A REVIEW ON CANCER IMMUNOTHERAPY VIA DENDRITIC CELLS

ALANAZI+MANSOUR+RASHED+M+ALOTAIBI+ABDULLAH+SAUD+M+AHMAD+MEESAQ

[Abstract] Cancer is considered as a devastating disease and a leading cause of deaths around the world. According to WHO，14 million cancer cases are seen in 2012. Cancer is usually asymptomatic at its initial stages，but it shows very pathetic signs and symptoms at advanced stages. There are various ways to diagnose cancer as taking images of body parts，some blood tests and histological study of body cells. The advanced malagnancies are not sensitive to therapies including surgery，chemotherapy and radiotherapy，and also accompanied by adverse effects，and also do not give the promising results. These adverse effects are usually toxic. Recent studies in immune therapy has shown non-toxic and effective results given by dendritic cells（DCs）. DCs are the potent antigen presenting cells and have ability to stimulate strong immune response in the body by activating T cells.DCs can be prepared in vitro，can be combined with cytokines，peptides and different molecules to develop cancer vaccines. These cancer vaccines offer low toxicity and have ability to induce anticancer immune response. Under the banner of immunotherapy，the aim of these vaccines is to increase bodys immune response against cancers. This article reviews the basic biology of dendritic cells，and future direction of DCs based cancer vaccines.

[Key words] Immunotherapy；Dendritic Cells；Cancer Vaccines

【中圖分類號】R185 【文獻標(biāo)識碼】A 【文章編號】2095-6851（2017）07-0-01

1.Introduction：

Cancer is considered to be one of leading cause of deaths worldwide.Cancer is a diseases characterized by out-of-control cell growth. There are over 100 different types of cancers， and each is classified by the type of cell that is initially affected[1]. it harms the body by forming tumors， prohibits the normal body function and also alters the other systems of body. According to the American Cancer Society， Cancer is the second most common cause of death in the US and accounts for nearly 1 of every 4 deaths.

The most common sites of cancer among men are lung，prostate，colon and liver.

The most common sites of cancer among women are breast， colon， lung， ovary and cervix.

1.1 Possible causes of cancers：

It is difficult to know the exact cause that why a cancer develops in person， and medical science is still trying to understand the numerous responsible factors. The researches show that there are various risk factors that increase the chances of cancer development. There are certain risk factors that include the things the person cannot control such as： gene mutation， family history， age.Although there are some risk factors that can be avoided， and the most suspected risk factors： alcohol， tobacco， obesity， radiations， sunlight ， viruses， or bacteria and occupational hazards which include lead， arsenic and asbestos.

1.2 Signs and symptoms：

If a cancer has spread （metastasized）， signs or symptoms may appear in different parts of the body.When it grows it begins to push nearby organs， vessels and nerves. Cancer of pancreas， for example does not show any symptoms until it grows large enough to press near by nerves that cause belly pain.A cancer may also cause symptoms like pain，fever，extreme tiredness （fatigue），skin changes ， lump in body parts or weight loss. This may be because cancer cells use up much of the bodys energy.

1.3 Diagnosis：

Cancers are diagnosed during routine screening examinations and screening test result suggests cancer. It includes：Lab tests； High or low levels of certain substances in your body can be a sign of cancer. So， lab tests of the blood， urine， or other body fluids that measure these substances can help doctors make a diagnosis[2].Imaging procedures： They create pictures inside the body as CT scan， ultrasound， X-rays， positron emission tomography（PET）or magnetic resonance imaging（MRI）.Biopsy： This removal of tissue is usually removed by a needle， endoscopy or surgery.

1.4 Management of cancers：

The cancer treatment is based on the type of cancer and the stage of the cancer.The treatment may have following components： surgery， chemotherapy， radiotherapy and immunotherapy. There are numerous types of cancer effecting different organs， so treatment also differs， but the above are the standard approaches. Patients with cancers that cannot be cured （completely removed）by surgery usually will get combination therapy， the composition determined by the cancer type and stage[3].It is done to extend and improve the quality of life. Currently， there is huge need for advancements and better treatment interventions of cancer.

1.4.1 Surgical treatment：

Surgery is the primary treatment for cancers. It is also used for initial diagnosis of cancer as well. It has two purposes staging and debulking （to remove the tumor as much as possible）. the studies shows this is best for the patients especially with advanced stage cancers. If the tumor is not spread， the surgery can increase the survival rate to great extent.

1.4.2 Chemotherapy：

Chemotherapy refers to the use of medicines to stop or slow the growth of tumors. Cancers are usually very sensitive to chemotherapy and often respond well initially.The drugs are given in the way that enters the bloodstream and reach all parts of body. The drugs can be injected intravenously（IV）， per oral（PO）or intraperitoneal（IP）.

1.4.3 Side effects of chemotherapy：

As chemo drugs kill cancer cells， they can affect the healthy cells of body. The reason is it kills all fast fast growing cells of the body such as hair. Side effects occur during chemotherapy are usually temporary and reversible. Common side effects are fatigue， nausea， vomiting， mouth sores， hair loss and neuropathy.Chemotherapy also damages blood producing cells in bone marrow， that cause low blood cells count. This can further result in increased chances of infections， increased bleeding tendencies and anemia.Some drugs may have permanent side effects. For example， cisplatin is a neurotoxic， ototoxic and nephrotoxic drug.

1.4.4 Radiotherapy for cancers：

After surgery sometimes radiations are suggested as therapy to kill the cancer cells.It can useful in treating the areas with cancer spread.

Radiotherapy can be delivered in two ways： 1）by radiotherapy device which is used outside the body. 2）by a short lived radio-active chemical （radio-active phosphorus）in the peritoneum.

Radiation therapy has several side effects including skin burns， changes， fatigue， hoarseness of voice and risk of secondary cancers （this is seen in patients who have had chest radiation who may be at a higher risk of developing breast cancer later in life）.

2.Cancerimmunotherapy：

It is used to treat the cancer patients that involves components of immune system. After many years the immunotherapy has become clinically validated treatment for many cancers. Immunotherapeutic strategies include ex vivo T and natural killer cells， oncolytic viruses， administration of antibodies and DC vaccines. It is now established that various components of the immune system play pivotal roles in protecting humans from cancer.Strategies to activate effector immune cells include vaccination with tumor antigens or augmentation of antigen presentations to increase the ability of the patients own immune system to mount an immune response against neoplastic cells[4].

Immune therapy can be passive or active. Passive immunotherapy involves the injection of biological products（i.e. antibodies）that directly kills the tumor cells. Active immunotherapy on other hand，directly evokes the immune response to kill the tumor by exposure to antigens. It can be through direct injection（ DNA， IL-2， RNA）or by antigen presenting cells（APC）such as dendritic cells（DC）. DCs are linked to immune system through various molecular sensors， that are capable to capture the microbes and transmit information to lymphocytes.

The immune system has potential to kill neoplastic cells.， however tumor cells themselves are weak antigen presenting cells （APCs）， which requires a strong generation of immunity in body， for this dendritic cells are the potent APCs. Nowadays it has been applied for various clinical trials to treat different malignant tumors.

3.Immunotherapyviadendriticcells：

Immunotherapy represents an alternative and rational approach for the treatment of cancer， including ovarian cancer.The immune system has the potential to kill neoplastic cells. Active immunotherapy as a measure to treat gynecological malignancies has been neglected for a long time and still is in its infancy.This approach relies on anticancer vaccines that are able to elicit an immune response against tumor-associated antigens （TAAs）in the human body. Numerous known TAAs include， tyrosine， survivin， p53， and telomerase. Several technical aspects of this type of immunotherapy should be considered[5].

First， TAA-based immunotherapeutic strategies can be divided into 2 groups： one， those that rely on products derived from whole cancer cells， including whole cancer-cell lysates， dendritic cell （DC）/cancer cell fusions， total cancer cell RNA or mRNA； and two， those that rely on one or more specific TAAs[5]. Second， TAAs can be administered as pure preparations， i.e.， proteins or DNA molecules， or via a carrier. DCs are one of the most common carriers used in this setting， for stimulating TAA-specific immune responses in vivo.A promising approach of the active immunotherapy type involves the injection of antigen-loaded dendritic cells （DC）， potent APC that play a central role in the induction of primary immune responses against cancer and pathogens[6].The human immunity is said to be a strong army with different kinds of weapons and dendritic cells are thought to be “General”of this army[7].

3.1 Basic biology of Dendritic cells （DCs）：

Dendritic cells are the most potent antigen-presenting cells（APCs）. These are bone marrow derived cells that are seeded in all tissues. They act as messengers between the innate and the adaptive immune system. Dendritic cells are found in lymphoid organs and at interfaces between our bodies and environment.

DC were first discovered by Paul Langerhans in the skin in 1868， these skin DC are now known as Langerhans cells. Later， first described by Ralph Steinman nearly thirty years ago. He found a population of striking dendritic-shaped cells in the spleen. Since DCs are so rare， initial studies were difficult and it was not until the 1980s that it became widely accepted that DCs were“professional APCs”.

Dendritic cells are derived from hematopoietic bone marrow progenitor cells. DC migrate via the blood to peripheral tissues ， here they are known as premature dendritic cells. These cells are characterized by high endocytic activity constantly sample the surrounding environment for pathogens such as viruses and bacteria. These antigens also carry such signals that cause futher maturation of DCs， begins as these cells take up infections by phagocytosis.

When compared with other APCs， such as macrophages， DCs are extremely efficient and can elicit very low numbers of T cells to respond[8].

3.2 Dendritic cells source：

DC are found in different populations within the body for example； bone marrow， blood， interstitial， Langerhans， mucosal surface-associated， afferent lymphatic， lymph node， tonsil and splenic DC. DC isolated from the blood are the most commonly used population of DC used in ex vivo studies due to their ease in isolation [9].Three main sources of DC have been used in immunotherapy programs， i.e. blood derived dendritic cells （BDC）， CD34 + stem cell derived DC （CD34 + DC）and monocytic derived dendritic cells（ Mo-DC）.

3.4 Functions of dendritic cells：

The main function of the dendritic cells is to present antigens. They have special ability to sense pathogens. Functions of DCs are divided into 3 categories：①Activation of T cells；②Play a pivotol role in immune tolerance， by eliminating those T cells cells bearing “self-reactive antigens”，before they can harm bodys own tissues，this mechanism is called central tolerance[10].；③Stimulation and differentiation of B cells， and help them to maintain their immune memory by forming antigen-antibody complexes.

3.5 How do they kill tumor cells：

These are the special cells that help immune system to recognize cancer cells. They break down cancer cells in small pieces， and then hold up these antigens to T cells. The T cells then start the immune reaction in the body.DCs have ability to acquire， process and to present T lymphocytes tumor-derived antigens， as well as to regulate the strength and duration of T cells responses.

The T cell receptors recongnize the tumor cells as antigens bound to the molecules of major histocompatibility（MHC）on the surface of DCs. The type I and II peptide binding proteins， interact and stimulate cytotoxic T lymphocytes and T helper cells.

The antigens from a cancer cell when enters the APC， are processed， spliced into peptides and then re-expressed on the cell surface linked to MHC proteins. This results in generation of CTLs which recognized and destroy only cancer cells which express the antigen.Therefore， DC play a key role in host defenses and in anti-cancer immune responses.

4.Clinicalusesofdendriticcellvaccines：

Researchers have been trying to make cancer vaccines for the past many years and first it was thought to be harder. Now in recent years the new cancer DC vaccines have developed that are known as “Adjuvants”. These vaccine are divided into two types， preventive vaccine and therapeutic vaccines. Since the past decade the dendritic cells have been used in clinical trials as cellular mediators of therapeutic vaccination of patients with cancer. This approach is further facilitated through indentification of in vitro culture methods， allowing generation of large numbers of dendritic cells on which cancer cells can be present to T cells[11]. Several vaccine are now focusing on dendritic cells in various ways， or on T cells. The vaccines focusing on dendritic cells are more potent as dendritic cells are master cells of immune system.The benefits of DC-CTL as adjuvants is to induce cytotoxic T cells as well as helper cells. These has been used in animal experiments and human trials. In these trials an increase in T cells response has been observed.

As DCs are collected from the person in whom it will be used， so this is complex and expensive process. The cells are collected from the blood and then cultured in labs， turned into immune cells by loading antigens， make them grow well and then injected back into patients body. These type of vaccines are known as “Autologous Vaccines”.

When dendritic cells are activated against a cancer antigen， it moblize all other agents including T cells， B cells， NK cells and other to attack that pathogen. Dendritic cell-based based immunotherapy is safe even in patients with advance disease.

Dendritic cells （DC）play an essential role in the induction and regulation of immune responses， including the generation of cytotoxic T lymphocytes （CTL）for the eradication of cancers. DC-based cancer vaccines are well tolerated with few side effects and can generate anti-tumor immune responses[12]. This has open new horizons to design more effective DC vaccines.

DCs vaccines can be injected through different ways such as： intravenously， intradermally， subcutaneously or by intranodal or intratumoral injection.

5.Futuredirectionsofdendriticcellsvaccines：

Over the past decade it has been found that DC cells have played critical role in stimulating immune responses that has increased their use in cancer and HIV. Much more work is still needed to determine the role of DCs cancer vaccines and their effects. In recent times DC vaccines have shown much success， as treatment of advance prostate cancer is an example of DC vaccine[13]. By this success， numerous clinical trials are evaluating cancer vaccines to treat prostate cancer at its early stage. Dendritic cell vaccine is also being developed as a first targeted therapy for the treatment of glioblastoma multiforme， the most common and aggressive form of brain cancer with poor survival rates.

An increasing evidence indicates that cellular immunotherapy based on DC vaccination has promise to create long-term protection and prevent metastatic spread of tumor. Fortunately， the DC vaccines have minimal side effects， which makes them very tolerable， but their response rate is very slow. This has raised a question that why DC vaccines are not in treating renal cell carcinoma and melanoma as successful in patients with epithelial ovarian cancer. The future strategy to overcome this problem could be to develop such vaccines that contain entire parts of patients tumor， which may give a good immune response.

Undoubtedly， DCs vaccines offer effective and less toxic approach to immune therapy， so in future they might also be modified with DNA encoding. Majority of trials are being taken in patients with breast， lung and colon cancer， and hopefully it is giving a rewarding approach to the treatment of cancer. Dendritic cell vaccines are likely to take the most attention in near future .In future the goal of immune therapy is to develop new drugs with combinations of small molecules to introduce new DC vaccine to fight against these devastating cancers. These clinical trials designs will involve patients with metastatic disease， and this will hep to employ new “immune response criteria”[14]. These new insights give consideration for the design and development of more effective immunotherapies during next decade. Furthermore， these immunological approaches are the hope that the natural responses against the tumor cells may help to prevent cancer relapse， and increase the survival rates.

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