*4.1.1 Monoclonal antibodies*

For the past 20 years, monoclonal antibodies are the most commonly used FDA approved treatment in clinical immunotherapy studies. They are large artificial proteins with high antigen specificity produced by particular B cells. Due to their antigen specificity, their capacity to bind to epitopes on the surface of the tumor cell is high [25]. So, antibodies specific to antigens of cancer cells are produced in ex vivo conditions and transferred to the patient to increase the immune response. Antibodies in these targeted therapies are guided directly to the antigen on the surface of cancer cells. Different signaling functions can be created by the interaction of monoclonal antibodies and receptors on the surface of malignant tumors. Antibodies are used in treatment can be classified as naked, conjugated, radiolabeled, chemically labeled, and bispecific monoclonal antibodies. Naked monoclonal antibodies are most commonly used in cancer immunotherapy and bind directly to the antigen without any radioactive markers or drugs. Conjugated monoclonal antibodies are used to transfer chemotherapeutic drugs or radiolabeled particles to cancer cells. Radiolabeled monoclonal antibodies are created by adding radioactive particles to naked antibodies. Chemically labeled antibodies are monoclonal antibodies with a high chemotherapeutic effect. Radioactive or chemically labeled monoclonal antibodies aim to destroy the target cell with the toxins they contain or the radiation they emit. Bispecific antibodies carry two types of antibodies in their structure and can bind to two different antigens that are receptors for these two antibodies at the same time [18, 26, 27]. The first drug including monoclonal antibodies approved by the FDA was rituximab (Rituxan, Genentech) was used in the clinic at 1997. Today, with developing technology, many new drugs have emerged for the treatment of different types of cancer [25].

#### *4.1.2 Adoptive cell therapy*

It gathered speed with the studies carried out in the 20th century about the discovery of tumor-specific antigens located not on healthy cells but just on the tumor cells. Thus the importance of adoptive T cell transfer has been understood. Adoptive cell therapy is the transfer of natural or genetically modified T cells to patients in *ex vivo* conditions instead of stimulating the immune system. The transferred cells can be autologous or allogeneic targeted to a particular antigen in the host cell. It was pointed out that the stage of an immune response in the host is skipped directly by this step. To create a targeted immune response, autologous cells can recognize tumor antigens, move towards the tumor and exit the circulation. The transfer of T cells to destroy tumor cells is carried out in two ways; the infiltrating (TIL) of tumor specific T cells from existing tumor cells and the use of genetically modified T cells to specifically identify tumor cells. In both methods, the T cell is processed *ex vivo* and then transferred back to the patient [28]. The first successful cellular therapy in history was performed on an advanced melanoma patient with autologous TIL. The specific T cell receptor (TCR) is obtained by genetically modifying T cells. T cells

and tumor-specific antigens are matched with HLA recognition by TCR technology. A minimal cytotoxic effect occurs by this natural pairing. TCRs also have disadvantages such as the low expression on the surface and short lifespan of T cells *in vivo*. Although the first studies ended up with disappointment, today, the other genetically modified T cell is chimeric antigen receptors, CAR. Many studies are conducted around the world on CAR-T technology and it is believed that positive results will be achieved in the near future [29, 30].
