**3. Historical background of cancer immunotherapy**

It is common knowledge that many cases of regression of tumor growth after high fever attacks or infectious diseases have been reported throughout history from Ancient Egypt to the 18th century. However, the relationship between the immune system and cancer was noticed in the middle of the 18th century with the developing technology. In the mid-18th century, two German doctors, Busch and Fehleisen, independently reported cases of tumor regressions of patients after erysipelas infection (*Streptococcus pyogenes* infection). In the literature, the first systematic immunotherapy study for the treatment of malignant tumors was conducted in 1891 by William B. Coley, a surgical oncologist. Coley injected the heat-inactivated *Streptococcus pyogenes* and *Serratia marcescens* organisms into the patient to stimulate the patient's immune system. After the project that he initiated, Coley has seen a regression in the tumor in more than 1000 sarcoma patients who cannot undergo surgical intervention. In a very short time, humanity evaluated this mixture as a great invention, "Coley Toxins". However, the word "toxin" was an unfortunate choice; the more acceptable name for the treatment was "mixed bacteria vaccine". Although the bacteria had some side effects such as fever and malaise, it is not as toxic as chemotherapy or radiotherapy and does not destroy the immune system [15, 16]. Coley's life-long cancer immunotherapy studies that will spearhead for many scientists have started after this project. In 1900, Paul Ehrlich stated that the first findings of the treatment, which would later be called antibody-mediated passive immunotherapy, had an important place in the treatment of tumors. In 1975, George Köhler and Cesar Milstein developed hybridoma technology for monoclonal antibody production. This was followed by the first successful use of monoclonal adults in human neoplasia in 1982 and the FDA (US Food and Drug Administration) approval of muromonab-CD3 (Orthoclone OKT3) in 1986. In 1997, both the first humanized monoclonal antibody, daclizumab (Zenapax), and the first monoclonal antibody for malignancy, rituximab (Rituxan), were approved by the FDA. This was followed by the FDA approval of gemtuzumab ozogamicin (Mylotarg) in 2000, the first toxin-bound monoclonal antibody, and ibritumomab tiuxetan (Zevalin) in 2002, the first radionuclidebound monoclonal antibody [17].

Another area that cancer immunotherapy has advanced was using the patient's body cells. In the 1960s, the tumor immune surveillance hypothesis was put forward by Burnet. Since 1995, persuasive studies on effective tumorspecific immunity have attracted great interest. In particular, many studies show the ability of dendritic cells to elicit tumor-specific T cell immunity has led to this situation. Following preclinical researches, many studies involving various types of cancer have been conducted in patients. Recent studies have also made the immunosurveillance hypothesis quite popular [18, 19]. Immunotherapy studies have increased their importance in the 21st century with the licensing of clinical studies carried out with developing technology and methods [20]. Immunotherapy was declared as "breakthrough of the year" by Science magazine in 2013 after the clinical success achieved and has become even more prominent. Also, in 2018 James Allison and Tasuku Honjo received the Nobel Prize in Physiology and Medicine for their work based on the use of the immune system to destroy cancer cells. In the past two decades, great strides have been made in cancer immunotherapy. With all these spectacular developments, the number of cancer immunotherapy studies is increasing day by day [21, 22]. There are certain categories in cancer immunotherapy applications. These are the mechanism of innate and acquired immune resistance, internal and external resistance to immunotherapy, self-neutralization of tumor cells and antigen- presenting cells, inhibition of immunity by exosome release mechanisms, the response of tumor cells to therapy. Like all other methods, cancer immunotherapy has several advantages and disadvantages. Higher precision and specificity, long-term survival rate, fewer side effects than traditional treatment methods, removing residual tumor cells and microscopic lesions that remain in the body after treatment and improving the body's immune function are the advantages of immunotherapy. Also, it can control and kill more than one tumor type and it uses the body's immune system to increase immune response. Higher treatment costs, various non-specific toxic side effects after treatment are the disadvantages of immunotherapy. There is a high selectivity for patients in treatment. When the tumor type is "immunosuppressant type" or "immune exclusion type", the effect of immunotherapy treatment is considerably weak. Additionally, in particular, the use of immune checkpoint inhibitors can have adverse consequences leading to autoimmune diseases and even death [23].

## **4. Classification of immunotherapy**

Cancer immunotherapy is generally classified in three ways; passive, active and combination immunotherapy depending on the mechanism of the therapeutic agent and the state of the patient's immune system. Classification of passive and active cancer immunotherapy studies is shown in **Table 1**.

#### **4.1 Passive immunotherapy**

The main purpose of passive immunotherapy is to increase the current antitumor response by using therapeutics that can be produced under laboratory conditions. It is preferred to use the treatment in patients with weak or dysfunctional immune systems. It is designed to attack tumor cells independently by modifying the components of the immune system in the laboratory. Monoclonal antibodies and adoptive cell therapy are frequently used passive immunotherapy methods [4, 20, 24].

*Immune System Modulations in Cancer Treatment: Nanoparticles in Immunotherapy DOI: http://dx.doi.org/10.5772/intechopen.94560*


#### **Table 1.**

*Classification of immunotherapy.*
