Immunotherapy, Its Types and Mechanisms

Introduction

The concept of immunotherapy elucidates the use of immunogens to boost or suppress immunity to pathogens that infect the body. The mechanism of action is that immunogens elicit an immune response and create an immunological memory that enables the body to mount an effective secondary response when they encounter similar pathogens [1, 2]. The understanding of the mechanism of immunology has led to the use of the administration of exogenous immune cells and molecules, such as antibodies, cytotoxic T-cells, tumour-specific T-cells, natural killer cells, and cytokines, as forms of immunotherapies [1, 2]. The ability of an immunogen to boost or suppress immunity of a body determines its effectiveness in the treatment and prevention of certain diseases.

Following the realisation that whole or parts of pathogens trigger immune responses in the body, immunologists isolate polysaccharides and proteins and then process them to form safe and effective immunogens [3]. Willian Bradley Coley, the father of immunotherapy, analysed 47 case reports in the early 20th century and demonstrated that spontaneous regression of tumours occurs concomitantly with infections [3, 4]. In 1893, Willian Bradley Coley prepared a combined immunogen from heat-killed Streptococcus pyogenes and Serratia marcecsens and used it to provide a wide array of immunity against different forms of cancer [4].

Since no one has established the mechanism of immunotherapy, the technique employed by Willian Bradley Coley remained unexplored. The emergence of modern immunology in the 1950s prompted Helen Coley Nauts, Willian Bradley Coley’s daughter, to explore and elucidate the mechanism of immunotherapy [4]. Eventually, the discovery and elucidation of the mechanism of immunology led to the advent of immunotherapy. Therefore, to expound the understanding of the concept of immunotherapy, this essay examines current and new types of immunotherapies and their mechanisms of action in the immune system.

Types of Immunotherapies and Their Mechanisms

Monoclonal Antibodies

Monoclonal antibodies comprise a type of immunotherapy used in the treatment of various diseases, including cancer and infectious diseases. Since monoclonal antibodies are identical in structure, they bind to epitopes of similar antigens and flag them for destruction by the immune system [5]. Monoclonal antibodies are large proteins produced artificially by B-cells through the process of cloning [6]. The structure of an antibody consists of constant and antibody-binding fragments, which are integral to the destruction of pathogens [5]. Monoclonal antibodies belong to the class G of immunoglobulins and exhibit immunogenic activity when bare or conjugated to chemicals [6]. When bare, monoclonal antibodies work by flagging pathogens, neutralising toxins, or blocking pathogenic signals. In their conjugated forms, monoclonal antibodies aid in the delivery of therapeutic agents to tissues and cells.

The examination of the mechanism of monoclonal antibodies shows that they interact with the immune system at the point of humoral immunity. In the body, plasma cells of the immune system generate antibodies, which are effector molecules that annihilate pathogens [5]. As their mechanism of action, monoclonal antibodies utilise cytotoxicity immune responses that are dependent on complement and antibodies [7]. Rituximab is an example of monoclonal antibodies employed in the treatment of malignancies associated with B-cells. Other examples of monoclonal antibodies used in the treatment of cancer are cetuximab, nivolumab, and panitumumab [6]. Thus, the interaction of monoclonal antibodies with the humoral immunity enhances their efficacy in the treatment of cancer and infectious diseases.

Checkpoint Inhibitors

The immune system has molecular switches that aid the body in regulating immune responses in line with the presence and the nature of immunogens. Through the checkpoints, the immune system can either upregulate immune responses to ensure sufficient clearance of pathogens and downregulate them to prevent the occurrence of autoimmune diseases [8]. For effective immune responses to occur, ligands and receptors on cell surfaces ought to interact and initiate a cascade of signals that lead to upregulation or downregulation of effector molecules in the immune system. In this view, checkpoint inhibitors activate the immune system and ensure that it is switched on to destroy camouflaging cancerous cells [9]. Typically, cancer cells produce numerous and diverse proteins that tend to switch off receptors and ligands mediating T-cell immunity.

Checkpoint inhibitors interact with the immune system at the cell-mediated immunity because they activate T-cells. The use of checkpoint inhibitors applies in the treatment of cancer because tumorigenic cells evade the immune system by switching off checkpoints of T-cell activation and causing downregulation of T-cells in the body [10]. As the mechanism of action, checkpoint inhibitors block receptors responsible for inhibiting the activity of T-cells, resulting in enhanced immune response to tumour cells [6]. In cancer therapy, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed death ligand 1 (PDL-1) are checkpoint proteins determining the activity of T-cells in the immune system [6, 10]. Drugs that inhibit these checkpoint proteins boost the production of T-cells, namely, suppressor, cytotoxic, and helper, which provide comprehensive anti-tumour immunity. Ipilimumab and pembrolizumab are examples of checkpoint inhibitors targeting CTLA-4 and PD-1 receptors in T-cells among patients with melanoma respectively [6]. Atezolizumab is an example of a drug that targets PDL-1 ligands in T-cells in patients with metastatic bladder cancer [10]. Therefore, checkpoint inhibitors comprise a dominant type of immunotherapy employed in the treatment of cancer because they target significant immune cells.

Cytokines

Cytokines constitute of a type of immunotherapy that uses chemical messengers in modulating signal transduction among cells in the body. They are diverse small proteins with sizes ranging from about 5-20 kDa that allows effective communication between cells [11]. Growth factors, chemokines, monokines, interleukins, interferons, tumour necrosis factors, and lymphokines are examples of cytokines that regulate immune responses in the body [6]. Growth factors function by stimulating cells to grow, proliferate, and differentiate into diverse immune cells in response to immunogens. Chemokines are chemical messengers that enable immune cells to migrate to inflamed sites in the body and attack pathogens [12].

Monokines are chemical messengers that attract macrophages to destroy flagged cells. CD4+ helper cells secrete interleukins, which regulate the growth, development, activation, and suppression of natural killer cells, macrophages, and CD8+ cytotoxic T-cells [11]. As signalling proteins, interferons act by triggering and boosting immune responses in host cells. When macrophages encounter cancerous cells, they secrete tumour necrosis factor to induce necrosis [13]. Lymphocytes secrete lymphokines to provoke an immune response that stimulates the production of antibodies. The combined effects of these cytokines enable the body to mount a robust immune response to diverse forms of antigens, leading to their annihilation.

The mechanism of action shows that cytokines are immune modulators that act through autocrine, paracrine, and endocrine signalling pathways. Cytokines interact with the immune system via the cell-mediated immunity because they are chemical messengers produced by monocytes, macrophages, and lymphocytes to regulate immunity [11, 12, 13]. Cytokines regulate cell-mediated immune response by controlling differentiation of leucocytes, migration of effector cells, and suppression of immune responses (6]. The emergence of recombinant DNA technology has made it possible to produce cytokines that treat infectious diseases and cancer. For example, interferon alpha and interleukin-2 are developed cytokines employed in the treatment of cancer [6, 12]. Interferon alpha is useful in the treatment of leukaemia, while interleukin-2 boosts the immune system to destroy malignant cells.

Cancer Vaccines

An increased understanding of the mechanism of tumour-specific immune responses has resulted in the development of immunotherapies that target cancer cells. Cancer vaccines comprise a form of immunotherapy that empowers the body to fight and destroy cancerous cells and antigens [14]. Like the mechanism of vaccination, cancer vaccines interact with the immune system at cell-mediated and humoral immunities because they use purified antigens, whole cancer cells, or antigenic parts of cancer cells to stimulate a strong immune response [14, 15]. Usually, cancer antigens enter into the systemic circulation due to tumour vasculature and treatment interventions, such as surgical procedures, irradiation, and chemotherapy, and stimulate immune response [15, 16]. However, these antigens evade the immune system because of the immunosuppression and low affinity of T-cells to self-antigens [6, 15]. The accumulation of regulatory T cells in tumours suppresses the immune system and prevents the destruction of cancer cells [15]. Thus, cancer vaccines aim to remove regulatory T cells and inhibit their suppressive effects on immunity but at the same time check the occurrence of autoimmunity.

Based on their mechanisms of action, cancer vaccines can be produced from dendritic cells, tumour cells, or antigenic peptides. Antigen-presenting cells (APCs), such as dendritic cells seize, process, and present cancer antigens on their surfaces, making them trigger immune responses [17]. Currently, artificial APCs produce antigens that originate from tumour-infiltrating lymphocytes (TILs). Established antigens, such as PA2024 of prostate cancer and CA-125 of ovarian cancer, expressed on the surface of antigen presenting cells elicit favourable immune responses against cancer cells [18]. Tumour cells or antigenic peptides rely on human leukocyte antigen in identifying tumour antigens and destroying cancerous cells. The process of antigens via major histocompatibility complex (MHC) class II and maturation in the thymus enables regulatory T cells to circumvent the challenge of autoimmunity [19]. Therefore, Oncophage and Provenge are examples of cancer vaccines used in the treatment of kidney cancer and prostate cancer, respectively [20]. Cancer vaccines activate cytotoxic T cells and empower the immune system to recognize and attack cancer cells.

Newer Types of Immunotherapies

Oncolytic Immunotherapy

Oncolytic immunotherapy uses recombinant or genetically modified viruses in eliciting immune responses to destroy cancerous cells. Oncolytic immunotherapy entails the infection of tumour cells with viruses to generate viral antigens. Oncolytic viruses are safe because they infect cancer cells and initiate their destruction through the process of oncolysis without spreading to healthy cells [21]. Since tumour cells evade the immune system by camouflaging as normal cells, oncolytic viruses enable their recognition by producing viral antigens and causing virus-induced cell death [21]. In essence, viral antigens trigger robust immune responses that flag and destroy tumour cells. Non-pathogenic viruses such as myxoma virus and reovirus or genetically modified viruses, for example, measles virus, vaccinia virus, and poliovirus produce viral antigens that elicit strong immune responses [22]. Oncolytic viruses are appropriate in immunotherapy because they provide multiple targets in tumour-immunity cycle and secrete interferons, antigens, and antibodies, which elicit strong anti-tumour responses [23]. The application of genetic engineering in the production of safe viruses offers promising avenues in oncolytic immunotherapy. The use of oncolytic therapy combined with chemotherapy and radiotherapy has proved to be effective in destroying metastatic tumours.

Adoptive Cellular Therapy

Adoptive cellular therapy is a newer type of immunotherapy that involves modification of T-cell receptors to identify pathogenic cells or cancerous cells. This type of therapy interacts with the immune system at the cell-mediated immunity level because it entails the use of T-cells [24]. The application of adoptive cellular therapy encompasses the removing T-cells from the blood, modifying them in the in-vitro environment, culturing to obtain numerous cells, and transferring them into a patient’s body. The modification of T-cells generates tumour-reactive lymphocytes using natural or artificial APCs [17]. Subsequently, the infusion of modified T-cells triggers an immense immune response because their receptors are tumour-specific. The most advanced and approved form of adoptive cellular therapy is chimeric antigen receptor T-cell (CART) therapy, which is useful in the treatment of acute lymphoblastic leukaemia (ALL) [25]. The overall mechanism is that modified T-cells employed in CART therapy recognise tumour-associated antigens and cause the body to mount a potent immune response.

Conclusion

The concept of immunotherapy involves the stimulation of the immune system using immunogens obtained from whole cells, parts of the cells, or purified antigens. The analysis of types of immunotherapies shows that the principle of stimulation or suppression of immune responses is crucial in boosting immunity of the body. Monoclonal antibodies, checkpoint inhibitors, cytokines, and cancer vaccines are main types of immunotherapies utilised in improving the immunity of the body. Oncolytic therapy and adoptive cellular therapy are novel forms of immunotherapy, which offer promising safety and efficacy in the treatment of tumours. Current research activities focus on the development of immunotherapies against human immunodeficiency virus, Zika virus, Ebola virus, malaria, and cancer.

References

  1. Disis ML. Mechanism of action of immunotherapy. Semin Oncol. 2014 Oct;41(5): S3-S13.
  2. Amaral T, Garbe C. Acquired resistance mechanisms to immunotherapy. Ann Transl Med. 2016 Dec;4(24): 1-4
  3. Vernon LF. William Bradley Coley, MD, and the phenomenon of spontaneous regression. Immunotargets Ther. 2018 Apr;7: 29-34.
  4. Decker WK, da Silva RF, Sanabria MH, Angelo LS, Guimaraes F, Burt BM, et al. Cancer immunotherapy: historical perspective of clinical revolution and emerging preclinical animal models. Front Immunol. 2017 Aug;8: 1-13.
  5. Wraith DC. The future of immunology: a 20-year perspective. Front Immunol. 2017 Nov;8: 1-6.
  6. Ventola CL. Cancer immunotherapy, part 1: current strategies and agents. P&T. 2017 Jun;42(6): 375-383.
  7. Stanculeanu DL, Zob D, Lazescu A, Bunghez R, Anghel R. Development of new immunotherapy treatments in different cancer types. J Med Life. 2016 Sept;9(3): 240-248.
  8. Dine J, Gordon RA, Shames Y, Kasler MK, Barton-Burke M. Immune checkpoint inhibitors: an innovation in immunotherapy for the treatment and management of patients with cancer. Asia Pac J Oncol Nurs. 2017 Jun;4(2): 127-135.
  9. Marin-Acevedo JA, Soyano AE, Dholaria B, Knutson KL, Lou Y. Cancer immunotherapy beyond immune checkpoint inhibitors. J Hematol Oncol. 2018 Jan;11(1): 1-25.
  10. Shih K, Arkenau HT, Infante JR. Clinical impact of checkpoint inhibitors as novel cancer therapies. Drugs. 2014 Nov;74(17): 1993-2013.
  11. Dugue GA, Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol. 2014 Oct;5: 1-12.
  12. Ahmed S, Malemud CJ, Koch AE, Athar M, Taub DD. Cytokines and chemokines: disease models, mechanisms, and therapies. Mediators of Inflamm. 2014 July; 2014: 1-5.
  13. Wynn TA. Type 2 cytokines: mechanism and therapeutic strategies. Nat Rev Immunol. 2015 May;15(5): 271-282.
  14. Karlitepe A, Ozalp O, Avci CB. New approaches for cancer immunotherapy. Tumour Biol. 2015 Jun;36(6): 4075-4078.
  15. Grenier JM, Yeung ST, Khanna KM. Combination immunotherapy: taking cancer vaccines to the next level. Front Immunol. 2018 Mar; 9: 1-9.
  16. Tanaka A, Sakaguchi S. Regulatory T cells in cancer immunology. Cell Res. 2017 Jan;27(1): 109-118.
  17. Neal LR, Bailey SR, Wyatt MM, Bowers JS, Majchrzak K, Nelson MH, et al. The basics of artificial antigen presenting cells in T cell-based cancer immunotherapies. J Immunol. Res Ther. 2017 Jun;2(1): 68-79.
  18. Klener P, Otahal, P, Lateckova, L, Klener, P. Immunotherapy approaches in cancer treatment. Curr Pharm Biotechnol. 2015 Nov;16(9): 771-781.
  19. Kasper IR, Apostolidis SA, Sharabi A, Tsokos GC. Empowering regulatory T cells in autoimmunity. Trends Mol Med. 2016 Sep;22(9): 784-797.
  20. Mannan S. Cancer vaccine trials. Immunother. 2016 Dec; 8(11): 1263-1264.
  21. Tsun A, Miao XN, Wang CM, Yu DC. Oncolytic immunotherapy for treatment of cancer. Adv Exp Med Biol. 2016;909: 241-283.
  22. Chiocca EA, Rabkin SD. Oncolytic viruses and their application to cancer immunotherapy. Cancer Immunol Res. 2014 Apr;2(4): 295-300.
  23. Bommareddy P, Shettigar M, Kaufman HL. Integrating oncolytic viruses in combination cancer immunotherapy. Nat Rev Immunol. 2018 Aug;18(1): 498-513.
  24. Smith AJ, Oertle JO, Warren D, Prato D. Chimeric antigen receptor (CAR) T cell therapy for malignant cancers: summary and perspective. J Cell Immunol. 2016 Nov;2(2): 59-68.
  25. Salmikangas P, Kinsella N, Chamberlain P. Chimeric antigen receptor T-cells (CART-Cells) for cancer immunology. Pharm Res. 2018 May;35(8): 1-8.