Cell therapy?


Yes, and experience is accumulating in this area. Patient’s guardians should seek professional advice on specific cancers regarding DC therapy and carefully weigh their treatment options (See review)

Can brain cancers be treated with Dendritic Cell therapy?


Yes, and there are trials in this area at the present. Patients should seek professional advice and weigh their treatment options. (See review)

Does one need to have one’s own fresh or frozen tumor tissue available to do Dendritic Cell Therapy?


Not always. Some trials require it and it is advisable to have tissue or related antigen available if one is to do Dendritic Cell Therapy for preventative purposes as there may not be sufficient tumor antigen in the circulation for the Dendritic Cells to pick up. However, if patients with advanced or metastatic disease, it is often possible to do “unloaded” Dendritic Cell therapy, where naked Dendritic cells are injected intratumorally or into the bloodstream where it would pick up antigens in vivo. One example of this approach in treating pancreas and gallbladder cancer was presented in ASCO ’04.

How effective is Dendritic Cell therapy in cancer?


Responses have generally been reported to be in the 20% range for heavily pre-treated otherwise untreatable late stage patient, depending on the type of cancer and the functional status of the patient. A larger percentage may not experience remission as such but remain stable with treatment. If seriously interested in the treatment, one should look into available trials, consider a consultation with a reputable and knowledgeable physician or at a treatment center to discuss prognosis and possible outcome as well as details relating to the therapy.

Are any drugs or procedures used as part of the Dendritic Cell Therapy?


Immune adjuvants are used to enhance or modulate the immune system during Dendritic Cell therapy. Such agents may include cytokines such as IL-2, GM-CSF, interferon; drugs such as ribavirin, thalidomide, low dose cyclophosphamide; as well as keyhold limpet hemocyanin (KLH), Bacillus Calmette Guerein (BCG), QS21, Montanide ISA-51. Procedures such as hyperthermia and ozone therapy are sometimes used as adjuvants as well.

Is Dendritic Cell Therapy safe?


Multiple early phases of Dendritic Cell therapy for cancer has been completed and establishes the treatment as generally safe.

Are there any contraindications to Dendritic Cell Therapy?


Recent radiation and chemotherapy which tends to depress the immune system are relative contraindications to Dendritic Cell therapy. Immunologic testing can better establish the condition of the immune system to help physicians determine if a patient is a good candidate for Dendritic Cell therapy. Recent blood transfusions, active autoimmune disease as well as pregnancy are also possible contraindications. Contraindications should be carefully discussed and reviewed with the consulting physician before proceeding.

Are there any clinical trials I can take part in?


There are a number of domestic trials in the US as well as start-up elsewhere in the world that you may qualify for, particularly for melanoma, renal cell cancer, and other solid tumors and leukemias as well. You should refer to our clinical trials section for more information to see if you are eligible.

What if a patient is not qualified for any active trials?


One can consider private treatment in Europe or elsewhere out of a trial setting is one is not eligible for clinical trials. If seriously interested or you need help in sorting out the pros and cons of various trials vs. private treatments as well as the details of the actual Dendritic Cell therapy protocols involved, one should consider a consultation with a reputable and knowledgeable physician to discuss choice of trials, prognosis and possible outcome as well as logistical details relating to Dendritic Cell therapy.

Is Dendritic Cell Therapy an expensive treatment?


If one enrolled in a clinical trial, the treatment itself should be free. If one opts to be treated privately, the treatment cost is comparable with other forms of cancer therapies (eg chemotherapy or newer targeted molecular therapies) and is generally under US 5,000 per treatment course depending on the center.

 

 

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