Activation Immunotherapy and Suppression Immunotherapy Report

Introduction

Immunotherapy is a technique for treating disease by way of suppressing, inducing, or enhancing the body’s immune response. Two kinds of immunotherapy have been identified based on their functionality; activation immunotherapy, and suppression immunotherapy. Suppression immunotherapies direct, suppress, or reduce existing immune response. On the other hand, activation immunotherapies amplify or elicit an immune system. Immunodulators are the key active constituents of immunotherapies, and since they have fewer side effects in comparison with existing drugs, medical practitioners find them more appealing.

The research paper attempts to explore the design of these two kinds of immunotherapy, their constituents, mode of action and reaction, and associated side effects. Further, the application of immunotherapy to treat specific conditions shall also be explored. In this case, emphasis is on the use of immunotherapy in cancer treatment, as well as the application of immunotherapy in Crohn’s disease.

Definition

American heritage defines immunotherapy as the “Treatment of disease by inducing, enhancing, or suppressing an immune response”¹. In this case, there are two kinds of immunotherapy, based on their functionality; activation immunotherapy, and suppression immunotherapy. The design of activation immunotherapies is such that they amplify an immune system. On the other hand, suppression immunotherapies direct, suppress, or reduce an existing immune response². Immunomodulators are the key constituents of immunotherapies. These are active agents, mainly cytokines, consisting of different collections of natural, synthetic, and recombinant preparations². We already have a number of immunomodulators licensed for patient use.

They include interferons, cellular membrane fractions, imiquimod, and G-CSF (granulocyte colony-stimulating factor). Other immunomodulators are still undergoing extensive preclinical and clinical trials to determine whether they should be used with human subjects, or not. They include various chemokines, glucans, oligodeoxynucleotides, and synthetic CpG (cytosine phosphate-guanosine). One of the reason why immunomodulatory regimen are appealing to the medical practitioners is that compared with the existing drugs, they have fewer side effects³. When immunomodulatory regimen have been used, they are less likely to bring about resistance in microbial diseases.

Activation immunotherapy

Cancer

The initial immunotherapy treatments entailed the administration of cytokines but with time, it was discovered that such cytokines had some adverse effects such as lymphocytes extraction from the blood. Even before the cells had been injected with the correct stimulatory cytokines, the lymphocytes would also swell in vitro, thereby suppressing the tumor antigen. Thereafter, the cells would exclusively aim at and wipe out the tumor expressing antigen³. This concept evolved into fully-fledge clinical trials in the 80s, in the US, on a routine basis.

This concept has been practiced in Japan since 1990. Researchers have enrolled different cancer victims in controlled randomized studies and as a result, they have reported a dramatic rise in the patient’s survival period ³. In addition, research indicates that the technique has an efficacy rate that is between 20 and 30% higher in comparison with conventional treatment techniques that utilizes cell based immunotherapy.

Cancer immunotherapy works by trying to stimulate the subject’s immune system so that it can not only reject tumors, but also destroy them³. In the case of non-invasive bladder cancer, BCG immunotherapy is applied. The attenuated live bacteria are instilled into the bladder by the BCG immunotherapy. The technique has proven effective in avoiding the reappearance of bladder cancer in at least two out of every three cases. In contrast, imiquimod is normally used in topical immunotherapy. Imiquimod is an interferon producing enrichment cream that facilitates the destruction of squamous cell cancer, actinic keratoses, basal cell cancer, warts, superficial malignant melanoma, actinic keratoses, and vaginal intraepithelial neoplasia by a patient’s killer T cells ⁴.

T cell based adoptive immunotherapy

Adoptive cell therapy has proved effective with metastatic melanoma patients. This kind of therapy founded on adoptive immunity. It makes use of autologous tumor-infiltrating lymphocytes. Adoptive cell therapy (ACT) attacks cancer via T cell-based cytotoxic responses. Genetically engineered or naturally reactive T cells are made more effective or expanded “in vitro” via various means. Thereafter, they are transferred ‘adoptively” into a cancer patient. For instance, tumor-infiltrating lymphocytes may be harvested “in vitro” through the use of highly concentrated allo-reactive, anti-CD3 and interleukin-2 feeders. In order to boost the activity of these T cells, IL-2 is administered exogenously, even as they are transferred into the patient. So far, the technique has recorded a 51% objective response rate with the tumors shrinking to barely visible size in some of the patients. A study carried out by Rosenberg et al showed how among patients with metastatic melanomas, the use of ACT may aid in the mediation of anti-tumor responses⁵.

Dendritic cell based immunotherapy

In dendritic based immunotherapy, dendritic cells are used to trigger a cytotoxic reaction towards an antigen. First, it is important to ensure that a patient’s dendritic sells are harvested. Thereafter, a viral vector can either e used to transfect the cells or they may also be pulsed using an antigen. Once activated, the dendritic cells have to be inserted into the patient. The effector lymphocytes (that is the CD8 + T cells, dendritic cells and CD4 + T cells) can then interact with antigens from the activated dendritic cells⁶. This triggers a cytotoxic response in the presence of the antigens. This particular therapy has found use in cancer immunotherapy whereby dendritic cells interact with tumor antigens, prompting the immune system to target them. Usually the tumor antigens are expressed on cancerous cells.

Suppression immunotherapies

Immune tolerance

The goal of immune tolerance therapies is to reorganize the immune system in such a way that it does not attack its own cells or cells. This is especially the case with organ transplant or an autoimmune disease. Through a brief treatment, this eliminates or reduces the needs for a patient to undergo through a process of life-long immunosuppression⁷. The possible attendant side effects are also eliminated or reduced where a transplant has occurred. In case of an autoimmune disorder, such as type 1 diabetes suppression immunotherapies helps to safeguard the body’s own function.

Allergies

Immunotherapy has also found use in the treatment of allergies. There are already a number of other allergy treatments in use, including corticosteroids or antihistamines; however, these only act to alleviate the symptoms. On the other hand, immunotherapy acts to decrease sensitivity to allergens, by way of altering these allergens.

Immunotherapy in the treatment of cancer

For many years, scientists have practiced immunotherapy with the hope of treating various forms of diseases. At the moment, there is a lot of research to examine the use of immunotherapy in cancer treatment. For many years now, researchers have known stimulating tumor cells in a specific way normally has an effect on the immune system of an individual⁷. This has seen scientists discover new ways of applying immunotherapy as either a supplemental or stand-alone cancer treatment. The immune system often ignores cancer cells due to its failure to recognize the disease as an immediate threat. Currently, scientists are working on ways to enable a person’s immune system recognize cancer cells and initiate an attack on them.

As researchers have discovered, this can be accomplished through several techniques. Once of the most basic methods is to ensure that the T helper cells are accorded proper mission objectives. This way, they are better able to not only attacks the cancer, but also ensure that it is fully destroyed. The technique is referred to as active immunotherapy since the kind of treatment that a patient receives interacts directly with his/her body immune system.

Another technique is passive immunotherapy whereby researchers come up with novel ways of “creating” antibodies as well as other types of cells that are able to mimic the human body’s immune system⁶. The design of these synthesized cells is that they initiate a direct attack on cancer cells using radioactive materials and toxins with no compromise on the natural immune system of the body.

A number of immunotherapies have been developed by researchers but a majority of them have not gone beyond the clinical trial stage of development. At the moment, the FDA has only approved a few immunotherapies to facilitate cancer treatment⁸. Monoclonal antibodies are the most popular type of immunotherapy and its use has been approved by the FDA. Cancer vaccines is another type of immunotherapy but a lot of research needs to be undertaken on it before it proves safe and effective for approval by the FDA.

Monoclonal antibodies utilize antibodies synthesized artificially in the laboratory. The role of these antibodies is to aid an individual’s immune system to initiate an attack on tumor cells. Therefore, monoclonal antibody treatment qualifies as a passive immunotherapy. There are two methods used by monoclonal antibody treatment. To start with, we have the naked monoclonal antibodies. This method utilizes antibodies containing either radioactive materials or toxins⁸. Once the antibodies come into contact with the tumor, they bind to the cells of the tumor. This triggers the immune system to initiate an attack on the tumor cells, destroying them³. These antibodies can also function as “deactivation” cells whereby an important function of the tumor is disabled by the naked monoclonal antibodies, in effect killing the tumor cells. Monoclonal antibodies can also be in the form of conjugated monoclonal antibodies. The treatment involves the fusion of the antibodies with either radioactive substances or toxins. Thereafter, the doctor programmes the antibodies to look out for the tumor cells, after which they bind to them. Concurrently, the drug is activated. The tumor cells are destroyed by these effects.

Toxic Targeted Therapy

This treatment involves exploiting an important function of tumor cells and destroying it, making it hard for them to survive. In administering this therapy, a patient is usually injected with a special drug that destroys the cells. The toxic targeted therapy can for example attack the growth factors of a tumor cell⁹. These structures enable the tumor cell to not only grow, but also divide at a faster rate compared with normal cells. Once the targeted therapy gets to where the tumor cells are located, the treatment, often concealed to resemble a growth receptor, is administered into them, resulting in their destruction.

Immunotherapy of Crohn’s disease

Crohn’s disease is a condition whereby the gastrointestinal tract is chronically inflamed. The condition is often characterized by instances of disease remission and relapses. Since the aetiology of this condition remains unknown. Symptomatic medical treatment is adopted with the intention of repressing the inflammatory response. Thus far, active Crohn’s disease is primarily treated using corticosteroids and in 70 % of the patients, the initial symptoms reduces rapidly

Sadly, a majority of the patients either become steroid resistant, steroid-dependent or are affected by side effects. Immunomodulatory drugs such as methotrexate, cyclosporine and azathioprine provide an alternative therapeutic option to treating the condition¹⁰. The low efficacy of these agents coupled with profound short and long term toxicity and inadequate selectivity limits their use. Recent researches into this area have identified specific mediators of this particular immune response. An enhanced activation of mucosal T cell is evident in Crohn’s disease. Immunomodulatory agents are usually designed for particular targets¹¹. They include cytokines and T lymphocytes that have been exploited in clinical and experimental studies on inflammatory bowel disease.

Data collected from a controlled clinical study undertaken by Montfrans, Camoglio and Deventer on the immunotherapy of Crohn’s disease revealed that the normal mucosal immune reaction tends to be suppressed and strictly regulated¹¹.

When an antigen-dependent (CD4+) and ill-controlled T lymphocyte is activated, pro-inflammatory cytokines are produced in large quantities in both inflammatory bowel disease and within the mucosal compartments³. This eases the brutality of inflammatory bowel disease. Through the use of controlled clinical trials, Montfrans and colleagues were able to reveal the potential advantages of anti-TNFa antibodies on patients with Crohn’s diseases who either had enterocutaneous fistulae or were steroid-refractory¹². The efficacy of anti-TNF-a is higher in reducing the activity of Crohn’s disease, in comparison with that of Recombinant IL-10. On the other hand, Th1–response could be inhibited by IL-10, thereby preventing the maintenance of remission or the containment of flare-ups¹³.

For these reason, there is the need for future studies to address questions about the benefits, toxicity, indications for use, time point of administration and long term use of immunotherapy in treating Crohn’s disease.

Conclusion

Immunotherapies function by either suppressing or activating the immune system. Activation immunotherapies amplify or elicit an immune system while suppression immunotherapies direct, suppresses, or reduce an existing immune response. Immonodulators are the active key constituents of immunotherapies and because they have fewer side effects compared with existing drugs, they are more appealing to medical practitioners. Examples of activation immunotherapies include dendritic cell based immunotherapy and T cell based adoptive immunotherapy. On the other hand, suppression immunotherapies consist of allergies and immune tolerance. Immunotherapies have found use in cancer mainly treatment through one of two ways; active immunotherapy, and passive immunotherapy. Toxic targeted therapy could also be used whereby a patient is injected with a special drug that destroys cancer cells. Immunotherapies have also found application in the treatment of Crohn’s disease- a chronic inflammation of the gastrointestinal tract. Most of the patients with Crohn’s disease either become resistant or dependent on corticosteroids administered to treat the condition. Anti-TNF-a are used as immunotherapies and because of their high efficacy, they reduce the activity of Crohn’s disease with fewer side effects.

Bibliography

American Heritage. The American Heritage Medical Dictionary. Boston: Houghton Mifflin Harcourt;2008.

Webster’s New World Dictionary. Webster’s two new college dictionary. Boston: Houghton Mifflin Harcourt ;2005

Masihi K N. Fighting infection using immunomodulatory agents. Informaheatlhcare.

Kono K, Takahashi A, Ichihara F, Amemiya H, Iizuka H, Fujii H, Sekikawa T, Matsumoto, Y, Prognostic significance of adoptive immunotherapy with tumor-associated lymphocytes in patients with advanced gastric cancer: a randomized trial. Clin Cancer Res, 2002;8(6): 1767–71.

Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: A clinical path to effective cancer immunotherapy. Nat Rev Cancer, 2008; 8(4): 299–308.

Carlos AG, Carlos ML, Santos MA, Pedro E, Santos S, Lopse-Pregal A. Immunotherapy and mast cell activation. Allerg Immunol 1998; 30(8):257-8.

Stewart, TJ, Smyth, MJ. Improving cancer immunotherapy by targeting tumor-induced immune suppression. Cancer Metastasis Rev, 2011 Mar;30(1):125-40.

Yang Q, Hokland ME, Bryant JL, Zhang Y, Nannmark U, Watkins SC, Goldfarb RH, Herberman RB, Basse PH. Tumor-localization by adoptively transferred interleukin-2-activated NK cells, leading to destruction of well-established lung metastases. Int J Cancer, 2003 July; 105(4):701-4. Web.

Hunder N, Wallen H, Cao J, Hendricks D, Reilly J, Rodmyre R, Jungbluth A, Gnjatic S, Thompson J, Yee C. Treatment of Metastatic Melanoma with Autologous CD4+ T Cells against NY-ESO-1″. N. Engl. J. Med, 2008; 358 (25): 2698–2703

Laclotte C, Oussalah A, Rey P, et al. Helminths and inflammatory bowel diseases. Gastroenterol. Clin. Biol, December 2008; 32 (12): 1064–74.

Munkholm P, Langholz E, Davidsen M, Binder V. Frequency of glucocorticoid resistance and dependency in Crohn’s disease. Gut, 1994; 35:360–2.

Croese J, O’neil J, Masson J, et al. A proof of concept study establishing Necator americanus in Crohn’s patients and reservoir donors. Gut, January 2006; 55 (1): 136–7.

Prescott, S. The allergy epidemic: a mystery of modern life. Crawley, W.A.: UWA Publishing;2011.