Drug Targeting and Stimuli Sensitive Drug Delivery Systems

By Alexandru Mihai Grumezescu

Drug Targeting and Stimuli Sensitive Drug Delivery Systems covers recent advances in the area of stimuli sensitive drug delivery systems, providing an up-to-date overview of the physical, chemical, biological and multistimuli-responsive nanosystems. In addition, the book presents an analysis of clinical status for different types of nanoplatforms. Written by an internationally diverse group of researchers, it is an important reference resource for both biomaterials scientists and those working in the pharmaceutical industry who are looking to help create more effective drug delivery systems.

• Shows how the use of nanomaterials can help target a drug to specific tissues and cells
• Explores the development of stimuli-responsive drug delivery systems
• Includes case studies to showcase how stimuli responsive nanosystems are used in a variety of therapies, including camptothecin delivery, diabetes and cancer therapy

• Language: English
• Publisher: Elsevier Science
• Release date: May 21, 2018
• ISBN: 9780128136904

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Series Preface: Pharmaceutical Nanotechnology

Alina M. Holban, University of Bucharest, Bucharest, Romania

Due to its immense applicative potential, nanotechnology is considered the leading technology of the 21st century. The science and engineering of nanometer-sized materials is currently employed for the development of numerous scientific, industrial, ecological, and technological fields. Biology, medicine, chemistry, pharmacy, agriculture, food industry, and material science are the main fields which have benefited from the great technological progress developed in nanoscience.

In the pharmaceutical field, nanotechnology has revolutionized traditional drug-design concept and the art of drug delivery. The idea of a highly specific nanoscale drug for the targeted therapy of diseases is now considered a feasible treatment for severe health conditions.

Some scientists believe that the pharmaceutical domain has been reborn by the important contribution of nanotechnology. The field of pharmaceutical nanotechnology has the potential to offer innovative solutions for all diagnosis, therapy, and prophylaxis domains. Application of nanotechnology tools in pharmaceutical research and design is likely to result in moving the industry from a blockbuster drug model to personalized medicine. The current main focus of clinicians is to treat patients individually, not their general diagnosed diseases, which are usually difficult to diagnose or incorrectly diagnosed. There are compelling applications in the pharmaceutical industry where suitable nanotechnology tools can be successfully utilized. By designing and modifying drugs at nanoscale, pharmaceutical nanotechnology could be useful not only for the development of completely new therapeutic solutions, but also to add value to existing products. This possibility opens perspectives of success for pharmaceutical companies in existing markets, but also for new markets.

Scientists have manifested an impressive interest on the field of pharmaceutical nanotechnology research in recent years. However, we face today a true dilemma of data unavailability, due to the multitude of existing information which can be highly inaccurate and contradictory. This is because of the lack of an efficient model for sorting the plethora of nanotechnology tools and information that exists, and strategically correlate those with potential opportunities into different segments of pharmaceutical research and design.

This series is trying to cover the most relevant aspects regarding the great progress of nanotechnology in the pharmaceutical field and to highlight the currently emerging trend of pharmaceutical nanotechnology towards the personalized medicine concept.

The 10 volumes of this series are structured to wisely offer relevant information regarding basic concepts and also to reveal the newest approaches and perspectives in pharmaceutical nanotechnology.

Nanoscale Fabrication, Optimization, Scale-Up and Biological Aspects of Pharmaceutical Nanotechnology, introduces the readers into the amazing field of nanoscale design. Also, this volume facilitate understanding of the biological requirements of nanostructured pharmaceutical formulations for advanced drugs.

In Design and Development of New Nanocarriers, the most recent progress made on the field of nano-delivery is discussed. Modern nanostructured drug carriers employ innovative solutions for the detection and treatment of various diseases in a personalized and efficient manner.

Design of Nanostructures for Theranostics Applications, highlights the impressive impact of nanotechnology in the development of combined diagnosis and therapy concept: theranostics.

Design of Nanostructures for Versatile Therapeutic Applications, offers a dynamic solution for immune modulation, treatment of diseases by natural-based products and infection control, while employing nanostructured solutions to achieve top results.

Nanostructures for the Engineering of Cells, Tissues and Organs: From Design to Applications, is a highly investigated and debated field; tissue engineering, is dissected through this volume. Here is shown how nanotechnology has advanced research and applications in the manipulation and engineering of cells and tissues in vitro.

Organic Materials as Smart Nanocarriers for Drug Delivery, deals with the specific world of organic nanomaterials, revealing their wide applications, types, and advantages in drug delivery.

In the volume entitled: Inorganic Frameworks as Smart Nanomedicines, the main focus is to discuss the variety and properties of inorganic nanostructures for therapy and drug delivery in the context of improved personalized medicine.

Lipid Nanocarriers for Drug Targeting, deals with recently developed lipid nanostructures and the advances made in drug targeting.

Drug Targeting and Stimuli-Sensitive Drug Delivery Systems, dissects smart stimuli-responsive nanosystems employed to specifically detect various biochemical conditions and control the release of drugs.

Fullerens, Graphenes and Nanotubes: A Pharmaceutical Approach, reveals major findings made on widely applied drug-design nanosystems, namely fullerens, graphenes and nanotubes. The impact of these nanostructures in pharmaceutical research is highlighted.

All 10 volumes are nicely illustrated and chapters are organized into a logical manner to be accessible to a wide audience. The series is a valuable resource of new and comprehensive scientific proof on the intriguing and emerging field of pharmaceutical nanotechnology, which could be of a great use for scientists, engineers, pharmaceutical representatives, clinicians, and any non-specialist interested user.

Preface

Drug Targeting and Stimuli Sensitive Drug Delivery Systems

This book reviews the recent progress in the field of drug targeting and stimuli-sensitive drug delivery systems. The book covers innovative approaches related to stimuli-responsive nanomaterials with single or multiple responses to physiological or other external stimuli. Concepts, advances, and preclinical and clinical status of different drug delivery systems are presented.

The book, Drug Targeting and Stimuli Sensitive Drug Delivery Systems, contains 20 chapters, prepared by outstanding researchers from China, United States, UAE, Brazil, Serbia, Spain, Portugal, Argentina, India, and Turkey.

Chapter 1, Treatment strategies in cancer—from past to present, prepared by Hatice Yildizhan et al., gives an up-to-date overview about targeted therapies that act by affecting the pathways responsible in cell growth, division, and spread of cancer cells. Following scientific and technological developments, new applications have arisen, such as gene-therapy, stem cell therapy, immunotherapy, and nanotechnology-derived therapies. Combination of chemotherapeutic with nanoparticles is a novel approach that is being used in the treatment of cancer.

Chapter 2, Nanotechnology-based drug delivery systems: challenges and opportunities, by Deepti Sharma et al. undertakes a detailed investigation of various factors that influence nanoparticles-based drug delivery systems, such as operational efficiency, safety, scaling up, and cost aspects.

Chapter 3, Nanotechnology applications in drug controlled release, prepared by Analía Simonazzi et al. presents a variety of nanodrug delivery systems such as nanoemulsions, lipid or polymeric nanoparticles, and liposomes investigated as functional drug carriers for treating a wide range of therapies, most notably cardiovascular defects, autoimmune diseases, and cancer. Designed nano-sized devices or drug carriers provide various advantages for effective drug delivery.

Chapter 4, Target specific delivery: an insight, prepared by Prasoon Pandey and Neelam Balekar, presents novel approaches in drug delivery strategy that has a known target, which may be organs, tissue, cells, or structures inside of cells (i.e. gene).

Chapter 5, Stimuli-responsive nanosystems for drug-targeted delivery, prepared by Carla M. Lopes et al. gives an overview of the most significant physical and chemical stimuli-responsive nanosystems and elucidates their current and relevant applications in controlled and targeted drug delivery attending different routes of administration.

Chapter 6, Stimuli sensitive ocular drug delivery systems, by Francisco O. Espinar et al. focuses on some new representative areas of ophthalmic drug delivery research: use of pharmaceutical nanosystems, and especially smart polymers. Stimuli-sensitive hydrogel systems show a markedly reversible sol-gel phase transitions in response to physiological stimuli (temperature, pH and present of ions in organism fluids, enzyme substrate) or other external (electric current, light). This kind of materials can improve the drug bioavailability by increasing the residence time of the formulation in the eye surface.

Chapter 7, Stimuli-sensitive nanomaterials for antimicrobial drug delivery, prepared by Smritilekha Bera and Dhananjoy Mondal covers recent studies in the development of stimuli-sensitive nanomaterials for antimicrobial drug delivery in the presence of light, pH, magnet, enzymes, and other endogenous and exogenous agents, which can activate the nanostructure to release the drug molecules at the target site avoiding obstacles and cytotoxicity en route.

Chapter 8, Stimuli-responsive micelles: a nanoplatform for therapeutic and diagnostic applications, prepared by Hema A. Nair et al. presents a detailed review of the various classes of stimuli-responsive micelles, the strategies in their design and the current advancement with respect to their drug delivery and diagnostic applications.

Chapter 9, Design of targeting peptides for nanodrugs for treatment of infectious diseases and cancer, prepared by Sanja Glisic and Veljko Veljkovic is an overview a new concept of the long-range intermolecular interactions for recognition and targeting between drugs and therapeutic targets. This concept was used for the development of the bioinformatics platform for design of targeting peptides for delivering antimicrobial and anticancer nanodrugs to therapeutic targets.

Chapter 10, Targeting drugs to cell and organ using nanoparticles, prepared by Mayuri V. Gurav and Satish B. Bhise gives a general overview about nanoparticulate systems which have great biomedical and pharmacological potentials, being able to convert poorly soluble, poorly absorbed, and labile biologically active substances into promising deliverable drugs. The core of this system can enclose a variety of drugs, enzymes, genes and is characterized by a long circulation time due to the hydrophilic shell which prevents recognition by the reticular-endothelial system. To optimize this drug delivery system, greater understanding of the different mechanisms of biological interactions, and particle engineering, is still required.

Chapter 11, Extracellular vesicles as a recipe for design smart drug delivery systems for cancer therapy, prepared by Carmen V.F. Halder et al. focuses on the recent progress and challenges in the engineering of exosomes as drug delivery vehicles.

Chapter 12, Advancements in exogeneous techniques for stimuli-sensitive delivery systems, prepared by Hemant K.S. Yadav et al. discusses stimuli-responsive nanocarriers that control the bio-distribution and effect of drugs in response to specific stimuli, specifically magnetic field, ultrasound intensity, and electric pulses.

Chapter 13, Ligand-directed tumor targeting with hybrid viral phage nanoparticles, prepared by Bhavin Dalal et al. presents recent progress in the development of hybrid viral phage nanoparticles that represents a novel approach to overcome limitations and demonstrates great flexibility and has potential for a wide array of applications. This utility is achieved by the ability to modify the hybrid genome to target any receptor with delivery of any transgene.

Chapter 14, Delivering miRNA modulators for cancer treatment, prepared by Marilene Estanqueiro et al. aims to describe the role of miRNAs in cancer pathology and their response to therapy, then reports the potential therapeutic role of miRNA modulators in cancer treatment and finally explores the applicability of different nanocarriers in the delivery of these molecules.

Chapter 15, Oral controlled and sustained drug delivery systems: concepts, advances, preclinical, and clinical status, prepared by Gaganjot Kaur et al. presents recent progress on controlled and sustained release dosage forms as well as techniques and technology used in development of modified drug delivery systems. In addition, recently preclinically and clinically analyzed oral-modified drug delivery systems have also been summarized.

Chapter 16, Hydrogels: from simple networks to smart materials—advances and applications, prepared by Shweta Sharma et al. highlights the synthesis, properties, and classification of hydrogels on the basis of response and activities. A special attention has been given to the developing trend of hydrogels from a historical perspective, from simple networks to smart materials. Examples of injectable hydrogels for therapeutic agent delivery have also been detailed. The chapter specifically describes the progress that has been made in the field of hydrogels for biomedical applications in the past 50 years, starting from the pioneering work of Wichterle and Lim in the 1960s.

Chapter 17, Recent advances in understanding of blood–brain tumor barrier (BTB) permeability mechanisms that enable better detection and treatment of brain tumors, prepared by Divya Khaitan et al. reviews recent studies on biology of blood–brain tumor barrier permeability regulation in brain tumors. The contributors also discussed nanomedicines, multimeric molecular imaging strategies, including development of peripheral benzodiazepine receptors (PBR) ligand-PK11195 for better metastatic brain tumor detection. Such agents with flurophores or therapeutics encapsulated in nanospheres are useful in detection of brain tumors, treatment, and monitoring.

Chapter 18, Polymeric nanocarriers for site-specific gene therapy, prepared by Geeta Arya et al., explored the strategies and advances made towards the development of polymeric nanocarriers in order to achieve site-specific gene delivery.

Chapter 19, Cyclodextrin-based polymeric nanosystems, prepared by Nazlı Erdoğar et al. gives an up-to-date overview about nanosystems based on natural and amphiphilic cyclodextrins. In addition, recent studies on cyclodextrin-based nano-sized drug delivery systems were summarized.

Chapter 20, Lipid nanoparticles: in vitro and in vivo approaches in drug delivery and targeting, prepared by Yi Lu et al. gives a brief introduction to the principle preparation techniques of lipid nanoparticles, while focusing on the in vitro and in vivo characterization methods. Furthermore, evaluation models for specific administration routes as well as cellular models are included.

Chapter 1

Treatment strategies in cancer from past to present

Hatice Yildizhan¹, Nezehat Pınar Barkan², Seçil Karahisar Turan², Özerk Demiralp³, Fatma Duygu Özel Demiralp¹, Bengi Uslu¹ and Sibel A. Ōzkan¹,    ¹Ankara University, Ankara, Turkey,    ²Hacettepe University, Ankara, Turkey,    ³HLC Esthetics Surgery Medical Center, Ankara, Turkey

Abstract

For many centuries surgery is the most commonly used cancer management. However curing knew that cancer would come back, with such an invasive method. For this reason, the use of therapeutics were engaged with this need. In the 19th century, regressive effects of hormone therapy on breast and prostate cancers were assessed. The invention of X-rays led to the use of radiation in cancer treatment. After a while, the cancer-causing effect of radiation was recognized and a need for new methodologies arose. For this reason, proton beams were used instead of X-ray radiation and chemical modifiers were developed, both to sensitize tumor cells to radiation and to protect normal cells. Chemical agents have been used since it was noticed during World War II, that they could kill cancer cells by damaging their DNA. Over time, novel chemotherapeutics were designed with minimum side effects and to maximum activity. Synchronous with the improvement of knowledge on cell biology, immunotherapeutic agents were engaged that could mimic normal cell growth process. However, because all these therapeutics have a mortal effect both on healthy and cancer cells, targeted therapies should be preferred. Targeted therapies act by affecting the pathways responsible in cell growth, division, and spread of cancer cells. Following scientific and technological developments, new approaches have arisen, such as gene-therapy, stem cell therapy, immunotherapy, and nanotechnology derived therapies. Combination of chemotherapeutic with nanoparticles is a novel approach that is being used in the treatment of cancer. With the development of imaging technologies and diagnostic methods, many cancer types may be detected in much earlier stages. The more cancer signaling pathways are determined, the better the diagnostics and therapies will be achieved.

Topics in this chapter can be summarized as surgical resection, radiation therapy, chemotherapy, ımmunotherapy, novel and target-specific therapies, and future perspectives. The main aim of this chapter is not to give exact information about survey of the current studies in this area since it is not possible to reach whole information of preclinical or clinical research.

Keywords

The role of diagnosis in treatment; well proven cancer therapies; cancer immunology; targeted therapy; current applications in cancer therapy

Chapter Outline

1.1 The Importance of Diagnosis in Cancer Therapy 1

1.2 Traditional, Well Proven Therapies 3

1.2.1 Surgery 3

1.2.2 Radiotherapy 6

1.2.3 Hormone Therapy 8

1.2.4 Chemotherapy 8

1.3 Targeted Therapies and Immunotherapy 17

1.3.1 Why Immunotherapy Is the Magician in Cancer Therapy? 18

1.3.2 Well Known Immunotherapeutic Agents and Their Advantages/Disadvantages 19

1.4 Smart Role of the Nanotechnology in Cancer Treatment 27

1.4.1 Brief List of Studies for Usage of Nanotechnology in Cancer Treatment 28

1.5 Conclusion 30

References 31

Further Reading 37

1.1 The Importance of Diagnosis in Cancer Therapy

Cancer is known as a kind of genetic disease and can be heritable or directly caused by severe alterations in genomic DNA. Past decades’ research shows us that cancer cannot be generalized for all patients, since there are single nucleotide polymorphism (SNP) factors and heterogenic natures of the tumor. At this point, recent research focused on the idiopathic therapies with the help of high-throughput technologies. This includes sequencing technologies (genomic, transcriptomic, proteomics and metabolomics) and bioinformatic applications. High-throughput applications have vital importance for diagnosis, assessing tumor heterogeneity, classifiying molecular signatures of the patient, and therefore has additional vital importance for the therapy determination and efficacy. Diagnosis is also part of treatment but this chapter would not contain detailed diagnosis strategies.

Even if it is not a good idea to categorize cancer in one way, there are several traditional ways for the classification of cancer. In this section, we cover how physicians decide to use which drugs for the purpose of patient treatment. But to emphasize it can be used again, physicians generally do not assign cancer as one disease; they must consider that each patient has his/her specialized disease. But with the traditional knowledge of cancer, it is identified in several subgroups.

By based on all this knowledge, the physician considers whether the patient has cancerous tissue or not. The next question is how it can be treated in these conditions with the safest drugs. Treatment period is also of vital importance; the patients progress must be followed by clinicians to get a route for future treatment strategies can also be used. At the first stage of treatment, the tumor is categorized as follows:

• cancerous tissue is indolent (or not),

• tumor is aggressive (or not), it has potential to metastasize (or not),

• identification of tumor grade.

The therapy must be planned by considering different factors, such as prime location of tumor, metastatic region, patient properties (age, gender, health status, etc.), stage of tumor or the cell type in the heterogenous tumor tissue. In addition to that, the therapy must be organized by a clinician and a pathologist, radiation oncologist, radiologist and nuclear medicine specialists, all must participate in the therapy of the patient. The success of the treatment must aim for local-regional control of the disease, prevention of future repetition of metastasizes, improving the life quality of the patient, and to improve long-term survival chances for patient. Possible cancer treatments can be summarized as: surgery, chemotherapy, radiation therapy, immunotherapy, and palliative care. These therapies can be applied alone or in combination, depending on the status of the patient. As expected, to decide which therapy would be applied has vital importance, especially for the patient’s life. During the treatment, numerous side effects can be observed. The most threatening side effect is to increase the incidence of secondary cancer formation. There can be other side effects, which will be explained further in this chapter. Gene expression arrays which are specific expression for a specific biological phenomena, often referred to as the key analytical tools to identify the biomarkers. In addition to that, bioinformatic applications are also very important applications to identify genes, whose expression correlates with a specific biological phenotype, drug responsiveness, or prognosis. After deciding the advantage/disadvantage chart of the therapy, the treatment can then be started by the clinicians.

1.2 Traditional, Well Proven Therapies

This chapter mainly focuses on ongoing fastidiously selected studies about cancer therapy. The main outline of this chapter is the timeline, from traditional applications to up-to-date studies. Traditional well proven therapeutic applications are not point out in detail. These studies are explained in short and studies are summarized in Fig. 1.1.

Figure 1.1 Traditional well known therapies widely used in cancer therapy. These therapies can be applied as collection or alone, depending on the cancer type and other factors.

1.2.1 Surgery

1.2.1.1 Surgery to treat cancer

1.2.1.1.1 Brief outline of the surgical application in cancer theraphy

Surgery has been used for many years as the main treatment to remove cancer tissue away from the body. The earlier a lesion is found, the easier it is to remove it. It also plays an important role for diagnosis and staging.

If cancer has spread from the primary site to other tissues of the body, surgery cannot usually cure it. With some types of cancer, surgery can help people to live for a long time and may sometimes lead to a cure.

1.2.1.2 Methods used in conventional surgery

1.2.1.2.1 Diagnostic

The surgeon removes the tumor and some normal tissue close to the lesion to have a clear margin. This procedure is called biopsy.

There are generally two main types of surgical biopsies.

1. Incisional biopsies: removal of a suspicious area for examination;

2. Excisional biopsies. removal of total lesion.

In some instances, like malignant melanoma, a wide margin must be excised with the primary lesion in order to decrease the risk of local recurrence. Until relatively recently, this involved removal of 5 cm of normal-appearing skin around the lesion, as well as the soft tissue down to, and including, muscle fascia (Hussussian, 2010).

At the head and neck area, in addition to standard incisional and excisional biopsies, fine needle aspiration cytology has become established as a minimally invasive technique with high sensitivity and specificity in a variety of lesions (Larson et al., 1984).

After a biopsy, the tissue is sent to pathology laboratory to examine. This gives more information about the cancer. The results helps the doctor plan further treatments, such as chemotherapy or radiotherapy.

1.2.1.2.2 Staging

Staging surgery is performed to find out the tumor size and where the tumor has spread. In the course of this surgery, the surgeon often removes some lymph nodes close to the cancer to find out if it has spread. Treatment is changed by the stage.

1.2.1.2.3 Curative or primary surgery

Curative (primary) surgery is usually preferred if the cancer is located in only one body part. It is quite possible that all of the cancered tissues can be removed in these operations, so surgery is the main treatment strategy in these cases (Chang et al., 2007; Silberman and Silberman, 2009). It may sometimes be combined with other procedures such as chemotherapy or radiotherapy (Kim et al., 2016).

1.2.1.2.4 Surgery to debulk cancer

Debulking surgery is applied to remove some of the cancer tissue. If taking out the entire tumor is not available without damaging the adjacent tissues or organs, a debulking procedure is performed (Piura and Glezerman, 1989).

1.2.1.2.5 Palliative surgery

If there are problems such as disability, pain, or discomfort caused by advanced cancer, palliative surgery can be performed. This surgery is not applied as a cancer treatment, but only used to reduce the cancer-related disorders and improve the cancer patients’ welfare. Sometimes certain cancers are more likely to cause bleeding; in this circumstances palliative surgery is an option to stop bleeding (Zhou et al., 2016).

1.2.1.2.6 Preventive (prophylactic) surgery

Preventive (prophylactic) surgery is performed to remove a suspicious tissue or a lesion that is likely to evolve to become a cancer. This surgery can be applied without any sign of cancer. An organ or a tissue can be removed from the person who has a genetical predisposition and involve in a high risk group for a specific type of cancer. This type of surgery is applied as a precaution to reduce cancer risk.

1.2.1.3 Reconstruction

If you have part of your body removed due to malignant tumor, it might be possible to have reconstructive surgery. The remaining part is recreated by using other body tissues with flap and graft operations or with prosthesis. In the past decade alone, there have been significant improvements in the quality of life of these patients in consequence of the improvements in one-stage reconstruction with musculocutaneous flaps and microvascular free-tissue transfers (Demiralp et al., 2014).

Examples of reconstructive surgery include breast reconstruction after a mastectomy and surgery to restore a person’s appearance and function after surgery to the head and neck area.

1.2.1.4 Types of Surgery

Conventional surgery requires large incisions through the skin, muscle, and other available body layers.

Newer surgical techniques are less invasive than conventional surgery. By using different types of surgical instruments and technology, the processes may cause less pain and reduce the amount of recovery time:

• Laparoscopic surgery: A laparoscope is a flexible, slender tube, which is inserted through an incision to view the body inside. This surgical procedure can be used for abdominal and gynecologic cancers.

• Cryosurgery: Cryosurgery uses liquid nitrogen, CO2, or argon spray to freeze and destroy atypical cells. This technique can be preferred in the treatment of precancerous states, in skin, cervix, and genital areas (McCarty and Kuhn, 1998).

• Laser surgery: This is a type of treatment in which powerful beams of light are used to cut through tissue. This technique can be used to destroy or shrink tumors like basal cell carcinoma, cervical, vaginal, esophageal, and nonsmall cell lung cancer.

• Mohs micrographic surgery: It is a surgical technique for the removal of certain skin cancers by taking special horizontal sections of skin tissue and examining them under a microscope. Mohs micrographic surgery (MMS) is a therapeutic option for the treatment of malignant cutaneous neoplasia. The main indications for micrographic surgery are relapsed, aggressive tumors in anatomic areas with high rates of recurrence or in areas where it is necessary to spare healthy tissue (Chagas and Santana Silva, 2012).

1.2.2 Radiotherapy

Traditional treatment contain three steps: chemotherapy, radiation, and surgery. They can be applied alone or in combination to get better results for the patient health. The use of radiation such as high-energy beams, X-rays, gamma rays, electron beams, or protons, to cure diseases is called radiotherapy. The discovery of X-rays in 1895 led to the usage of radiation in medical applications, such as investigation and diagnosis (X-rays) and treatment (radiotherapy). This therapy is chosen when the location of cancer cells is only in one part of the body, which is also means this therapy can be applied to patients who have nonmetastatic cancer. However, this does not mean radiation cannot be applied to the type of cancer which is spread through the whole body. In these situations, it can be applied to kill cancer cells just in one part of the whole.

Radiotherapy destroys unwanted cancer cells in the treatment site by damaging DNA. The goal of this treatment is to apply the highest doses to cancer cells, while administering the lowest doses to the adjacent healthy cells. Radiation can be given alone or combine with other treatments, such as surgery or chemotherapy. This combined procedure may help primary treatments be more effective.

Radiation applications can be used for cancer treatment, reducing the size of the tumor, controlling the tumor growth, and also for decreasing the pain. Radiotherapy is used before (neoadjuvant) or after (adjuvant) other treatments. The aim is to make the main treatment more effective.

1.2.2.1 Types of Radiotherapy

There are several different types of radiotherapy and ways to give it, which can be used to treat cancer; the common types are three-dimensional (3D) conformal radiotherapy and intensity modulated radiotherapy (IMRT).

• İmage-guided radiotherapy (IGRT)

• 3D conformal radiotherapy

• İntensity-modulated radiotherapy

• volumetric-modulated arc radiotherapy (VMAT)

• stereotactic ablative radiotherapy (SABR)

Three-dimensional conformal radiotherapy the radiation beam to the cancer cells. The main advantage for 3D conformal radiotherapy treatment is to give a high dose of radiotherapy to the cancer cells and reduce the radiotherapy dose for normal healthy cells (Rahman et al., 2016).

IMRT shapes the radiation rays very close to the cancer tissue. It can also vary the strength of the radio spectra so that different areas of the body get different doses of radiation. This may help reduce the amount of radiation given to normal cells around the cancer tissue. VMAT is a type of IMRT. It focuses the radiation on the cancer cells and the main advantages of this radiotherapy treatment is the short treatment time period. It may also help to reduce the risk for surrounding organs, reducing side effects by using low radiation (Halperin et al., 2013).

SABR is a new type of radiotherapy. It is also known as stereotactic body radiotherapy. The main one is Cyberknife, which is a type of SABR. SABR delivers a higher dose of radiotherapy; the applied dose is higher, usually three to five treatments over 1–2 weeks is adequate for different kinds of cancer. It is important that this treatment is carried out very accurately to reduce the risk of damage to healthy tissues from the high dose of radiation. There are also some risks for some of the cancer types, such as in pancreatic cancer treatments and a risk of damaging the stomach or bowel from high doses of radiation, which could cause side effects (Jain et al., 2013).

Another application of the SABR is fitted onto the patient’s head. This system is called Gamma Knife (Cheah et al., 2016). The limitation of the Gamma Knife is mainly in its usability outside the head, although the new generation of Gamma Knife can treat tumors up to C2 vertebra level.

All the systems are used in conjunction with a stereotactic frame fixed onto the skull of the patient. Firstly, 3D coordinates of the tumor should be determined by the stereotactic frame, and the radiation delivered accurately to the target tissue. Small circular collimators fitted at the end of the treatment head as tertiary collimators were used for narrowing the beam of X-rays from a conventional linear accelerator. This system is also requires a stereotactic frame to be fixed onto the patient’s head and used invasive or minimally invasive procedures. These methods of conformal dose delivery to the target tissue reduce radiation dose to the surrounding normal tissues (Sawarkar et al., 2015).

1.2.2.2 Main objective of radiotherapy

Radiation therapy is one of the most common treatments for cancer and mainly aims to damage DNA of the cell by applying energy, photons, or charged particles.

Radiotherapy destroys unwanted cancer cells in the treatment site by damaging the DNA. Radiation can be given alone or combine with other treatments, such as surgery or chemotherapy. This combined procedure may help your primary treatment more effective.

Radiation oncologists may apply radiation to cure or reduce the tumor size, to control the tumor growth or to relieve pain. Radiotherapy is used before (neoadjuvant) or after (adjuvant) other treatments. The aim is to make the main treatment more effective.

1.2.3 Hormone Therapy

Hormones are natural components of all living organisms. In humans, they are synthesized by glands and these natural products are also used in medical treatment for different purposes. As discussed in this book, the main aim of cancer treatment is to get rid of malignant cells from the body. In addition to surgery, radiotherapy, and chemotherapy, hormone therapy is one of the contrary methods of therapy. Like other kinds of treatment, choice of treatment process with hormones or hormone antagonist depends on type, location, and stage of the cancer. Generally used hormone-based drug are listed in Table 1.1. Naturally, hormones are carried through body via the blood stream and they take important roles in controlling the differentiation and growing of cells and organs. Because of their effect on gene expression of the cells, hormone-targeted therapy is widely used in cancer treatment (Sweeney et al., 2015). Corticosteroids and glucocorticoids play an important role in the secondary management of cancer. Hormone therapy is mainly used in the treatment of hormone-source tissue cancers, such as breast, ovarian, prostate, endometrial, and kidney cancer (DeVita et al., 2008). In addition to these cancer types, hormone treatment can also have adverse effects on some other kind of cancer, such as B-cell non-Hodgkin lymphomas (Kuo et al., 2016). Hormone therapy can only be used in hormone sensitive type of cancers and generally aims to stop hormone synthesis and prevention of hormone-positive effect on cancer cells by interfering with their interactions (Brunton et al., 2005).

Table 1.1

1.2.4 Chemotherapy

Chemotherapy can be identified as the use of chemically formulated drugs for the treatment of cancer and other diseases. Separate from surgery and radiation, chemotherapy is used to treat cancer through the whole body, which makes it a valuable tool for treatment of metastatic cancer. In the last decade of the 20th century, researchers discovered how cancer is differentiated from normal cells. After that, cancer treatment verged to the direction of preventing cancerous pathways.

In this part, simple stages which can be used as one-size-fits-all approaches are summarized. The critical stages for drug discovery can be ordered as: characterization of target cancer cells by using high throughput approaches (genomics, proteomics, etc.); getting leading profiles of these cells, which can also be called biomarkers of cancerous process; create candidate chemical formulas; then make different cancer-specific assays (cell proliferation assay, mobility assays, or others that are specific for each cancer type) for each chemical. After making the selection of candidate drugs, apply in vivo assays for drugs and as the last few number of drugs can pass phase studies. As the last of these stages there would be just one chemical which can be tested by the FDA team. Fig. 1.1 summarizes these challenging steps. These steps take nearly 20 years just for one chemotherapy drug.

At the chemotherapy drug discovery stage, computers are one of the valuable tools for researchers to minimize the biological application steps. The use of gene expression arrays and bioinformatics makes it possible to discover information about candidates genes.

1.2.4.1 Main logic of chemotherapeutic application

For both earlier discovered drugs and ongoing studies, one of the most important things in drug studies is to identify the effective target. The selection of a new target for cancer drug discovery is increasingly based on the strength of the evidence that it represents a dependence or vulnerability for a given stratified set of cancer patients, commonly defined by their molecular genetic status. The target can be classified as different subgroups. In this chapter, we classify them based on their role in the cancer process. The drug can aim to activate/deactivate the target and to disturb cancer cell proliferation or metabolic activity of the cell, such as protein synthesis, mobility of the cell; and act directly on DNA to achieve double-strand DNA breaks. These main steps in cancer chemotherapy will be explained in detail through this chapter.

1.2.4.2 Cell cycle inhibitor drugs

Cancer cell pathology is caused by their uncontrolled cell proliferation. Therefore, the first selected drug for treatment is to target cell cycle control. Uncontrolled cell proliferation is one of the hallmark of the cancer and that is why the cell cycle is still one of the most popular topics in cancer research, even if there is a special subgroup, named mitotomics. Since they are not cancer-cell specific agents, cell cycle studies are not come up but they have great potential to get approved from FDA, by usage in cancer patient treatments. To be able to control the cell cycle is double-sharped edge treatment way for now. However, there are also some exceptions. As in the case of some cancer cells lack of double strand breaks checks which is normally functional in the normal cell. In normal cells, the system has been evolved in the direction of destroying the genomic instability, but in cancer cells this is not the case. This control mechanism is known as mitotic catastrophe and it is a kind of antiproliferative mechanism, such as apoptosis, senescence, and necrosis (Galluzzi et al., 2012; Vitale et al., 2011). This term was identified in 2012 and in recent research it is widely used, since destroyed mitotic catastrophe is represents a break point for cancer cell. Therefore, fixing these mechanisms can be a good option for the treatment of cancer. Even if this mechanism has not been fully understood, better understanding of the paths can create new opportunities to overcome the development of tumor tissue. The action mode of these drugs can be summarized as microtubule targeting agents, polymerizes/depolymerizers, mitotic spindle targets, mitotic checkpoint targets, mitotic exit inhibition mechanisms, centrosome disruption, and G2 checkpoint abrogation (Gee, 2015). Mitotic catastrophe is characterized by different studies, but the main idea is based on disappearing of the multinucleated cell form. In this chapter, docetaxel can be given as an example of a mitotic catastrophe action chemotherapeutic agent. Docetaxel has been used in the therapy of human breast cancer cell and small lung cancer cell; it is known as a microtubule stabilizing taxane agent (Crown and O’Leary, 2000). As a general rule, apoptosis has been known as the main mechanism for cancer treatment, but recent results show that we need more complex, multi-factorial solutions. In 2005, Morse and colleagues showed the docetaxel action mode by assessing the viability of cells after treatment, cell cycle check point, and micronucleated cell scoring. The results of this study show that this widely used chemotherapeutic agent action is based on fixing mitotic catastrophe (Morse et al., 2005).

As seen until this point, traditional chemotherapy drugs mainly focused on the genomic changes and checkpoints of the cancer cells to destroy tumor tissue. Yet it is not the best point since genomic change cannot be performed and is restricted, the main focus for chemotherapeutic drugs is focused on cancer cell proteins. For this purpose, researchers make detailed studies to acquire information about the cancer cell proteome, such as The Human Proteome Atlas project (Cancer atlas—The Human Protein Atlas, n.d.). Since there is much more knowledge about proteome than the genome, recent research targets cancer-specific critical proteins, rather than the genome.

1.2.4.3 Antimetabolitic agents

As discussed in the previous section, inhibition of cell proliferation is one of the most focused types of cancer therapy. During replication, cells must make double all components, such as DNA, RNA and other macromolecules. Therefore, a group of cancer drugs aims to interfere cell proliferation by acting directly on DNA replication. These drugs are called antimetabolites and can be explained as a group of chemical molecules that are able to block DNA or RNA synthesis (Henderson and Mandel, 1963). These drugs can act selectively, which means they can kill cancer cells selectively (but not totally), since the normal adult cells are mainly found in quiescent state, which means they are not replicating continuously (Parker, 2009). At this point antimetabolic agents (which are summarized in Table 1.2) can be called minimal toxic agents for the cancer suffer patient and they are part of an effective treatment. Many of the antimetabolic drugs act via the same paths and they are mainly used to treat leukemias, breast cancer, ovarian cancer, and where possible, other types of cancers.

Table 1.2

As discussed previously, antimetabolites are a kind of cytotoxic agent and they are structurally similar to purines, pyrimidines or nucleosides, but are chemically different to their analog. The main logic behind these drugs is based on two ideas. The first is the inhibition of the key enzymes that are essential for DNA synthesis, therefore they inhibit replication of DNA and so impair cell proliferation. The other mode of action of these drugs is the incorporation of them instead of the nucleotide, causing double strand breaks or immature replication termination (Liekens et al., 2009; Vande Voorde et al., 2012). These drugs generally take a role in the S phase of cell proliferation. They can be assessed by the short half-time of the chemical therefore, their activity is dose- and delivery time dependent (Lind, 2011).

Antimetabolites are divided into different subgroups: antifolates (whose action mechanism is summarized in Fig. 1.2), antiprimidines, antipurines, thymidylate synthase inhibitors, and arabinosides.

Figure 1.2 Antifolates (A), thymidylate synthase inhibitors (B), and arabinosides (C) samples and mechanisms. Source: Reprinted with permission from Elsevier (Lind, M.J., 2011. Principles of cytotoxic chemotherapy. Medicine (Baltimore), Oncology: Part 1 of 2, 39, 711–716).

1.2.4.4 Antibiotics like antitumor drugs

There are also other kinds of drugs which are sourced by microorganisms such as Streptomyces spp. These drugs are also known as anthracycline-based drugs. Even if they are isolated microorganisms, their mode of action are dissimilar to antibiotics. Indeed, there is no exact explanation how these drugs impede cancer cells, but they are widely used, especially in the treatment of ovarian and breast cancer, and Kaposi’s sarcoma. The short list of these drugs are summarized in Table 1.3. Mode action of the antitumor drugs can be summarized as: through the intercalation of DNA, they can cause double or single strand DNA breaks, which can start a reaction that can cause oxidative stress in the cancer cell. Doxorubicin-based formula drugs are used by clinician, such as Myocet and Doxil. Doxorubicin, which is the first encapsulated drug categorized as antitumor drug, is used in the treatment of solid tumors, transplantable leukemias, and lymphoma (Slingerland et al., 2012). Since its capsulation formula, this drug is thought to be a selective drug. In addition to its FDA-approved formula, doxorubicin-based drugs are searched for different delivery formulas to improve its selective-binding capacity. For example, antibody embedded liposomes (immunoliposomes) are one of the key topics for cancer treatment. The antibody-coated studies are valuable since, through identification of cancer cell–specific antibodies, these conjugated drugs can selectively bind cancer cells. This conjugation is generally observed at the end site of a PEG polymer (Schnyder and Huwyler, 2005). There is also other research focused on triggered release of drugs, studied to be able to get selective drugs for cancer treatment. The main basis of triggered released mechanisms is that, when the capsules encounter cancer cells (which has specific cancer cell biomarkers), it will open and release drugs (Coyne et al., n.d.). Otherwise, it will not open and the cytotoxic drug cannot getting by the normal cell. The trigger-starting tool can be thermo-sensitive, enzyme-sensitive or acid-triggered (Rivankar, 2014).

Table 1.3

This kind of chemotherapeutic drugs are also tried to deliver in biological particles are also one of the most promising way for the local chemotherapeutic drug treatment. Doxorubicin is one of the drugs which has potential in this kind of therapy, because of its physicochemical parameters (Tonetti et al., 1991).

1.2.4.5 Different types of drug delivery

As discussed earlier, drug delivery has vital importance and it is one of the key topics. If these studies are successful, they will offer lots of advantages, in comparison to well-known dosage form methods. The main advantages of these promising approaches can be summarized as follows:

• better understanding and controlling of drug dosage (Benita and Donbrow, 1982),

• since encapsulation is prepared by enteric-coated dosage, they can be selectively absorbed by the intestine (Felt et al., 1998),

• Beside the mechanic difficulties, it would be easier and less complex to prepare the drug, with respect to compression into tablets or solution (Hombreiro Pérez et al., 2000; Passerini and Craig, 2002),

• even if encapsulation is not enough to protect drugs from the environmental conditions, encapsulation is better than tablet form of drugs. This technique can be supply drugs better protection from unbeneficial conditions such as humidity, oxygen, heat (Carrasquillo et al., 2001).

To summarize the advantages of the capsulated drugs; highly protected barrier for drug against the environmental conditions and the biological process which can lead the degradation of the drug. Since protection from the degradation and triggered opening of the capsule, it is possible to control the time of release and keep the drug in the body for a long time, over months. This technique also can create an easier administration of the drug. Time control can also be performed by encapsulation technology, which will be vitally adverse for some kinds of disease treatment. Microparticulate drug delivery systems are an interesting and promising option when developing an oral controlled release system. As discussed, the biggest disadvantage of the chemical-based treatments is being unable to target the specific tumor cell. These drugs also affect normal cells and the results sometimes can be worse for patient. Hopefully, because of encapsulation technology, it would be possible to treat only unhealthy cell without any loss of the healthy cells (Bioencapsulation_Innovations_2015_01.pdf, n.d.; Carrasquillo et al., 2001; Lind, 2011; Wang and Hu, 2012).

1.2.4.6 Topoisomerase inhibitors

Other widely used drug groups contain topoisomerase inhibitors. Topoisomerase is a kind of enzyme that takes a role in the 3D structure of DNA; they catalyze the breaking and handling of the phosphodiester backbone of the DNA. They are important factors for DNA replication and transcription, since they supply DNA transition by cleavage or re-ligation reactions (Champoux, 2001). In cancer research, they are popular reagents, since it is thought that by blocking of the topoisomerase enzymes, it would be possible to block the ligation step of DNA during replication or transcription steps, would result in single- or double-strand DNA breaks. These breaks would disturb the integrity of genomic structure of cells and therefore apoptosis or necrosis mechanism would be activated. Fig. 1.3 illustrates topoisomerase inhibitor drugs active at different stages of the cell cycle.

Figure 1.3 The DNA topoisomerase II are one of the major target for cancer treatments. The chemical molecules take role at least one step of the topoisomerase activity steps and they are called topoisomerase inhibitor or topoisomerase poisons. The agents are able to stabilize DNA+isomerase enzyme complex are called topoisomerase poisons. But the agents that take role at different stage of the topoisomerase activity are called catalytic inhibitors. In the figure; the ATPase domains of topoisomerase II are shown in light blue, the core domain in dark blue, and the active site which is tyrosine residue are shown in red color. Aclarubicin and suramin drugs act as inhibitors and they impede the binding between DNA and enzyme complex. Merbarone, ICR-187 act as poisons and they stabilize the bound between DNA and topoisomerase. Novobicin is a kind of drug whose mode of action is based on inhibition of ATP binding. Source: Reprinted with permission from Elsevier.

Mammalian cells normally encode seven different topoisomerase enzymes. Four of the topoisomerase encoding genes encode type I enzymes while the other three parts encode type II topoisomerase enzyme. As indicated, topoisomerase enzymes are generally divided into two subgroups, according to which enzyme they act on. Type I toposiomerase is monomeric structured enzyme found in mammalian cells. This enzyme binds double-strand DNA and prevents torsional stress during replication or transcription cleavage of single strand DNA. Topoisomerase I inhibitors are mainly used in the treatment of colorectal and ovarian cancers. Topoisomrase I inhibitors include lamellarin D, irinotecan (CPT-11), topotecan, and camptothecin chemical drugs. The topoisomerase I inhibitor agent camptothecin is known as the most effective anticancer agent around the world (with respect to agents which are used in clinical side). There are different forms of camptothecins: topotecan and irinoyecan, and they are approved by FDA in the treatment of ovarian and lung cancer and colon cancer. There are, however, several limitations of these drugs. These limitations include spontaneous inactivation in the blood; because of rapid reversal of the drug, they need much more time for infusions; and because some types of cancer cells which express more membrane transports respect to other cancer cells can show resistance to these derivatives drugs (Pommier, 2006).

Unlike the type I form, topoisomerase II enzymes are found in multimeric form which are called a and b domains. These enzymes bind to the double strand of the DNA, forming double strand breaks in the DNA to pass through between two strands during replication steps. When the topoisomerase II inhibitors take a role in the cell, they form double strand breaks and cells verged themselves into apoptosis mechanism. The epipodophyllotoxins, which contain etoposide, and teniposide are the most well-known topoisomerase II inhibitors (Lind, 2011).

1.2.4.7 The unexpectedly good results from the proteasome inhibitor drugs in cancer treatment

Through the discovery of the first proteasome inhibitor, bortezomib (velcade, PS-341), proteasome inhibitors have taken a leading role in the treatment of cancer, especially in the treatment of multiple myeloma. Proteasome inhibitors have been investigated nearly for 20 years alongside cancer therapy. As mentioned, bortezomib is known as the first proteasome inhibitor drug, which has a history since 1994 from lab-bench to 2003, and its approval by FDA (Teicher and Tomaszewski, 2015). Now, second and third generations drugs take place in the drug markets. Before detailing information about these drugs and their drug studies, it would be good idea to give summary information about proteasome.

What is the proteasome? And why it is so important in MM treatment?

Proteasome, is a multimeric protease complex and takes a vulnerable role in cellular protein regulation; this regulation has vital importance in the activation/deactivation of important paths (Palombella et al., 1994). Well controlled protein recycling is very important for cell viability and the pKa value of protein must stay in a neutral position. As indicated many times in this chapter, the concentration of proteins must be under strict continuous control, since they are the main players of genomic expression and are therefore lead the work of the cell. Their concentration is taken under control by degradation mechanisms and this degradation process is performed by the ubiquitin-proteasome system (Garland Science—Book: The Biology of Cancer + 2, n.d.). Those proteins which have multiple domains are degraded by proteasomes (Varga et al., 2014). The balanced function of the proteasome is important for cell viability since it takes a role in cell daily life. Due to the half time and evolution rules of the cell, proteins have a half-life and regarding to this system proteins completed their life and function; they are polyubiquitylated. Through the complexity of the ubiquitylation, ubiquitylated proteins are transported to proteasomes and their degradation is performed. As is known, malignant cell activity is much higher than normal cells and they can increase their activity by higher expression of required proteins. A higher number of protein means higher proteasome activity. After realizing the vital importance of the proteasome for malignant cells due to their genetic instability and rapid proliferation, researchers focused on inhibition of proteasome activity and the explained or suspected action mode of proteasome inhibitors are summarized in Fig. 1.4.

Figure 1.4 Mode of action of proteasome inhibitor drugs. The known actions are: increment of pro-apoptotic proteins, downregulation of oncogenic pathways, and cell cycle arrest.

Even in its 20-year short history, proteasome inhibitor drugs yield unexpectedly good results in cancer treatment, therefore they have a premium role in the drug markets and studies are still going on (Crawford et al., 2011).

1.3 Targeted Therapies and Immunotherapy

One of the most promising treatment strategy in cancer treatment. Targeted therapies can also be called a subgroup of immunotherapy and can be defined as the type of therapies that directly and solely affect cancer cells. Unlike traditional therapies, targeted therapies are expected to not to have harmful effects on normal body cells. As discussed earlier, for example, in chemotherapy, drugs block all of the proliferating cells indiscriminately, whether they are malignant or not. It is expected that these therapy agents also target cell cycle, oncogenic paths, metastatic cells like chemotherapeutic drugs, but specifically kill the malignant cells not other normal cells (Joo et al., 2013). The complex nature of the biology of mammalian organisms remind us that we need to continue this research. Normally, immune systems have a high erection capacity and are very effective against foreign cells such as bacteria, viruses, and abnormal cells. This feature of the immune system has been used for medical purposes for a long time. The first targeted therapy was performed in the 1940s (Lee, 2012). The major aim of these targeted therapy studies are based on educating the immune system cells and factors to be able to recognize as foreign and kill cancer cells specifically. The immune system is normally programmed to recognize and eliminate foreign cells, while unperturbed by the body’s own cells, blocking malignant cells in daily life. We also know that cancer cells are the body’s own cells, they are just a differentiated form of the normal tissue cells. Even with these differentiation steps, cancer cells are also native to body and, in most cases, immune system cells are not enough to realize their differentiated form and label them as foreign. Therefore, the main question here is: which changes are required to change immune cells for focusing them to cancer cells?

In this chapter, we will try to explain the functionality of immune cells in cancer treatment, ongoing targeted therapy, immunotherapy studies, and FDA-approved targeted therapy drugs. To be able understand this topic, we have included summary knowledge on how immune cells perform the selective identification steps. Understanding the immune systems mechanism would be helpful to overcome the main obstacles of these therapy studies.

Before detailing this part, we intend to highlight the irreplaceable role of biomarker studies in targeted and personalized medicine therapy. For biomarker discovery, the Cancer Genome Atlas is of vital importance to identifying novel targets and cancer-specific expressions. At the end of this project, it is assumed that it would be possible to be able to overcome present limitations. Characterization of tumor heterogeneity is open to developing new and specific treatment strategies. These methods are also important for cancer therapy and for the cell-based therapy applications in medicine. This topic is too complex to explain in just one part, so we aim to focus just the main points of immunotherapy and targeted therapy.

1.3.1 Why Immunotherapy Is the Magician in Cancer Therapy?

The immune system is the defense mechanism of the organism and protects the organism against different kinds of foreign factors to block disease formation. To be able to succeed in its function, the system must be able to recognize and label the cause of disease factors as foreign. These factors are pathogens, viruses, fungi, etc. The important point of this labeling is based on the ability of the immune system to distinguish self and nonself cells. At this point, immune system cells are also specialized to distinguish unnatural form of the cell from their native stage. Most species’ immune systems are mainly divided into two groups; innate immunity and adaptive immunity. Mode of actions of the two types of immune mechanism are humoral immunity and cell-mediated immunity, respectively (Beck and Habicht, 1996).

As just discussed, the immune system serves two types of attack and they discriminate their targets via the recognition of specific surface proteins which are served by these agents and these surface molecules, which can be called antigens. Via unique protein–protein interactions, immune systems became capable of discriminating self and nonself and label the foreign agents (Berek et al., 1991; Liu et al., 1996; Restifo and Gattinoni, 2013).

The immune system cells contain a high number of different types of cells to be able to manage their complex function. Each group and subgroup of cells have different and interwoven functionality cells. The most common and well known group of the cells are T lymphocytes, macrophages, B-lymphocytes, dendritic cells, and natural killer cells. We do not plan to discuss the function of these cells in detail. Even if they all have different function, they are member of an infrangible group. Macrophages are the first activation part of the immune system and generally act as an eater of the foreign factors, to be able to warn and alert other immune system cells. Dendritic cells are also found as first activated ones and they are the main antigen-presenter cells. B cells are the factory of the immunoglobulins/antibodies. These protein structure molecules are one of the main players of immunotherapy. These molecules label the cell and start a path cascade to provide the eating of the foreign factor by macrophage. T lymphocytes are the headliner of the immune system since they are the killers. They are activated by antigen-presenting cells. Antigen presentation is performed by HLAs for human or MHCs for other organism. As mentioned, for the activation of immune system cells, they must be triggered by the specific antigens. During this antigen presentation, there are a huge number of proteins and they are all potential target for cancer treatment. In this chapter, it is not an option to be able to explain whole immune system but, to sum up the general mechanism: when a mammalian cell is a target, infected or malignant cell expresses antigens (these antigens are the biomarkers of the malignant cells) on their surface. After that, the antigens which are represent via HLA/MHC-1 or antigenic protein, are opsonized by antibody molecules or digested by macrophages. At the end of these interactions, specific T cells come and kill the target cells (Andersen et al., 2006; Castelli et al., 2000; Boon and van der Bruggen, 1996; O’Byrne and Dalgleish, 2001).

During the evolution of cancer, malignant cells use different mechanisms, such as low availability (which is actually a protection mechanism to block auto-immune disease), blocking the expression of the HLA expression (Cho et al., 2000; Drake et al., 2006); now they can escape from the immune system. A low number of tumor-specific immune cells, such as T cell CD4+CD25+FoxP3+ (regulatory T cells), myeloid-derived suppressor cells, tumor-associated macrophages is found and it is one of the application to increase the number of these cells and also it is important to regulate the number of the intratumoral secretion of inhibitory cytokines such as transforming growth factor-β, tumor necrosis factor (TNF-α), and interleukin-10, the expression of negative accessory molecules for T-cell activation within the tumor microenvironment (B7-H1, B7-H4), and various phenotypic alterations that result in immune escape by the downregulation of tumor antigen expression, MHC molecules, and other molecules essential for antigen processing (Chen et al., 2013).

In this chapter, it is commonly mentioned that tradition therapy applications are just such as killing the fly by using hatchet. While killing the malignant cells, patient also loose her/him own cells, too. And also these methods are not totally kill the cancer cells, they always have potential to live up and metastasize over and over. But to direct the body’s own defense mechanism to kill these transformed cells or usage of well targeted strategies can be more promising on getting permanent and less adverse results.

1.3.2 Well Known Immunotherapeutic Agents and Their Advantages/Disadvantages

Cancer treatment is still one of the uncomplete studies from around the world. In spite of the favorable effect of the small chemicals, hormone therapies, radiotherapies, and surgery applications; cancer is still one of the most harmful diseases around the world and the treatment strategies have adverse side effect on patient lifestyle. One of the most promising treatments is targeted therapy and immunotherapy. Recently, monoclonal antibodies are hot topics in this area but in addition to that cell based therapies also have good ratio in patient survival (Kim et al., 2004; Mendelsohn, 1997; Weiner and Link, 2004).

There are several antibody-based drugs in the sector which are approved by FDA. Their structures show some varieties: some of them are found in chimeric form, some of them are murine-sourced, while some are found in humanized form. These drugs mainly target cancer-specific biomarkers. If the cell has these markers, they are opsonized by the monoclonal antibodies and this monoclonal labeling ends up with killing of the cells. Here again we see the importance of the biomarker studies. Rituximab (Rituxan), Tositumomab (Bexxar), Ibritumomab (Zevalin), Gemtuzumab (Myolotarg)*, Alemtuzumab (Campath), Transtuzumab (Herceptin), Cetuximab (Erbitux), Panitumumab (Vectibix), Bevacizumab (Avastin) drugs are those monoclonal antibodies that are approved by FDA to be able to use in different cancer treatments (Okur and Brenner, 2010).

Immunotherapy applications are divided into the three main groups in this chapter: cellular therapy, adoptive cell transfer therapy, and genetic modifications of the immune cells.

1.3.2.1 Cellular immunity

Cellular immunotherapy can be explained as the kind of therapy which is based on usage of cell-based vaccines. The source of these vaccine cells is derived from tumor cells or antigen presenting cells, which are direct to express tumor-specific antigens or the adoptive transfer of the effector T cells. These applications are still under investigation for future treatments. The main