|Year : 2015 | Volume
| Issue : 3 | Page : 175-180
A new alternative cancer treatment modality: Immunotherapy
Vidhya Kalanjiam, GV Murali Gopika Manoharan
Department of Oral Medicine and Radiology, Tamil Nadu Government Dental College and Hospital, Chennai, Tamil Nadu, India
|Date of Web Publication||4-Aug-2015|
Department of Oral Medicine and Radiology, No. 4, Elango Street, J.B. Nagar, R.C.C. (Post), Avadi, Chennai - 600 109, Tamil Nadu
In recent years, progress in understanding the natural immune system has led to research and development of an alternative therapeutic approach called immunotherapy that promises to provide a remarkable breakthrough in the future. Immunotherapy, also called as biological therapy, is a type of cancer treatment that uses the body's immune system to fight cancer. It exploits cells that often have different molecules on their surfaces called as antigens. Immunotherapy is used to provoke the immune system by attacking those antigens as targets. This review of literature is an attempt to summarize the various methods of immunotherapy - Toll like receptor targeting therapy, cell-based therapies through natural killer cells, dendritic cells, T-cells, vaccination (immune activation therapies), cytokine and chemokine therapies.
Keywords: Cytokines, immunotherapy, monoclonal antibodies
|How to cite this article:|
Kalanjiam V, Murali Gopika Manoharan G V. A new alternative cancer treatment modality: Immunotherapy. SRM J Res Dent Sci 2015;6:175-80
|How to cite this URL:|
Kalanjiam V, Murali Gopika Manoharan G V. A new alternative cancer treatment modality: Immunotherapy. SRM J Res Dent Sci [serial online] 2015 [cited 2019 Dec 13];6:175-80. Available from: http://www.srmjrds.in/text.asp?2015/6/3/175/162179
| Introduction|| |
Immunotherapy, also called as biological therapy or biotherapy is the treatment of disease "by inducing, enhancing or suppressing an immune response." Another definition says that it is the "treatment to stimulate or restore the ability of the immune (defense) system to fight infection and disease."
William Coley, MD, a New York surgeon, was the first person to note that getting an infection after surgery helped some cancer patients fights the disease better. In the late 1800s, he began treating cancer patients by infecting them with certain kinds of bacteria, which came to be known as Coley toxin. Immunotherapy uses certain parts of our own immune system to fight against cancer. This can be done in a couple of different ways:
- Stimulating a patient's own immune system to work against cancer cells.
- Giving immune system components such as laboratory processed immune system proteins to a patient to attack cancer cells.
| Immunotherapy: A Review|| |
Oral cancer is a global health problem with increasing prevalence and mortality rates. It is the sixth most common cancer in the world.  Worldwide, the annual incidents exceed 3,000,000 new cases.  In high-risk countries such as Sri Lanka, India, Pakistan and Bangladesh, oral cancer is the most common cancer in men and may contribute up to 25% of all new cases of cancer. The risk of developing oral cancer increases with age and the majority of cases occur in people aged 50 or over. Cancer of the buccal mucosa is more common among Asian populations due to betel quid/tobacco chewing habits. Oral cancer constitutes, the largest group of malignancies in the Indian subcontinent with an incident rate as high as 30-40%. Data from National Cancer Registry program of the Indian Council of Medical Research have confirmed the fact that oral cancer is the most prevalent cancer in males as well as third most common in female population. Squamous cell carcinoma (SCC) is the most common malignant carcinoma of the oral cavity.
To fight against the bleak picture painted by these facts, development of new therapies for oral cancer has become a priority. This forms the motivation for this article. Conventional therapeutic approaches for oral cancer have always been surgery, chemotherapy, and radiotherapy. In recent times, immunotherapy is fast emerging as one of the promising alternative therapeutic modality. This article reviews the principles of immunotherapy and its application.
Better understanding of how the normal immune system works is needed to know the role of immunotherapy in cancer treatment. Our immune system defends the body against foreign substances such as bacteria, a virus or tumor cell. When the body discovers such a substance; several kinds of cells go into action in what is called an immune response. Immune response is the integrated body system of organs, tissue, cell and cell products that differentiates self from nonself and neutralizes potentially pathogenic organisms.
Macrophages are the body's first line of defense and have many roles. They are the first cells to recognize process and present antigen to the T-lymphocytes, and they also produce factors like interleukin (IL)-1 for the differentiation of B and T-lymphocytes. Macrophages also produce substances called cytokines that help to regulate the activity of lymphocytes. Lymphocytes are one of the main types of immune cells. They are divided mainly into B and T-cells. B lymphocytes produce antibodies-proteins (gamma globulins) that recognize foreign substances (antigen) and attach themselves to them. Each B cell is programmed to make one specific antibody. When a B cell comes across its triggering antigen, it gives rise to many large cells known as plasma cells. Each plasma cell is essential for producing antibody. An antibody matches an antigen. Whenever the antibody and antigen interlock, the antibody marks the antigen for destruction. B cells are powerless to penetrate the cell, so the job of attacking these target cells is left to T-lymphocytes. Lymphocytes are cells that are programmed to recognize, respond to and remember antigens. T-cell membrane contains either cluster of differentiation (CD) 4 or CD8 molecules. When CD4 molecules are present, it combines with the antigen presented by major histocompatibility complex (MHC) II proteins which will be in turn presented by the monocytes, macrophages and dendritic cells when stimulated by the antigenic substance the T-cells make lymphokines that signal other cells through cell-mediated immune response. Other T-cells with CD8 molecules combine with the antigen presented by MHC I, are recognized and killed directly. Dendritic cells are known as the most efficient antigen-presenting cell type with the ability to interact with T-cells and initiate an immune response. Dendritic cells are receiving increasing scientific and clinical interest due to their key role in the immune response and potential use with tumor vaccines. There are different types of white blood cells that are part of the immune response. Neutrophils or granulocytes are the most common immune cells in the body. With an infection, their number increases rapidly. 
The immune response is a coordinated effort, the immune cells communicate with each other by secreting a large number of special protein molecules called cytokines. There are many different cytokines. Examples of these are ILs, interferons (IFNs), tumor necrosis factors, prostaglandins and colony-stimulating factors (CSFs). The immune system keeps an eye on all of the substances normally found in the body. Entry of any foreign substance in the body alerts the immune cells that in turn communicate with other cells to make the immune system attack it.
Many people with healthy immune systems develop cancer because of immune systems inability to fight against cancer on its own. Sometimes the immune system doesn't see the cancer cells as foreign because the cells are not different enough from normal cells and sometimes even if it does, the response might not be strong enough to destroy the cancer. To overcome this, researchers have found ways to help the immune system recognize cancer cells and strengthen its response so that it will destroy them. In cancerous condition, our immune response is weakened; like alteration of MHC Class I and tumor antigen expression, dysregulated expression of adhesion/co-stimulatory molecules by tumor and/or antigen-presenting cells, changes in T-cell signal transduction molecules that is, cell death receptor signaling, induction of immune suppressive cytokines vascular endothelial growth factor (VEGF) IL-10, transforming growth factor-beta, prostaglandin E2, induction of immunosuppressive cells, secretion of suppressive factors, immune defects in T-cells, malfunction of dendritic cell system. So immunity is not strong enough to fight against the cancer cells. But immunotherapy actually reverses this balance. It strengthens our immune system to attack cancer cells.
[Figure 1] shows the different types of immunotherapy. Some brief information about each of the types is given below.
Monoclonal antibodies (targeted immunotherapy)
In the presence of antigen, our immune system produces antibodies to fight against the infection. Monoclonal antibodies (MAbs) are made in a laboratory, and then given to patients. They act like antibodies the body naturally produces. It is intravenously injected and acts by targeting the specific (antigen) protein present on the surface of the cancer cells.  When MAbs attach to a cancer cells, they may accomplish the following goals:
- Allow the immune system to destroy the cancer cells by tagging the cancer cells; enabling our immune system to recognize them easily (through antibody-dependent cell-mediated cytotoxicity and complement system).
- Prevent cancer cells from growing rapidly by blocking the signals from the growth receptors on the cancer cells.
- Deliver radiation directly to the cancer cells in low doses sparing the normal cells (radioimmunotherapy).
- It helps to diagnose cancer.
- Carry powerful drugs directly to cancer cells.
Different types of MAbs are naked (these antibodies do not carry anything along with them) and conjugated (these antibodies carry particles along with them for example radiolabeled antibodies or chemolabeled antibodies).
The MAbcetuximab, which binds to the epidermal growth factor receptor, is used for the treatment of patients with recurrent or metastatic head and neck SCC (HNSCC).  SCC is the most common malignant carcinoma of the oral cavity.
Alemtuzumab used to treat chronic lymphocytic leukemia binds to the CD52 antigen found on lymphocytes. Once attached, the antibody attracts immune cells to destroy cancer cells. Ibritumomab used to treat non-Hodgkin's lymphoma binds to CD20 antigen on lymphocytes and delivers radioactivity to the B cells. Brentuximab targets the CD30 antigen on the lymphocytes along with a chemo drug called (mono methyl auristatin E) to treat Hodgkin's lymphoma. Bevacizumab targets a cell protein VEGF that affects tumor blood vessel growth. While the efficacy of cetuximab has been proven through various researches, the other MAbs and their efficacy are still under investigation. 
Cancer vaccine is another type of immunotherapy to help the immune system fight disease. A vaccine exposes the immune system to a protein (antigen), which triggers the immune system to recognize and destroy that protein or related materials. There are two types of cancer vaccines: Prevention vaccines and treatment vaccines. A prevention vaccine is given to a person with no symptoms of cancer to prevent the development of a specific type of cancer or other cancer-related diseases and a treatment vaccine helps the body's immune system fight cancer by training it to recognize and destroy cancer cells. It may prevent cancer from coming back, eliminate any remaining cancer cells after other types of treatment, or stop cancer cell growth. A treatment vaccine is designed to be specific, which means it should target the cancerous cells without affecting healthy cells.  The types of treatment vaccines are:
- Tumor cell vaccines are made from the whole cancer cell obtained from the patient, which are then processed in the laboratory in a more likely way so that it can be attacked by the patient's immune system. Injecting the processed cancer cell into the patient evokes the patient's immune system to attacks these cells and any similar cells in their body. Tumor cell vaccine can be either autologous (tumor cells taken from the same person) or allogeneic (tumor cells from someone other than the patient being treated).
- Antigenic vaccines are similar to the tumor cell vaccine instead of collecting the whole tumor cell only one or two antigens are used for making the vaccine.
- Dendritic cell vaccines: Dendritic cells are the special immune cells in the body that help immune system by antigen processing and presentation in such a way, so that the T-cells can recognize and kill it. Researchers are now making use of the dendritic cell for immunotherapy.  These vaccines are autologous vaccines, made by collecting the tumor antigen, after which it is made to bind with the dendritic precursor. Dendritic cell precursor with the taken in tumor antigen are processed in the laboratory with the cancer antigens and other chemicals to convert them into mature dendritic cell, these cells are then injected back into the patient to evoke immune response particularly the T-cells against cancer cells.
Nonspecific immunotherapies also help the immune system destroy cancer cells. This type of treatment does not have any specific target. Instead, it generally stimulates the immune system. Most nonspecific immunotherapies are given after or at the same time as another cancer treatment, such as chemotherapy or radiation therapy. However, some nonspecific immunotherapies are given as the main cancer treatment. Two common nonspecific immunotherapies are: IFNs and ILs.
Injecting the ILs particularly the IL-2, stimulates the growth of B and T-cells monocytes and natural killer cells and also helps in the release of other chemical mediators. Other ILs such as IL-7 and IL-12 are now being studied to fight against cancer. ,
Interferons - Alpha boosts the ability of certain cells to attack cancer cells. It also slows the growth of cancer cells as well as the blood vessels that tumor need to grow. IFN-alpha is used against Hairy cell leukemia, T-cell lymphoma, non-Hodgkin lymphoma, melanoma and Kaposi sarcoma.
Granulocyte-macrophage-CSF causes the bone marrow to make more of certain types of immune cells and blood cells. For example, sargramostim are used to boost white blood cells. 
It is also found that not only cytokines but various other drugs also have nonspecific immune boosting ability like imiquimod and Bacilli Calmette Guerin via toll-like receptors (TLRs). ,
Recent studies have suggested that the signaling occurs via TLRs which are newly identified receptor molecules recognizing many pathogens are involved in the induction of anti-cancer immunity by stimulating immune competent cells such as macrophages, T-cells, and natural killer cells, and by inducing cytokines.  TLRs are cell surface proteins that are expressed mainly on such as macrophages and dendritic cells. Apart from that it is also present on the normal epithelial cells. On these lining epithelia, researchers identified that the TLRs (pattern-recognition receptors) recognizes the pathogens through specific arrangements of molecules known as pathogen-associated molecular patterns. Thus TLRs signaling activates both innate and adaptive immunity once activated, they initiate signaling pathways leading to the release of cytokines and chemokines, which recruit immune cells inducing further cytokine production, the production of angiogenic mediators and growth factors, all of which may influence tumor progression. ,
It is the treatment especially for cancer in which lymphocytes removed from a patient are cultured with IL-2 (as to generate lymphokine-activated killer cells or induce proliferation of tumor-infiltrating lymphocytes [TILs]) and are returned to the patient's body to mediate tumor regression. This is an attempt to give the patient immune system the ability to overwhelm remaining tumor via T-cells, which can attack and kill cancer. There are many forms of adoptive T-cell therapy being used for cancer treatment; culturing TILs or TILs, isolating and expanding one particular T-cell or culturing with cytokines like IL-2, IL-1 (cytokine-induced killer [CIK] cell therapy, lymphokine-activated killer cell therapy), and even using T-cells that have been engineered to potently recognize and attack tumors (genetically engineered T-cell therapy). ,
This method uses a cancer patient's own T-lymphocytes with anti-tumor activity (TIL), expanded in vitro and reinfused into the patient with cancer. In order to increase the persistence of infused cells in the blood for a longer period, before infusion of the TILs, lymphodepletion of the recipient is required to eliminate regulatory T-cells as well as normal endogenous lymphocytes that compete with the transferred cells for homeostatic cytokines.
Lymphokine activated killer cell therapy (LAK) therapy
LAKs are generated from peripheral blood mononuclear cells (PBMCs) after in vitro culture in the presence of IL-2. It can be from both healthy donors and cancer patients can be used to generate LAK cells. Also, IL-2 can be used to generate LAK cells in cancer patients in vivo. These cells are potent enough to fight against the tumor cells.
CIK cell therapy
This method of adoptive cell therapy is introduced because of the less efficacy of the LAK cells. CIK cells are generated from PBMCs after in vitro activation by multiple factors including IL-2, IL-1, IFN-γ.
Dendritic cell CIK cell (DC-CIK) therapy
Inability of CIK cells to recognize the tumor cell due to lack of antigen-specificities, development of DC-CIK came in to action. It is generated by culturing of CIK cells in the presence of antigen-specific pulsed DC. These cells showed increased efficacy that is, increased lytic activity against cancer cells.
Genetically engineered T-cell therapy
Since in some patients there are insufficient number if TIL cells in the tumor, viral vectors carrying genes coding T-cell receptors specific to tumor antigens or chimeric antigen receptors are genetically introduced into PBMC or TILs. Genetically engineered T-lymphocytes have high avidity and tumor reactivity.
Targeting immune system checkpoints
Recently therapies targeting immune system check points are emerging. Our immune has "checkpoints" - molecules on immune cells that need to be activated (or inactivated) to start an immune response, which will help the cancer to attack the immune systems using this check point for progression. To prevent this new drugs are now emerging to target the check points to always keep the immune system in alert position. One such drug is Ipilimumab. This targets the cytotoxic T-lymphocyte (CTL) associated protein-4 molecules (check points) on the T-lymphocytes. 
Overall survival rate, controlling the symptoms and improvement in the quality of life should be the primary goal of the cancer treatment. Recent researches have indicated that immunotherapy is emerging as an effective treatment modality of oral cancer. Ohtani et al. conducted a study to evaluate the clinical efficacy of adoptive immunotherapy using ex vivo-activated CTL in the treatment of patients with advanced oral and maxillofacial cancers with stage IV disease at diagnosis. Lymphocyte assay revealed that the percentage of CD4+ T-cells decreased, and that of CD8+ T-cells increased among infused lymphocytes compared to that in unstimulated PBMCs, and infused lymphocytes produced a significantly higher level of IFN-γ than PBMCs or tumor cells alone. In a representative patient who refused surgery, tumor regression was confirmed after CTL infusion. Computed tomography clearly indicated a significant reduction in tumor size followed by the complete disappearance of the tumor. Histological examination showed that the cancers in patients receiving CTL therapy were heavily infiltrated with lymphocytes and also found that the other patients who received CTL therapy as adjuvant therapy showed neither recurrent disease nor new disease lesions thus proving that CTL induction using autologous tumor cells as immunogens has potential anticancer efficacy in refractory oral and maxillofacial cancers. 
Results from the study conducted by Ahn et al. proved that the TLRs 7 agonist, Imiquimod inhibited oral SCC (OSCC) through apoptosis and necrosis. After binding to the TLR 7 leads to upregulation of cytokines with tumor growth inhibitory propertities, Imiquimod exerted direct apoptotic activity through activation of apoptosis-related molecules against tumor cells. The study also confirmed the Imiquimod induced necrotic cell death of OSCC cells. Their results proved that Imiquimod is an effective therapy for OSCC. 
A study conducted by Baselga et al. revealed that the combination of cetuximab and platinum chemotherapy is a well-tolerated approach to the treatment of the poor-prognosis patient population with platinum refractory recurrent or metastatic SCCHN. 
Bonner et al. have identified through their research that cetuximab when combined with Radiotherapy increases both the duration of disease control and survival in Stage III or IV nonmetastatic, measurable SCC of the oropharynx, hypopharynx, or larynx than treatment with radiotherapy alone. 
Recently IL as neoadjuvant is being used before surgical resection of OSCC. One such clinical study is by Tímár et al. which proved that OSCC treated with IL injection showed marked altered the composition of tumor-infiltrating mononuclear cells and increased CD4:CD8 ratio. The study reported that IL administered to advanced OSCC as first line treatment before the conventional therapy-induced alterations in infiltrating immune cells. The study observed increased tumor infiltrating CD4 cells, higher CD4:CD8 ratio, marked altered pattern of inflammatory cells predominantly neutrophils and eosinophils and even histopathologically the proportion of collagenous stroma in tumor tissue after treatment increased when compared with controls. 
Masato reported that OK-432, (penicillin-killed and lyophilizes preparation of a low virulence strain of Streptococcus Pyogenes), exhibits a marked therapeutic effect in OSCC patients via TLRs. It elicits the anti-tumor effects by converting the immature dendritic cell with tumor antigen into mature dendritic cell to present the antigen to the lymphocytes for the production of CTL against the cancer cells via TLRs and it also induces the generation of natural killer cells, cytokines and IFNs. 
Okamoto infused activated OK-432 intralymphatically. The study revealed that the injection primed both innate and adaptive immunity. 
Ruan et al. showed that TLR-9 signaling could directly promote cancer cell invasion and also suggest that the use of anti-TLR-9 agents may reduce tumor cell proliferation in OSCC as well as reducing metastatic potential.  Similarly Alison Mary rich have concluded that, there are a variety of TLR pathways that may provide therapeutic targets for the management of OSCC.  All these promising researches lead a researcher Hailing Lu said that the world of cancer immunotherapy is on a predictable course to become a major component of cancer therapy, and TLR agonists will likely play an important role. 
Though many past researches have already proven the efficacy of immunotherapy, many more large clinical studies will be needed in the future to represent immunotherapy, the future direction in the treatment of oral cancer.
| Conclusion|| |
Exploiting the fact that oral cancers are mainly due to immune system dysfunction, immunotherapy is now fast emerging as a novel and effective therapy by stimulating or enhancing the body's own immune system. Based on recent advancements and the promising results, immunotherapy promises to be one of the effective treatment modality for the treatment of oral cancer in the future either as monotherapy or combined with other forms.
| References|| |
Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol 2009;45:309-16.
Mehrotra R, Pandya S, Chaudhary AK, Kumar M, Singh M. Prevalence of oral pre-malignant and malignant lesions at a tertiary level hospital in Allahabad, India. Asian Pac J Cancer Prev 2008;9:263-5.
Kumar V, Abbas AK, Fausto N, Mitchell RN, editor. Robbins Basic Pathology. 8 th
ed. Philadelphia, PA, USA: Elsevier Publications; Saunders Elsevier, 2007. p. 189-99.
Rapidis AD, Wolf GT. Immunotherapy of head and neck cancer: Current and future considerations. J Oncol 2009;2009:346345.
Mehra R, Cohen RB, Burtness BA. The role of cetuximab for the treatment of squamous cell carcinoma of the head and neck. Clin Adv Hematol Oncol 2008;6:742-50.
Palucka K, Banchereau J. Cancer immunotherapy via dendritic cells. Nat Rev Cancer 2012;12:265-77.
Juhua Zhou. Advances and Prospects in Cancer Immunotherapy, New Journal of Science, vol. 2014, Article ID 745808, 13 pages, 2014. doi:10.1155/2014/745808.
Lu H. TLR Agonists for Cancer Immunotherapy: Tipping the Balance between the Immune Stimulatory and Inhibitory Effects. Front Immunol 2014;5:83.
Rich AM, Hussaini HM, Parachuru VP, Seymour GJ. Toll-like receptors and cancer, particularly oral squamous cell carcinoma. Front Immunol 2014;5:464.
Okamoto M, Sato M. Toll like receptor-targeting immunotherapy for oral cancer. J Oral Sci Int 2004;1:1-15.
Ohtani T, Yamada Y, Furuhashi A, Ohmura Y, Nakamura S, Kato H, et al.
Activated cytotoxic T-lymphocyte immunotherapy is effective for advanced oral and maxillofacial cancers. Int J Oncol 2014;45:2051-7.
Ahn MY, Kwon SM, Cheong HH, Park JH, Lee J, Min SK, et al.
Toll-like receptor 7 agonist, imiquimod, inhibits oral squamous carcinoma cells through apoptosis and necrosis. J Oral Pathol Med 2012;41:540-6.
Baselga J, Trigo JM, Bourhis J, Tortochaux J, Cortés-Funes H, Hitt R, et al
. Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 2005;23:5568-77.
Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al.
Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:567-78.
Tímár J, Ladányi A, Forster-Horváth C, Lukits J, Döme B, Remenár E, et al.
Neoadjuvant immunotherapy of oral squamous cell carcinoma modulates intratumoral CD4/CD8 ratio and tumor microenvironment: A multicenter phase II clinical trial. J Clin Oncol 2005;23:3421-32.
West E, Morgan R, Scott K, Merrick A, Lubenko A, Pawson D, et al.
Clinical grade OK432-activated dendritic cells: in vitro
characterization and tracking during intralymphatic delivery. J Immunother 2009;32:66-78.
Ruan M, Zhang Z, Li S, Yan M, Liu S, Yang W, et al.
Activation of Toll-like receptor-9 promotes cellular migration via up-regulating MMP-2 expression in oral squamous cell carcinoma. PLoS One 2014;9:e92748.