1. INTRODUCTION:
Cancer is group of disease involving abnormal cell proliferation and is able to spread or invade to other parts of the body. Group of cells that have undergone uncontrolled cell growth often form a mass or lump, called as tumours or neoplasm. Environmental factors are the reason for great majority of cancer. Other causes include inherited genetics. Environmental factors include tobacco, obesity, infection, radiation, stress, lack of physical activity and environmental pollutants. Not all tumours are cancerous; benign tumours do not spread to other parts of the body. Different type tumour includes carcinoma, sarcoma, lymphoma, leukaemia, blastoma, germ cell tumour. Cancer treatments include chemotherapy, targeted therapy, radiation therapy, surgery, and immunotherapy. Here we discuss about immunotherapy through dendritic cell vaccination.
Immune system has the ability to destroy or eliminate tumour cells. Studies conducted in both laboratory animal and humans shown that immune system has the potential to identify and destroy neoplastic cells. Power and specificity of immune system is used to treat tumours. Numbers of protein antigens expressed by cancer cells are recognized by T cells, as a result it leads to the development of antigen specific immunotherapy. Specialised family of antigen presenting cells present on mammalian immune system known as Dendritic cells (DCs) (or accessory cells),which are exclusively strong and have the potential to present captured antigens to lymphocytes. This property has encouraged their current application to therapeutic cancer vaccine. They have been successfully used in clinical pilots study to induce tumour specific immunity as well as clinical response in selected patients. Dendritic cells are isolated and loaded with tumour antigen ex vivo, and are administered as a cellular vaccine to experimental animals, lead to induction of protective and therapeutic anti-tumour immunity. In pilot clinical trials of DC vaccination for patients with non-Hodgkins lymphoma and melanoma, inductions of anti-tumour immune-responses and tumour regressions have been observed. Additional trials of DC vaccination for a variety of human cancers are going on, and methods for targeting tumour antigens to DCs in vivo are also being explored. The antigen-presenting properties of DCs thus assure the development of effective cancer immunotherapies.
2. BIOLOGICAL ASPECTS OF DENDRITIC CELLS
Dendritic cells are antigen presenting cells (APCs) in mammalian immune system. They are also called as accessory cells. Dendritic cells are present in tissues that are in contact with the external environment which include skin, inner lining of nose, stomach, lungs and intestine. Also found in immature state in blood. They act as messenger between natural and acquired immune system. Major function of dendritic cell is to capture antigenic material and present it to the adaptive (acquired) immune system (T cell and B cell). Dendritic cells will migrate to the lymph nodes after their activation, where they initiate and produce the adaptive immune responses by interacting with T cell and B cell. They grow into branched projection at certain developmenatal stage, hence the name dendrites. However, they are different from that of dendrites of neuron.
Fig. 1: Dentritic cell in skin (National Cancer Institute (NCI), USA) [1] (Reproduced with permission)
2.1. STRUCTURE OR DENDRITIC CELL
Skin is anatomically divided in to two layers; epidermis and dermis. Langharhan cells are the major antigen presenting cells found in epidermis. But recent studies shown that dermis also contain dense network of APCs that consisting of dendritic cells and macrophages. Dendritic cell, monocyte and macrophages are the component of mononuclear phagocyte system. DCs are extremely efficient when compared to that of other APCs such as macrophages and can obtain very low number of T cell to respond, hence they are known as professional APCs. Dendritic cell also known as natural adjuvant because of the way in which they help to initiate immune response [2].
Fig. 2: Dendritic cell (Source: Sriram Subramaniam, National Cancer Institute (NCI), USA) [1] (Reproduced with permission)
2.2. TYPES OF DENDRITIC CELL
Dendritic cell include plasmacytoid DCs (pDCs) conventional DCs (cDCs) and monocyte derived DCs. Lymphoid and conventional DCs are formed from lymphoid and myeloid precursors. Plasmacytoid DCs are absent from the skin during steady state condition, they have only been identified in inflamed skin where they promote repair, and mediate systematic pro-inflammatory-response.
Conventional DCs found in healthy non lymphoid tissue, a small proportion of these cDCs undergo maturation process called as homeostatic maturation that involves morphological and phenotypical changes that leads to their migration to draining lymph nodes.
Following homeostatic maturation, non-lymphoid tissue cDCs unregulated their expression of MHC class 2 molecule and they can transport cutaneous self antigen to the T cell zones of the draining lymph nodes. cDCs and monocyte derived DCs that are found in healthy dermis have short life span and are replaced by bone marrow derived, blood borne precursors that extravasate continuously and they are known as pre-cDCs [2].
2.3. LIFE CYCLE OF DENDRITIC CELLS
Dendritic cells are derived from hematopoietic bone marrow progenitor cells. These progenitor cells are initially convert into immature dendritic cells, Immature DCs are having high endotoxic activity and low T-cell activation potential. Immature dendritic cells will convert into mature form after they have come in contact with presentable antigen and they begin to migrate into lymph node. Immature DCs degrade proteins present on the pathogen into small fragments by the process known as phagocytosis, after maturation present those fragments of protein using MHC molecule.
In peripheral tissue, DCs capture antigen through several complementary mechanism. Antigen loaded DCs migrate to the lymph node through afferent lymphatics, Which in turn induce protective immune responses by presenting captured antigen in the form of peptide by processing the proteins that bind to MHC 1 and MHC 2 molecule. DCs process lipid antigens differently and are loaded them on to non classical MHC molecule of the CD1 family. Different T cell responses are produced depending on whether the antigen is captured by DCs in peripheral tissue or directly in lymph nodes. CD4+T Cells and CD8+ T cell interaction with DCs lead to their differentiation into antigen specific effector T cell with different function [2].
DCs can also interact with cells of innate immune system, including natural killer cell (NK cell), phagocyte and mast cell. DCs also have significant role in controlling humoral immunity. DCs directly interact with B cell and indirectly induse the development and differentiation of helper T cell. Life span of antigen- bearing dendritic cells depends upon signals from pathogen and T cells. DC survival is regulated by these signals by modulating expression of Bcl- 2 family proteins [2].
3. CANCER THERAPY HISTORY AND DEVELOPMENTS
Even if the idea of exploiting the immune system for cancer therapy has been around for more than two centuries, immune therapies are only recently become a main stream for cancer therapy [3]. In 1777 a surgeon, James Nooth injected himself with malignant tissue in order to prevent cancer development. It was the first attempt to immunize against cancer [3, 4]. Cancer immunotherapy formally started in 1891[4]. William coley was known as father of immune therapy. He was described that after injection of bacterial preparation regression of cancer was seen and he postulated that this was due to anti tumour activity [5]. Foundation for the Cancer immune surveillance theory was the hypothesis made by Paul Ehrlich in 1909 [6] that the immune system could protect the host against developing cancers. Views of Thomas and Burnet’s on the critical role of the immune system in preventing the development of cancer were supported by a series of mouse tumour transplantation experiments conducted during the mid-1940s to early-1960s , which led to the hypothesis that tumour cells express specific “antigens” that permit their recognition and elimination by the immune system [7- 11]. The interactions between the immune system and cancer cells were defined in the following decades, resulting in the central tenet of cancer immunotherapy: the finding that CD8+effector T cells (also called cytotoxic T lymphocytes[CTLs]) are capable of selectively killing tumour cells after recognition of specific antigens expressed on the tumour cell surface in association with major histo compatibility complex (MHC) molecule[12, 13].
More recently, other immune components such as natural killer cells have been shown to contribute to the host defence against cancer [14]. Most currently available immunetherapeutics exploit T-cell immune responses against cancer [13].
4. DENDRITIC CELL VACCINE FOR CANCER THERAPY
Cancer immunotherapy exploits the specificity of immune system and thus it is significant in treating tumours. In the antigen specific therapy, vaccination with attachment of the antigen together with an adjuvant is used to produce the therapeutic T cells. Dendritic cells (DCs) are often called ‘nature’s adjuvant because of its unique properties and thus have become the natural agents for antigen delivery. DCs are having the ability to control both immune tolerance and immunity hence they are now at the centre of the immune system. Thus, DCs are an essential target to generate immunity against cancer [2].
The basic concept behind DC therapy is to exploit the intrinsic antigen-presenting properties of DCs to elicit a potent tumour antigen specific T cell driven immune response [15, 16]. Ex-vivo generated DCs used as carrier of cancer vaccine. Dendritic cell therapy aspires to “train” the host’s immune system to recognize and enables the generation of immunologic memory [17, 18].
Dendritic cells are highly specialized antigen presenting cells (APCs) and they are instrumental in the development of adaptive anti-tumour immunity [2, 19]. DCs provide T cell with antigenic ‘signal 1’ and co-stimulatory ‘signal 2’. An additional polarizing ‘signal 3’is also provided by DCs, hence it lead to the development of immune responses towards type-1 or type-2 immunity. Type 1 or type 2 immunity associated with particular effect or mechanisms and having the ability to induce cancer rejection. DCs are also having the potential to produce an additional signal (signal 4) regulating organ specific trafficking of immune cells [20].
Important features of DCs such as their maturation status, migratory potential and cytokine production were shown to be important for inducing high number of Th-1 type CD4+ T cells and CD8+ CLTs by DC based cancer vaccine. Secretion of high IL-12p70 has been shown to enhance the ability of DCs to induce tumour specific Th-1 cells and CLTs, and to promote tumour rejection in therapeutic mouse models.
Numerous clinical studies have been conducted across a wide range of cancer types, including phase 3 clinical trials in melanoma, prostate cancer, glioblastoma, and renal cell carcinoma. These studies provided ample evidence that DC therapy is safe and capable mounting protective anti-tumour immunity without major toxicity [15].
4.1. CHOICE OF TARGET ANTIGEN
The primary immunological goal of DC-based cancer therapy is to immunize or vaccinate patients by inducing tumour antigen specific T cell immune response through intrinsic antigen presenting ability of DCs [21].The selection of tumour antigens for loading the DCs is an important parameter.
To facilitate and rationalize this process, the Translational Research Working Group of the National Cancer Institute has proposed a number of criteria for assessing the suitability of a given tumour antigen for immunotherapeutic targeting [22]. Based on this report, preference should be given to antigens that are:
i) Over expressed in the tumour cell compartment but not(or only minimally) expressed in normal cells and tissues;
ii) Consistently over expressed among patients with a given tumour type and, within each patient, expressed in most to all tumour cells;
iii) Play a role in the malignant phenotype;
iv) Contain both CD8+and CD4+ T-cell epitopes
v) Immunologically relevant and
vi) Hold clinical relevance [22, 15].
Mutated antigens and shared non-mutated self-antigens are example of tumour antigen that is used to generate broadly applicable vaccines; non-mutated self-antigens have frequently selected. The development of RNA sequencing technologies can be use to determine the complete range of mutated antigens from the primary tumour and metastases of a patient, thereby help to modify therapeutic vaccines against patient’s tumour [2].
Antigen can be directly delivered to DCs in vivo using chimeric proteins that are consisting of an antibody that is specific for a DC receptor fused to a selected antigen. The induced immunity was found to be protective in various diseases, including cancer, infectious diseases such as malaria and HIV [23].
Distinct subsets of DCs elicit distinct immune responses by use of vaccines that target surface molecules that are expressed on different subsets of DCs. This confirmed earlier studies that were carried out in vitro or in vivo with purified DC subsets. In this regard, CD8+ DCs that express the cell-surface protein CD205 (also known as Ly‑75) present delivered antigens in the context of both MHC class I and MHC class II molecules. Furthermore, targeting antigen to these distinct receptors on DCs leads to the generation of T cell-mediated responses through independent pathways. Thus, DCs expressing CD205 generate a TH1 cell-mediated immune response in an IL‑12‑independent, CD70‑dependent mechanism [2].
5. APPROACHES FOR THE GENERATION OF DENDRITIC CELLS
Dendritic cells are generated by two approaches:
(a) Purification of immature DC precursor from peripheral blood and
(b) The in vitro differentiation of DCs from peripheral blood monocyte or CD34+ hemtopoietic progenitor cells.
The former was the first method utilized in clinical
studies of DC vaccination and it represents the most direct method of DC
isolation. Circulating immature DC precursors can be isolated from T-cell and
monocyte-depleted peripheral blood, representing less than 0.5% of peripheral
blood mononuclear cells (PBMC) after 1-2 days of in vitro culture (in the
absence of cytokines). During this time DC precursors undergo maturation and
acquire a low buoyant density.It was then purified by density-gradient
centrifugation. DCs isolated in this manner possess potent allostimulatory
activity and the ability to prime naive CD4+ T helper cells and CD8+ CTLs to
exogenous antigen in Vitro. From PBMC products by single leukopheresis
procedure yield of 5
106 DCs are typically obtained.
In vitro culture of monocytes or CD34+ progenitor cells in the presence of cytokine combinations that include GM-CSF can also be used for the generation of large number of DCs.
5.1. SOURCE OF DENDRITIC CELL PRECURSOR
Human CD34+ hematopoietic progenitor cells purified from bone marrow, umbilical cord blood, or peripheral blood and mobilized with cytokines such as granulocyte colony-stimulating factor (G-CSF) or GM-CSF can serve as a source of precursors for the in vitro expansion of DCs. In the presence of GM-CSF and TNFα, CD34+ cells expand 10-30 folds to yield characteristic DCs that share many of the immune phenotypic and functional properties of monocyte-derived DCs(mo DCs), these are the DCs by far the most commonly used DC type in DC vaccination [15, 24]. This type of DC vaccine is usually produced by isolating CD14+ monocytes from leukapheresis products; they are then cultured 5-6 days into immature DCs with GM-CSF and IL-4 [25]. Immature DCs are considered as poor stimulators of immunity. Next step in DC vaccine manufacture is to trigger their maturation is by exposing them for another 2 days to pro inflammatory cytokine cocktail composed of TNFα, IL-1β, IL-6, and prostaglandin E2 (PGE2), they are commonly referred to as “Jonuleit” cytokine cocktail [26]. Hence immature DCs are converted into mature DCs.
5.2. CULTURE MEDIA
The type of culture media used influences functional capacity of DCs. Culture media used and the reagents used for DC manufacturing must comply to good manufacturing practice requirements. Choice of cell culture medium determines the potency of final DC vaccine. Serum which is often added to culture medium has negative influence on fuctionality of DC vaccine in vitro [27].
5.3. CULTURE TIME
The gold-standard protocol for moDC generation encompasses 1 week of culture, Including 5 days for differentiation of monocytes into immature DCs and 2 days for converting these immature DCs into mature DCs [28, 15].
5.4. DIFFERENTIATION PROTOCOL
The most commonly used cytokines for inducing moDC differentiation are GM-CSF and IL-4 [21, 15]. The choice of DC differentiation regimen is an important determinant of the immunogenic quality This is supported by the observation that the ability of moDCs to stimulate antitumor immunity can be dramatically improved by replacing IL-4 with IL-15 or IFN-α . Such alternatively differentiated DCs can also exert direct cytotoxicity toward AML cells [15].
DCs derived from CD34+ cells, obtained from breast cancer patients can stimulate autologus peripheral blood CD4+T cells to proliferate in response to an MHC class2 restricted peptide. DCs transduced with tumour antigen encoding DNA or RNA can stimulate in vitro expansion and maturation of CTLs from autologus peripheral blood lymphocytes and the resulting CTLs are capable of lysing tumour cells [24].
6. PRECLINICAL STUDIES OF DC VACCINATION
The stimulation of anti-tumour immune responses by injection of antigen-loaded DCs has now been studied extensively in animals. Initially, it was found that naive animals are protected from lethal tumour challenge when they were injected with DC-enriched preparations of splenocytes or epidermal cells pulsed with tumour lysates. Next, it was shown that administration splenic DCs, purified by density gradient pulsed with either soluble protein tumour antigen expressed by B cell lymphoma could induce protective anti-tumour immunity. Thus, it was clear that the ex vivo delivery of purified tumour antigen to a defined population of APCs could result in an effective tumour vaccine.
The approach can be fully exploited by the development of techniques for generating large numbers of DCs in vitro from murine bone marrow cultures supplemented with GM-CSF or GM-CSF plus IL-4 (added to suppress the outgrowth of monocytes). Such bone marrow-derived DCs, when pulsed with model tumour antigen derived MHC class I-restricted peptides, can induce potent anti-tumour CTL responses, as well as protective tumour immunity in vaccinated mice. These responses are noticeable after injection of as few as 105 cells and are dependent on CD8+ T cells. Furthermore, administration of peptide-pulsed DCs was able to cure animals bearing recognized tumours up to 1 cm3 in size. It demonstrates the remarkable potency of the vaccination approach. Importantly, protein-pulsed DCs elicit comparable CTL activity and tumour protection.
These results demonstrate the in vivo activity of antigen-pulsed DC vaccines against tumours. In these experiments, genes encoding foreign proteins are introduced into tumours to serve as model tumour antigens, the model systems employed are highly artificial. Such tumours tend to be highly immunogenic. In addition, for most human tumours the sequences of potential tumour-antigen peptides are unknown. Vaccination using DCs pulsed with un fractionated peptides acid-eluted from the class I MHC molecules on the surface of tumour cells markedly suppressed the growth of tumours, even when initiated seven days after tumour inoculation. These studies are providing the proof of principle for antigen pulsed DC vaccine against tumours [24].
7. CLINICAL TRIALS OF DENDRITIC CELL VACCINATION
7.1. NON-HODGKIN’S LYMPHOMA
Hsu and colleague [29] reported that DCs pulsed with a tumour antigen could elicit specific tumour-reactive T cells and have clinical efficacy. The clonal immunoglobulin (idiotype) expressed by non-Hodgkins lymphomas was the target antigen of this study. This protein, which preserves antigenic determinants unique to each B-cell tumour, has been validated as an immunotherapeutic target in both animals and humans. Tumour regression was found in patients suffering from refractory lymphoma when they were passively immunised with specially made anti-idiotypic monoclonal antibodies. Vaccination using tumour-derived idiotype protein coupled to the foreign carrier protein keyhole limpet hemocyanin (KLH), along with a chemical immunologic adjuvant (SAF-1), can induce humoral and cellular anti-idiotypic immune responses as well as tumour regressions in some cases. Then it was found that idiotype-pulsed DCs could cure established disease in a murine lymphoma model. The ability to purify DCs from peripheral blood, led to the 1993 initiation of a pilot clinical trial to study the practicability and safety of idiotype-pulsed DC vaccination in patients with non-Hodgkin’s lymphoma.
In this trial, four patients with low-grade lymphoma and measurable disease resistant to chemotherapy first undergo leukopheresis to collect PBMCs. Collected PBMCs were purified using density-gradient separation techniques, peripheral blood DC precursors were divided and cultured overnight in the presence of either KLH or tumour-derived idiotype protein, after which they were washed free of protein and infused intravenously. Each patient received three monthly DC infusions (median of 5×106 DC per infusion), followed two weeks later by subcutaneous booster injections of idiotype protein and KLH, with a final DC infusion given five to six months later.
No toxicities were observed following infusion of the antigen-pulsed DCs and it was found that all four patients developed strong humoral and cellular proliferative responses to the control KLH protein. More importantly, all four patients developed cellular proliferative responses specific to their own idiotype protein, no specific anti-idiotype antibody responses were seen.
7.2. MALIGNANT MELANOMA
The molecular characterization of melanoma antigens recognized by T cells has recently resulted in a variety of melanoma vaccine trial. Melanoma antigens include the gp100, MART-1, tyrosinase, MAGE-1, and MAGE-3 proteins, whose class I MHC-binding epitope peptides have been mapped. Mukherji and colleague [30] found that intradermal administration of monocytes cultured in GM-CSF and pulsed with a MAGE-1 MHC class I-restricted peptide could elicit peptide and autologous melanoma-reactive CTLs in patients with advanced melanoma. No significant therapeutic responses recently described when 16 melanoma patients immunised using DCs loaded with melanoma peptides or tumour lysates.
7.3. PROSTATE CANCER
Several prostate-tissue-associated antigens are now being explored as target for immunotherapy of prostate cancer. Prostate tissue antigens include prostatic alkaline phosphatase (PAP), prostate-specific membrane antigen (PSMA), and prostate antigen (PSA). A dose escalation trial of partially purified peripheral blood DCs pulsed with recombinant PAP protein have carried out by Valone et al [31] in 12 patients with advanced prostate cancer. Intravenous administration of 0.3, 0.6, and 1.2×109 pulsed cells/m2 body surface area monthly for three months resulted in T-cell proliferative responses to PAP in all patients, the magnitude of which was related to cell dosage. Toxicity was limited to myalgias in three patients. Clinical outcomes have not been reported.
7.4 MULTIPLE MYELOMA
Multiple myeloma represents another B-cell malignancy potentially agreeable to immunotherapy directed at the tumour idiotype. Myeloma cells do not express immunoglobulin on their surface. Idiotype-derived peptides complexed to cell-surface class I MHC molecule could be recognised by the induction of CTLs was principal to this approach. Pilot trial of DC vaccination for lymphoma and extensive preclinical studies demonstrated that host T cells can recognize the idiotypic determinants of myeloma proteins. A trial of vaccination with idiotypic M protein-pulsed DCs was initiated in 1995 for multiple myeloma patients following autologous peripheral blood stem cell (PBSC) transplantation.
In this trial myeloma patients first receive high-dose melphalan and total body irradiation followed by PBSC rescue. After one month, patients receive two monthly intravenous infusions of peripheral blood DCs pulsed with M protein purified from pre transplant sera. After that five subcutaneous booster injections of idiotype coupled to KLH in adjuvant were given. Immune responses to the vaccine have been limited to patients achieving complete remissions prior to vaccination. In one such patient, idiotype-specific T-cell proliferative and cytolytic responses were induced following vaccination.
8. FUTURE APPLICATIONS
Powerful antigen-presenting properties of DCs are exploiting for the development of immune therapeutics against cancer. Although the vaccination approaches described above have demonstrated clinical activity and feasibility, techniques for targeting tumour antigens to DCs in situ may eventually prevent the need for ex vivo manipulation of DCs [24].
In the future, consideration should also be given to the coordination of DC based immunotherapies with other treatment modalities. The concurrent systemic administration of cytokines such as IL-2 may enhance the efficacy of tumour vaccine, it was recently described in the case of a peptide based melanoma vaccine strategy. Favourable immune responses may be further improved if techniques can be devised to correct the deficient antigen presenting properties of tumour cells and to neutralize the soluble immunosuppressive factors (e.g. IL-10, VEGF) produced by tumour cells.
9. CONCLUSION:
Dendritic cells are considered to be the most potent antigen-presenting cells and powerful tool for eliciting anti-tumour immunity; hence their properties are exploited in the immunotherapeutic for treating various types of malignancies. Even though tumour antigen–presenting properties of DCs in therapeutic vaccination has been shown to work effectively in mice and promising results are obtained from in vitro studies, their clinical benefit for patients with cancer is limited. Successful vaccination strategies for fighting cancer and infectious disease are likely to be those favour the uptake and presentation of antigens by DCs, and is accomplished either by targeting of antigen to DCs in vivo or loading antigen to DCs ex vivo. Further the integration of fundamental tumour immunology research with well designed clinical trials of DC-based vaccination promises to improve methods for generating clinically effective anti-tumour immunity.
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Received on 18.05.2016 Modified on 26.06.2016
Accepted on 28.06.2016 ©A&V Publications All right reserved
Res. J. Pharmacology & Pharmacodynamics.2016; 8(3): 141-147.
DOI: 10.5958/2321-5836.2016.00026.4