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2.2. Cytotoxic ruthenium(II)-arene SCCs

However, only after Morales and his colleagues demonstrated in that the use of BCG was accompanied with the cancer regression, the vaccine was approved as the complementary treatment of bladder cancer [ 29 ]. Treatment of this type of cancer with the M. This therapy is most often used after resection to eliminate accurately the cancer cells and to prevent recurrence [ 29 ].

The dose and duration of treatment are strictly dependent on the stage of cancer. Clinical observations show that recurrence is much less likely to occur after tumor resection or resection and chemotherapy when BCG is administered intravesically [ 30 ]. In addition, the pool of proinflammatory cytokines is increasing, which enhances the immune response of the body by activating the phagocytosis of cancer cells. Providing the selected vitamins during therapy may increase the survival of M.

Streptococcus pyogenes was originally used in the treatment of bone sarcoma by Dr. William Coley. However, the emergence and development of other treatments for cancer, especially chemotherapy and radiotherapy, caused that for many years, the concept of using this microorganism was forgotten. Fortunately, the concept of anticancer therapy with the use of S. Presently, the S. They are most often found in the head and neck area of children under the age of two. The pathological development of lymphatic vessels is primarily associated with impaired lymph flow, which in turn manifests itself in the formation of cysts.

Changes in children resemble goiter, similar to that one, which is associated with an enlarged thyroid gland. Treatment primarily involves surgical removal of the cyst, but this is not an easy task, and is often burdened with numerous adverse effects, including death [ 34 , 35 ]. An alternative and safer method of treatment is sclerotherapy. Streptococcus pyogenes OK is injected into pathologically changed lymphatic vessels. In Japan, this microorganism has been successfully used in the treatment of lymphangiomas in children since The mechanism of action of the microorganism is also based on the sensitization of the immune system.

Activated cells destroy the neoplasm, further growth is inhibited, and the lymphangioma is reduced. Studies using flow cytometry have shown that the first day after suspension administration, the numbers of neutrophils and macrophages, as well as lymphocytes, rapidly increase. Due to the appearance of inflammation immediately after the procedure, the lesion may be swollen, but therapeutic effects are noticeable after a few months [ 33 , 35 — 37 ]. Moreover, studies conducted in the years — showed the great effectiveness of this strain also in the treatment of intraoral ranula.

Complete regression occurred in Obligate anaerobes and facultative anaerobes have potential to be used in anticancer therapies because they grow best under conditions of significant oxygen unavailability hypoxia. Oxygen is delivered to the cells through blood vessels which penetrate mainly the tumor surface area. That results in impaired diffusion of oxygen into the tumor and hypoxia. The anaerobic environment creates favourable conditions for the development of anaerobic bacteria, for example, Clostridium spp.

The greatest advantage of using these microorganisms is that they locate directly inside the tumor, in contrast to chemotherapeutics, which spread throughout the body with blood, also destroying normal, healthy cells [ 39 — 41 ]. In the context of hypoxia and the antineoplastic therapy, the most common type of bacteria being in use is Clostridium , due to the anaerobic nature of the rods. The history of the use of Clostridium in the fight against cancer dates back to , when Connell published an article describing the regression of advanced cancer under the influence of enzymes produced by Clostridium histolyticum [ 42 ].

Since then, more research has been done on the use of Clostridium. The attenuated strain of Clostridium novyi -NT has positively undergone phase I and phase II clinical trials, giving extremely promising results for the treatment of leiomyoma [ 39 — 41 ]. The mechanism of the anticancer activity of Clostridium spp. In addition, it produces specific proteins that can be conjugated to specific chemotherapeutics.

This allows the drug to enter the tumor. In traditional chemotherapy, drugs are not able to penetrate into the tumor precisely due to its external vascularization and internal hypoxia [ 39 — 41 ]. Salmonella enterica serovar Typhimurium, an etiological agent of typhoid fever, shows similar features as Clostridium. It is a relatively anaerobic rod that can also be located in the necrotic tumor regions.

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In the treatment of cancer, the attenuated strain Salmonella typhimurium VNP is used for safety reasons [ 43 ]. Clinical trials on the use of this microorganism for melanoma treatment began in [ 16 ]. In addition, the VXM01 antitumor vaccine, which is based on the attenuated strain of Salmonella typhi , has successfully passed phase I clinical trials. This bacterium has a plasmid-encoding expression of VEGFR2 vascular endothelial growth factor receptor The vaccine blocks the angiogenesis process. The formulation was tested in individuals with pancreatic cancer [ 44 ].

Man has always looked for a mythical panacea, the cure for every illness. Alchemists sought it out in the Middle Ages. Such a legendary substance does not exist, but ideal drugs are still sought by biologists, chemists, physicians, and the other researchers. Ideal means as much as possible safe and effective. This concept is also rooted in research into cancer therapies, which can be evidenced by ever more courageous and original ideas, including the use of microbes; today too daring, in the future they could set standards [ 45 ].

The most recent anticancer strategies use the achievements of various scientific disciplines, for instance, nanobiotechnology. Nanoparticles nanocapsules , lipid vesicles with a chemotherapeutic drug inside, are the object of growing interest. Nanoliposomes are able to deliver the drug inside the tumor [ 46 ]. However, they are not a perfect solution because many of the particles do not reach the target. As mentioned earlier, the tumor is only vascularized from the outside, which makes it impossible for chemotherapeutics to reach the inside of the lesion. Limiting the spread of the drug only to the tumor area would significantly reduce the adverse effects of chemotherapy [ 40 ].

For the mentioned reasons, it was decided to take a closer look at very original bacteria named Magnetococcus marinus MC1 [ 19 ]. This microorganism has cilia, arranged in two bundles located at one pole, which enable the bacteria to move. The unique feature of this bacterium structure is the presence of magnetosomes—special elements which are magnetite particles Fe 3 O 4 surrounded by membranes, forming chains in the cytosol [ 47 ].

In addition, this microorganism shows negative aerotaxis capacity, that is, prefers an environment that is poor in oxygen [ 48 ]. These properties make the Magnetococcus marinus a useful tool to destroy cancer cells. Using a powerful magnetic field, the same as in the MRI technique magnetic resonance imaging , it would be possible to direct bacteria containing magnetosomes to the site of the tumor.

The bacteria will be located precisely in the areas of hypoxia, in that case inside the tumor, where they would deliver a chemotherapeutic encapsulated in nanoliposomes attached to the bacteria surface. Toxoplasma gondii is an obligatory intracellular protozoan. It can be life-threatening to people with impaired immunity or pregnant women, who can suffer abortion or foetal malformation. The primary hosts are Felidae e. In healthy individuals, the immune system inhibits further development of the protozoa [ 49 , 50 ].

It turns out that the protozoan and its lysate, called TLA Toxoplasma lysate antigen , containing antigens of the microorganism, can be used to treat not only neurodegenerative diseases [ 49 ] but also cancer [ 49 , 51 , 52 ]. In particular, the research focuses on the use of the uracil auxotrophic carbamoyl phosphate synthase mutant Toxoplasma gondii CPS in the treatment of the most aggressive types of cancer: melanoma, pancreatic cancer [ 53 ], lung cancer [ 49 , 52 ], and ovarian cancer [ 54 ].

As a result of the administration of this strain, an increase in the level of IL, a cytokine which mediates the inflammation, and the activation of other immune cells were observed. In addition, IL is responsible for inhibition of angiogenesis, leading to hypoxia and tumor growth slackening [ 54 ]. Moreover, the expression of the CD31 molecule angiogenesis marker is reduced, and the Th1 lymphocytes appear, which also causes a significant inhibition of the formation of blood vessels [ 49 ]. Recent studies in the mouse model indicate that the use of T.

Malaria, caused by protozoa of the genus Plasmodium , is one of the most common parasitic diseases in the world. The parasite is transmitted from a healthy person through an Anopheles mosquito. The life cycle includes two hosts, an intermediate host—a human being, and a primary one—a mosquito.

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When the mosquito bites, sporozoites enter the body through blood vessels and then move to the liver where they enter hepatocytes very rapidly, thanks to the apical complex, and in that way, they avoid contact with the host immune system. Here, the sporozoites form schizonts, within which there are numerous divisions, and merozoites are formed. Merozoites are released into the bloodstream about 30 days after the infection. From this point, an erythrocytic cycle starts, and it is responsible for the clinical symptoms of malaria.

Merozoites penetrate erythrocytes and turn into trophozoites and then again into schizonts with merozoites inside. Every 48 hours, new merozoites are released and the cycle repeats, destroying more and more red blood cells. After several cycles, some of the merozoites create gametocytes that can be sucked out with blood by a mosquito. Gametes in the body of the mosquito combine to create a zygote and then an ookinete that penetrates the intestinal epithelium of the mosquito, forming an oocyte [ 55 , 56 ].

Plasmodium falciparum is considered to be the most malignant causative agent of malaria because it aggregates erythrocytes and thrombocytes that adhere to the vascular endothelium, which can lead to the closure of vascular light and thus damage to vascular walls and even necrosis [ 57 ]. However, despite all the negative features of the parasite, it can be used to treat cancer. Salanti et al.

The placenta is a specialized organ whose main function is acting as a mediator between the mother and the baby. Cells proliferate, and proangiogenic factors cause vascularization of the placenta, which develops and grows throughout the pregnancy, forming a cellular syncytium [ 58 ]. It turns out that the placenta and tumors have more in common than just the cell proliferation rate. Chondroitin sulphate is also present on the surface of many tumor cells.

Thus, the rVAR2 protein, which is a recombinant version of the VAR2CSA malarial protein, was developed and after being conjugated to the appropriate part of the diphtheria toxoid it was tested for suitability in the destruction of tumor cells. Both in vitro studies on tumor cell lines and in vivo studies on the mouse model showed the high effectiveness of the strategy used, with the best effects observed for certain types of melanoma with high expression of chondroitin sulfate [ 22 , 58 ].

Anticancer therapy with the use of microorganisms is often marginalized and neglected. A very narrow group of researchers strive to investigate and develop cancer treatment methods using microorganisms, either as vaccines that activate the immune system to fight disease or as vectors for the transmission of antitumor therapeutics. Very often, these studies go unnoticed, despite significant achievements in the field of immunotherapy. With this method of treatment, people who have been failed by conventional treatment are more likely to recover, what is more important, this type of therapy is more selective and therefore less burdensome for the entire organism of the patient [ 18 — 22 ].

Of course, like every treatment, this one also has certain disadvantages. There is primarily a risk of developing infection and related consequences, including death. In experimental studies, laboratory animals have been used to show that the most effective strain actually destroyed cancer, but animals died because of infection by pathogens. It is therefore very important to ensure the safety of the patients, especially by using only adequately attenuated microorganisms. Only a perfect balance between the attenuation of a microorganism and its immune stimulatory ability can guarantee the proper effect.

In addition, the costs associated with clinical trials and the introduction of a new product to the market are extremely high. Legal regulations are also very complicated, due to the not fully known impact of microbes on cancer. An accurate diagnosis and carrying out proper tests are absolutely necessary. The research on Plasmodium falciparum is a good example of how difficult it is to move from the experimental phase to the implementation stage. Another concern at the moment is the limited use of microbial preparations.

As mentioned above, there are over two hundred different cancer diseases and only for a few of them where the bacterial preparations have been developed or introduced. So far, there is no general-purpose universal bacterial preparation, each type of cancer requires a specially selected optimized strain Table 1 , and it is difficult to believe that this kind of universal microbe-based treatment could be ever compiled.

However, microbial therapy and research on other bacterial preparations should not be stopped. Relatively recently, a number of reports have been published regarding the use of a padeliporfin derivative palladium bacteriopheophorbide monolysine taurine, WST in the treatment of prostate cancer [ 59 — 62 ]. WST, in contact with infrared light, induces the synthesis of reactive oxygen species and inhibits angiogenesis, which leads to tumor necrosis. The compound that was the starting point for WST was isolated from ocean-bottom bacteria. The bacteria have developed photosynthetic pigment bacteriochlorophyll to adapt to near-total darkness.

They use the smallest light source as energy. Journal of Immunology Research. Indexed in Science Citation Index Expanded. Journal Menu. Special Issues Menu. Subscribe to Table of Contents Alerts. Table of Contents Alerts. Abstract Cancer remains one of the major challenges of the 21st century.

Introduction According to the report of Ferlay et al. Back to Sources The beginnings of the use of microbes in cancer therapy date back to the nineteenth century. Bacteria Used as Anticancer Agents The antitumor efficacy of microorganisms is extremely diverse. Blood 91 , — Small, E. Granulocyte macrophage colony-stimulating factor—secreting allogeneic cellular immunotherapy for hormone-refractory prostate cancer.

Lipson, E. Laheru, D. Allogeneic granulocyte macrophage colony-stimulating factor secreting tumor immunotherapy alone or in sequence with cyclophosphamide for metastatic pancreatic cancer: a pilot study of safety, feasibility, and immune activation. Salgia, R. Vaccination with irradiated autologous tumor cells engineered to secrete granulocyte-macrophagecolony-stimulating factor augments antitumor immunity in some patients with metastatic non-small-cell lung carcinoma. Higano, C. Genitourinary Cancers Symposium , a07 Kantoff, P.

Sipuleucel-T immunotherapy for castration-resistant prostate cancer. Butterfield, L. Adenovirus MARTengineered autologous dendritic cell vaccine for metastatic melanoma. Ribas, A. Role of dendritic cell phenotype, determinant spreading, and negative costimulatory blockade in dendritic cell-based melanoma immunotherapy. Coley, W. The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases.

Oncolytic Viruses for Cancer Therapy: Overcoming the Obstacles

Redelman-Sidi, G. The mechanism of action of BCG therapy for bladder cancer—a current perspective. Saltzman, D. Cancer immunotherapy based on the killing of Salmonella typhimurium -infected tumour cells. Expert Opin. Bermudez-Humaran, L. A novel mucosal vaccine based on live Lactococci expressing E7 antigen and IL induces systemic and mucosal immune responses and protects mice against human papillomavirus type induced tumors. Toussaint, B. Live-attenuated bacteria as a cancer vaccine vector. Wood, L. Attenuated Listeria monocytogenes: a powerful and versatile vector for the future of tumor immunotherapy.

Bolhassani, A. Prospects and progress of Listeria -based cancer vaccines. Aduro press release. Cecco, S. Cancer Drug Targets 11 , 85— Lesterhuis, W. Cancer immunotherapy—revisited. Bijker, M. Superior induction of anti-tumor CTL immunity by extended peptide vaccines involves prolonged, DC focused antigen presentation. Toes, R. Peptide vaccination can lead to enhanced tumor growth through specific T cell tolerance induction. Enhanced tumor outgrowth after peptide vaccination. Functional deletion of tumor-specific CTL induced by peptide vaccination can lead to the inability to reject tumors.

Hailemichael, Y. Cho, H. Optimized peptide vaccines eliciting extensive CD8 T cell responses with therapeutic antitumor effects. Zom, G. TLR ligand-peptide conjugate vaccines: toward clinical application. Wen, Y. Supramolecular peptide vaccines: tuning adaptive immunity. Sultan, H. Designing therapeutic cancer vaccines by mimicking viral infections.

Zhu, X. Toll like receptor-3 ligand poly-ICLC promotes the efficacy of peripheral vaccinations with tumor antigen-derived peptide epitopes in murine CNS tumor models. Zhang, H. Janssen, E. Nature , 88—93 Rosalia, R. Dendritic cells process synthetic long peptides better than whole protein, improving antigen presentation and T cell activation. Larocca, C. Viral vector-based cancer vaccines. DiPaola, R. Arlen, P. Clinical safety of a viral vector based prostate cancer vaccine strategy. Vaccine based immunotherapy regimen VBIR for the treatment of prostate cancer.

Jorritsma, S. Delivery methods to increase cellular uptake and immunogenicity of DNA vaccines. Vaccine 34 , — Sardesai, N. Electroporation delivery of DNA vaccines: prospects for success. Diken, M. Issues Mol. Naturally occurring nucleoside modifications suppress the immunostimulatory activity of RNA: implication for therapeutic RNA development.

Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Lundstrom, K. Vaccines 4 , 39 Lu, D. Optimization of methods to achieve mRNA-mediated transfection of tumor cells in vitro and in vivo employing cationic liposome vectors. Cancer Gene Ther. Wasungu, L. Cationic lipids, lipoplexes and intracellular delivery of genes. Release , — Little, S. Phua, K. Transfection efficiency and transgene expression kinetics of mRNA delivered in naked and nanoparticle format. Su, X. In vitro and in vivo mRNA delivery using lipid-enveloped pH-responsive polymer nanoparticles.

Nanoscale 6 , — Kranz, L. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Fu, J. Ali, O. Vaccines combined with immune checkpoint antibodies promote cytotoxic T cell activity and tumor eradication. Massarelli, E. Combining immune checkpoint blockade and tumor-specific vaccine for patients with incurable human papillomavirus related cancer: a phase 2 clinical trial.

JAMA Oncol. Romano, E. Hodi, F. Improved survival with ipilimumab in patients with metastatic melanoma. Khong, H. Adjuvants for peptide-based cancer vaccines. Cancer 4 , 56—67 Peptide vaccines in cancer-old concept revisited. Moran, A. Murata, S. De Smedt, T. OX40 costimulation enhances the development of T cell responses induced by dendritic cells in vivo. Sorensen, M. Adenoviral vaccination combined with CD40 stimulation and CTLA-4 blockage can lead to complete tumor regression in a murine melanoma model.

Vaccine 28 , — Linch, S. Schwartzentruber, D. Yang, Y. Antitumor Effect of a DNA vaccine harboring prostate cancer-specific antigen with IL as an intramolecular adjuvant. Anguille, S. Interleukin dendritic cells as vaccine candidates for cancer immunotherapy. Ferrara, T. Combining radiation and immunotherapy for synergistic antitumor therapy. Gameiro, S. Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T cell killing.

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Quoix, E. Amsen, D. Tissue-resident memory T cells at the center of immunity to solid tumors. Blanc, C. Targeting resident memory T cells for cancer immunotherapy. Front Immunol. Marincola, F. Escape of human solid tumors from T cell recognition: molecular mechanisms and functional significance. Garrido, F. Cancer , — Mimura, K. Pollack, B. Srivastava, R.

Download references. Correspondence to Kathrin Jansen. Reprints and Permissions. Article metrics. Advanced search. Skip to main content. Subjects Cancer immunotherapy Vaccines. Abstract Recent advances in several areas are rekindling interest and enabling progress in the development of therapeutic cancer vaccines.

Introduction In terms of lives saved, vaccines have been the greatest triumphs of medicine. Cancer vaccine antigens The choice of antigen is the single most important component of cancer vaccine design. Full size image. Vaccine vectors Several vaccine constructions have been tested for anticancer therapy, and lessons from these have pointed the way to substantial improvements. Combinations with other therapies Cancers arise despite the presence of immunosurveillance that routinely detects and eliminates abnormal cells, indicating the evolution of immunosuppressive and evasive mechanisms.

Conclusions and perspectives Cancer immunotherapy has experienced tremendous progress in the last decade, including dramatic expansion of our understanding of how cancer cells evade the immune system and the development of several new therapies that are benefitting cancer patients. References 1. Article Google Scholar Google Scholar Gene Therapy - Principles and Challenges. The improvements in the past 20 years in the molecular biology have evoked optimism in the treatment of cancer and yielded a number of targeted drugs in the market.

However, the curative treatment of the cancer has still been possible with only the early diagnosis and early intervention in the vast majority of the solid tumors. Almost half of the cancer patients diagnosed each year have been dying of the disease throughout the world. In particular, the patients with distant metastasis have no hope of cure with the current treatment modalities. It has long been suggested that the cancer has evolved from a single cell transformed by the influence of the environmental factors such as physical, chemical factors, and viruses.

Changes in hundreds of genes, so-called mutations, are required to transform a normal cell into a cancer cell. The major functional changes that transform a cell are mainly the activation of oncogenes or inactivation of tumor suppressor genes. The overexpression of oncogenes and loss of function of tumor suppressor genes usually induce malignant transformation. Those changes are also required for further growth of tumor cells. A transformed cell usually gains some important biological properties to establish a malignant disease. Those properties, including uncontrolled proliferation, evasion of growth suppressors, inhibition of apoptosis, replicative immortality, angiogenesis, proliferative signals, invasion, and metastasis, are discussed in detail in a recent review of Hanahan and Weinberg [ 1 ].

Although the conventional chemotherapy has mainly focused on direct tumor cell killing, a vast majority of current targeted therapies have aimed to eliminate one or more of the above-mentioned properties of cancer cells. The targeting of angiogenesis, proliferation pathways, and immune system has yielded a number of drugs that are already in the market.

Nodules of cancer cells cannot grow beyond 1—2 mm without expanding their blood supply to access every increasing need for oxygen and nutrients. In order to generate the additional blood supply, the tumor tissue stimulates the elaboration of its own vessel network, through a process called angiogenesis [ 2 ]. If one could cut the blood supply of the tumor, it cannot grow beyond 1—2 mm, which means that they cannot grow enough to be diagnosed by the current diagnostic technology and cannot cause a clinical disease.

The tumor vascular targeting therapy or antiangiogenetic therapies like bevacizumab and aflibercept targeting ligands of angiogenesis or small tyrosine kinase inhibitors of angiogenesis pathway receptors or signaling molecules have already emerged as standard therapeutic drugs in various tumors [ 3 ]. The overexpression of oncogenes and the loss of function of tumor suppressor genes are usually involved in both malignant conversion of the cells and further growth of tumor cells. A new generation of small molecules targeting proliferation pathways, like gefitinib, erlotinib, and imatinib, has been developed to block the cancer-causing signals within cancer cells and become standard treatments in those patients with mutations of EGFR or c-KIT [ 4 ].

Antibody molecules, targeting the EGFR family of receptors like trastuzumab, cetuximab, and panitumumab also block the growth-promoting signals that push cancer cells into an unregulated pattern of growth [ 5 ]. In contrast to standard chemotherapy, which is quite damaging to the normal tissues of the body as well as the cancer tissue, the targeted drugs are quite specific for the cancer cells and therefore relatively free of side effects.

Although majority of the cancer patients has a fairly intact immune system, the cells of the immune system do not usually respond to tumor cells because the immune system cannot differentiate the normal and cancer cells and therefore cannot fight against them. Immunotherapy or cancer vaccine therapy aims to activate immune system against tumors.

Likewise, a dendritic cell-based vaccine, sipuleucel T, for the treatment of metastatic prostate cancer has been approved 2 years ago [ 7 ]. Hundreds of genes have been involved in the action and regulation of those pathways. The generation of cancer through a series of changes in the normal cellular genes makes the disease a genetic disease at the cellular base. The involvement of genes in the development of the disease also makes the disease a good candidate for gene therapy. Therefore, gene therapy has emerged as the hope of curative treatment modality in cancer.

Gene therapy can be defined as the delivery of genetic elements to the cancer cell or to the cells of the immune response in order to correct the abnormalities in the cancer tissue or to induce an immune response against the cancer cells. The corrective strategies can involve replacing missing or defective genes, i. There are some prerequisites for a successful gene therapy program in cancer, such as a suitable target to be replaced or modified, a carrier to reach the interest of gene to the cell, a successful targeting of the vector, and a sufficient expression of the therapeutic genes in the target cells.

Besides a strong therapeutic efficacy, safety is also mandatory for the success of the treatment. Unraveling the mystery of the genetic changes in the development of cancer has been proposed many genes as targets for gene therapy studies. The second step in gene therapy following the identification of a suitable gene is to introduce it into the target cell. Different vehicles vectors have been used to introduce the genes into the cells, such as viral vectors, nonviral vectors, and cell-based carriers.

The mainly used viral vectors in cancer gene therapy are retroviruses, adenoviruses, and adeno-associated viruses. The gene therapist uses the capability of the virus to enter and reprogram the action of cells for purposes of therapy. The therapeutic genetic element is first placed into a viral backbone to produce a complete therapeutic viral vector.

Alternatively, the therapeutic genetic elements can be delivered into the cancer cells through droplets of fat called liposomes or nanoparticles. The genes themselves, in the form of naked DNA or DNA packed into particles can be administered locally or systemically. A third way of delivering genes to the target tissues is accomplished by using living cells such as irradiated tumor cells, blood cells, and mesenchymal or neuronal stem cells.

All of these cells have the capability to home to particular types of target tissue through the blood stream. In this way, the therapeutic genes can be placed into the brain or other target tissues because of the homing properties of those cells. For the safety of the procedure and the increased therapeutic efficacy, the genes of interest should be expressed in only target cells or tissues.

Sparing of the normal cells and tissues is one of the keystones in their clinical use. The target specificity of the vectors could be achieved by the targeting of those specific to the tumor cells or tissues. There are three main ways of transferring genes into the tumor cells: nonviral vectors, viral vectors, and cell-based vehicles. For most of the tumors, a relatively short-term expression of therapeutic genes may be sufficient to kill the tumor cells.

Rapid clearance of viral vectors from the blood stream has enabled the development of synthetic gene delivery vectors. However, an important drawback for these approaches is to carry the DNA of interest to the distant metastatic deposits. The nonviral gene delivery vectors have usually been injected locally to the tumors. Although local injection is reasonable for tumors as melanoma, head and neck cancers, or peritoneal carcinomatosis; it is not suitable in patients with hematogenous metastases.

The limitations of the viral vectors are also valid for the nonviral vectors for gene therapy. They have to survive through the blood stream to be arrested in the target tumor tissue, to extravasate, and to bind to specific cells and to enter the cells and then to reach the nucleus. Plasmid DNA , which is mostly used as nonviral gene therapy modality, is easily degraded by nucleases [ 11 ]. Therefore, some strategies to reduce the size and prevent the degradation have been developed. The most commonly used agents for gene delivery are cationic lipids [ 12 ].

The cationic head group of the lipids binds to DNA and the lipid tail enables the collapse of the DNA lipid complex [ 13 ]. However, the transgene expression efficiency is very low with lipoplexes. It has been shown that only a very small portion of the systemically injected DNA could be reached to tumor tissue [ 14 ]. Lipid-based formulations of gene delivery have been predominantly limited to the intratumoral or local applications.

The systemic administration carries the potential risk of adverse inflammatory and immune reactions. The development of systemic lipid delivery systems with the modifications to reduce the systemic toxicity could have the potential for clinical use in cancer gene therapy. In an animal model of breast cancer, folate-targeted lipid—protamine DNA complexes LPD-PEG-folate have been shown to reduce the tumor volume and increase the survival when administered systemically [ 14 ]. Neutral liposomes composed of DOPC 1,2-dioleyl-sn-phosphatidyl choline and DOPE 1,2-dioleyl-sn-phosphatidyl ethanol amine and polycationic carrier proteins as protamine, polylysine, polyarginine, polyhistidine, or polyethynilemine PEI are also suitable to carry the DNA [ 15 — 18 ].

The hydrophobic polymers , such as polyethylene glycol PEG , polyhydroxy propylmethacrylamide pHPMA , and polyvinyl pyrrolidine pVPyrr , have also been used to mask the positive charge of DNA to extend its half-life in the blood [ 19 , 20 ]. Both the neutral liposomes and hydrophobic polymers yield less toxicity when administered systemically.

The leaky nature of the blood vessels of the tumors allows the influx of macromolecules as polymer shielded DNA into the tumor. The PEGylation of plasmid DNA has been reported to circulate in the blood several hours and passively accumulate in the subcutaneous tumors in animals [ 21 ]. Viruses have the natural ability to deliver the nucleic acids within its own genome to specific cell types, including cancer cells. This ability makes those attractive and popular gene-delivery vehicles. Retroviruses, adenoviruses, adeno-associated viruses, herpes simplex virus, poxviruses, and baculoviruses are commonly modified and used as gene therapy vectors in cancer.

Additionally, chimeric viral-vector systems combining the properties of two or more virus type are also developed. Retroviral vectors derived from retroviruses contain a linear single-stranded RNA of around 7—10 kb and have a lipid envelope. The viral particles enter the mammalian cells expressing appropriate receptors for retroviruses [ 22 ].

The dsDNA transcribed in the cytoplasm forms a nucleoprotein preintegration complex PIC by binding cellular proteins [ 23 ]. The PIC migrates to the nucleus and thereby integrates the host genome. The ability of transgene expression in only dividing cells is an advantage of retroviral vectors for cancer gene therapy to avoid undesired expression in nondividing cells of surrounding tissues. The incorporation of retroviral genes into the host genome provides long-term expression of transgenes.

Although this is advantageous, a nonspecific incorporation of viral DNA could impair the function of host gene or induce aberrant expression of a cellular oncogene [ 24 ]. Although retroviral vectors have been the most widely used gene transfer vehicles in the clinic, the risk of insertional oncogenesis seen in the trial of X-SCID infants in has limited the use of retroviral gene transfer systems in humans [ 25 ]. The possibility of generating replication-competent retroviruses is another safety issue regarding the clinical use of those vectors [ 26 ]. Lentiviral vectors derived from retroviruses can cause stable integration of the transgene into the host genome with long-term gene expression.

The ability of transducing both dividing and nondividing cells make those vectors more suitable and efficient gene transfer vehicle over retroviruses. Targeting strategies of vectors at the level of cell entry and transgene transcription improved the use of lentiviral vectors in gene therapy trials [ 27 ]. However, the biosafety concerns of random integration to the host genome as in retroviruses are the limitations of those vectors. Adenoviral vectors are widely used to introduce the therapeutic genes into the tumor cells. They can infect a broad range of cell types, transfer the genes being not dependent on cell division, and have high titers and high level of gene expression [ 28 ].

The most widely used serotypes of adenoviruses to develop vectors in human cancer gene therapy studies are type 5 Ad5 and type 2 Ad2. They have the capacity of approximately 8—10 kb of therapeutic genes with first-generation vectors and up to 36 kbp with gutless third generation adenoviral vectors [ 29 ]. However, along with the immunogenic potential, the broad range of host cells by adenovirus limits its systemic use in human cancer gene therapy trials [ 30 ]. Targeting strategies have enabled the use of adenoviral vectors in human gene therapy trials. Adenoviral vectors cannot integrate to cellular genome and express the transgene episomally.

They cannot induce random mutations. However, the transgene expression is limited to 7—10 days postinfection [ 31 ].

Journal of Immunology Research

Therefore, repeated administrations of the vector are needed to achieve sustainable responses in cancer treatment. Adenoviruses could be engineered either as replication deficient by deleting the immediate early genes of E1 or replication-competent keeping the E1 region. Replication-competent adenoviral vectors will be further discussed in the section of oncolytic viruses.

They belong to parvovirus family and require a helper virus such as adenovirus or herpes virus for lytic replication and release from the cell [ 33 ]. They can infect a wide variety of cells independent of cell cycle. This property makes AAV as suitable vectors for cancer gene therapy. Furthermore, unlike adenoviruses, they elicit little immune response when infect the normal host cells. Another advantage of AAV over adenoviruses is their ability to integrate the transgene into a particular spot on the 19th chromosome of human cells [ 34 ]. Unlike retroviruses, AAV cannot induce mutations.

However, the major drawback of AAV is its limited cargo capacity of approximately 4 kbp of therapeutic genes. AAV could transduce certain cell types. Therefore, targeting strategies such as modification of viral capsid proteins, binding monoclonal antibodies, or bispecific proteins have been developed to improve the efficiency of AAV systems in cancer gene therapy [ 35 , 36 ]. Baculoviruses are enveloped viral particles with a large dsDNA of approximately 80— kb. They naturally infect insect cells. There have been no diseases related to baculoviruses in humans.

Along with their highly safety profile in humans, they seem very useful gene therapy vehicles with their highly large cargo capacity of approximately 40 kb with possible multiple inserts, easy manipulation, and production [ 37 ]. Autographa californica multiple nucleopolyhedrovirus Ac MNPV is the most widely used types of baculovirus in gene therapy studies. It has a circular dsDNA genome of kb [ 38 ]. They can easily transduce mammalian cells, including many types of cancer cells, and cause high transgene expression in the host cell [ 39 ]. They are already approved for the production of human vaccine components such as Cervarix GlaxoSmithKline in cervical cancer and Provenge Dendreon in prostatic cancer [ 40 ].

It has a natural tropism to nerve tissues and cannot integrate into the host genome [ 41 ]. The HSV vectors can be designed in three different types as amplicons, replication-defective, and replication-competent vectors [ 42 ]. In general, the replication-competent HSV vectors are used as oncolytic agents in cancer gene therapy studies [ 43 ].

Poxviruses were the first viruses to be used as gene therapy vectors. They have been used in the in vitro production of proteins and as live vaccines. The attenuated forms of poxviruses have been developed and used in the development of genetic cancer vaccine trials [ 44 ].

Oncolytic Viruses for Cancer Therapy: Overcoming the Obstacles

The immunostimulatory properties of poxviruses make them preferable agents to induce immunity against tumors. In particular, the attenuated MVA virus derived from chorioallantoid vaccinia Ankara CVA , a Turkish smallpox vaccine strain, has been widely used in cancer vaccine development strategies [ 45 ]. The systemic administration of the gene therapy vectors usually failed because of low titer achieved in the target tissue and insufficient transgene expression.

The clearance of the vector by the immune system, sequestration, and nonspecific binding to nontarget tissues are the major drawbacks of viral and nonviral vectors [ 46 , 47 ]. In general, in vivo targeting has relied mainly upon the enhanced leakiness of the tumor vessels, allowing the extravasation and access to tumor cells. Besides, the target tropism, extravasations in tumor site, and poor penetration of the vectors into the tumor tissue are the major problems for the vectors to eradicate the metastatic tumor deposits.

Cell carriers have the potential of eliminating those problems. They are stable and most of them have tumor homing properties and can be administered locally, such as intraperitoneal or intratumoral injections or systemically. In case of the use of autologous cells, they will not be cleared by the immune system.