Introduction
Nowadays, immunotherapeutic applications are widely used for treating cancer. Specific parts of immune system of person is used to fight with specific diseases for instance cancer. The war between immune system and cancer can be done in several ways. The first way is to evoke the patient’s immune system to function smarter and more successful in order to attack cancer cells. The second way is to give immune system components to patient. Importantly, immunotherapy has been used to cure some types of cancer in the last few decades and the scientists are now testing the newer types of immune treatments. Lots of treatments are involved in immunotherapy and these treatments work in different ways. Very simply, some treatments are used to enhance the immune system of the body in general and other treatments are used to help the immune system for training in order to fight with cancer cells. In some types of cancers, using immunotherapy is better. It is effective to use immunotherapy by itself in these types of cancers. However for other types of cancers, immunotherapy is more effective when other treatments are used as well.
To understand the immunotherapy, the function of the immune system should be understood. Immune system consists of organs, specific cells, protective substances against infections and several other diseases. The substances that are normally found in the body are followed by the immune system. If a new substance is detected and if the immune system does not recognize it, the immune system will attack to it. The immune response has its ability to annihilate anything including strange substance and germs and cancer cells are the examples. Specifically when the cells are altered and these cells are growing out of control, cancer starts. However, sometimes the immune system can not recognize cancer cells as foreign cells. Thus, the ability of immune system to fight with cancer on its own is limited. Sometimes the immune system can not recognize the cancer cells. Sometimes it recognizes the cancer cells but the response of the immune system might not be enough to annihilate the cancer cells. To overcome thşs problem, researchers have been studying several ways to help immune system to recognize the cancer cells and to make the immune system’s response to be enough for destruction of cancer cells.
Immunotherapeutic applications can be categorized into five groups. The first group is cancer vaccines. The cancer vaccine category relies on the viral and bacterial immunization’s advantageous effects. Patients are immunized with the cancer vaccines in order to make the patients’ immune systems active against the specific tumor antigen. The second group of immunotherapy is targeted monoclonal antibodies. This is one of the antibody based approach. Monoclonal antibodies can be constructed from human or murine antibody components. These components bind to the specific tumor-associated antigens. The third group of immunotherapy is immune checkpoint regulation. The immune checkpoint regulation is an antibody based approach. Immune checkpoint inhibitors and checkpoint blockade immunotherapy are included in this strategy. The fourth group is immunotoxin therapy. Immunotoxin is a protein, it is human-made and the toxin kills the cell when it binds to the sepecific cell and taken into the cell by endocytosis. The fifth and the last category of immunotherapy is adoptive cell therapy. In this strategy, the immune cells of the patient are modified with specific cancer cells and then they are given to the patient again. Natural killer cell immunotherapy and chimeric antigen receptor therapy are the types of adoptive cell therapy. In this review, an overview of these five strategies will be given with focusing on their applications in non-small cell lung cancer.
Cancer Vaccines
The aim of the immunotherapy with cancer vaccines is to create or increase the immune response against tumors by using a whole cell that is biologically active or by using specific protein antigen. The administration of cancer vaccine to the patient is done in order to augment the reactivity of immune system. The cancer vaccines for non-small cell lung cancer can be categorized into two as cell based vaccines and antigen specific vaccines.
Cell Based Vaccines
Belagenpumatucel-L (Lucanix) is a cell based vaccine. Allogenic non-small cell lung cancer cell lines that exposure to radiation and that is transfected with a TGF-β2 antisense gene plasmid are used to produce Lucanix. This strategy is based upon the knowledge that the level of TGF-β is interrelated with the poor prognosis in the non-small cell lung cancer patients and it includes immunosuppressive effects. A phase III clinical trial evaluated the overall survival in patients that are in the period after completing 12 weeks of chemotherapy. Acording to the analysis, the overall survival was improved (20.7-13.4 months) and 40 vs. 10 months was the median survival of patients treated with radiotherapy. (21)
Tergenpumatucel-L is another cell based vaccine composed of three genetically modified allogenic lung tumor cell lines with the α-galactosyltransferase moiety on the cell surfaces. This enzyme creates a congenital immune reaction and this reaction kills the foreign non-small cell lung cancer tumor cells. In a phase II clinical trial, 28 patients that have metastatic non-small cell lung cancer or recurring disease received the vaccine with a median overall survival of 11.3 months. Patients that received chemotherapy after vaccinated with Tergenpumatucel-L had much better overall response to ensuing chemotherapy treatments compared to the patients that were not vaccinated with the prior Tergenpumatucel-L.
Scientists have tested the peptide vaccines in solid tumors for instance a peptide vaccine against the indoleamine 2,3-dioxygenase enzyme. In a phase I trial, a partial response was progressed after one year of treatment with the vaccine and in six patients long lasting stable disease was detected. The median of overall survival was 25.9 months.
Antigen Specific Vaccines
MAGE-A3 is a type of antigen specific vaccine and it was developed against melanoma-associated antigen-A3. MAGE-A3 is a tumor specific antigen and 35-50 % of non-small cell lung cancer have expression of melanoma-associated antigen A3.According to the results from a phase II clinical trial when MAGE-A3 vaccine was utilized in non-small cell lung cancer, the interrelation between the expreesion of a gene and immune related transcripts was observed. And tha trial showed that they are connected with better outcome.
Tecemotide (Stimuvax, L-BLP25) is another antigen specific vaccine. It targets the mucin-1 (MUC-1) glycoprotein. The overexpression of MUC-1 occures in lung cancer and it is connected with poor prognosis. According to the preclinical studies, a strong immune response is provided by this glycoprotein against lung cancer. The results from “Stimulating Targeted Antigenic Response to Non-Small Cell Lung Cancer (NSCLC)” clinical trial shows that no significant difference occured in the overall survival between placebo and tecemotide vaccinated patients.
TG4010 is produced from a modified vaccinia virus. The sequence that encode the MUC-1 and IL-2 is included in the vaccinia virus. According to the results of a Phase IIB trial, an increase occured in 6 months progression free survival in the patients immunized with the TG4010 vaccine in comparison to the patients who received chemotherapy alone.