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ONPS1050 Guidelines For Postgraduate Report

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Question:

Discuss the concept of immunotherapy. What are the various types of therapies, and how do they interact with the immune system? Give some examples of various types of immunotherapies. What are some of the newer types in development?

 

Answer:

Introduction

Immunotherapy is used for the purpose of treating the disease by two different ways, suppressing or activating the immune system. Immunotherapies are designed to trigger or exhibit an immune response are called activation immunotherapies. On the other hand, the therapies that suppress or reduce the immune response are known as suppression immunotherapies (Gorelik et al., 2015). Immune therapies can be used to treat the infections caused by foreign invaders by killing them and resolve the autoimmunity in which the person’s immune system attacks in its own cells or organs. This report focuses on the concept of immunotherapies in detail, along with the various types of therapies and their interaction with the immune system. The report also describes the new types of immunotherapies that are under the process of development.

Concept of Immunotherapy

The immune system is the collection of specific or particular cells, organs, and the substances that assist in protecting an individual from different diseases and infections. The immune system prepares substances and immune cells that travel throughout the body for its protection from germs causing infections. The immune system tracks all the substances that are normally found in the body (Rosenberg and Restifo, 2015) an alarm is raised by the immune system whenever it comes in contact with a new substance that is not recognizable. This further causes the immune system to attack such substance on a primary basis (Eggermont, Kroemer, and Zitvogel, 2013) For example; substances such as certain proteins are contained by the germs which are not found normally in the human body. In other words, such substances are considered to be "foreign" by the immune system and therefore, it attacks them. The immune response bears the capability of destroying anything that contains a foreign substance such as cancer cells or germs

 Immunotherapy can also be called biological therapy is a type of cancer treatment with the help of which the natural defenses of the body to fight the disease are boosted. The use of substances made by the body or laboratory is made by immunotherapy for the purpose of improving or restoring the immune system function (Rosenberg and Restifo, 2015). Immunotherapy performs its work by way of slowing or stopping the growth of disease cells, stopping the spread of cancer to different parts of the body, assisting the immune system in the destroying of cancer cells. In the recent time, the researchers, pharmaceutical companies and clinicians have shown great interest in immunotherapy especially due to its promise of treating different forms of cancer. Immunomodulatory regimens are popular as it leads to fewer side effects as compared to that of the existing drugs (Salama, Postow, and Salama, 2016)

 

Various Types of Therapies and their Interaction with the Immune System Activation Immunotherapies

Dendritic Cell-Based Pump-Priming- in this type of therapy, the cytotoxic response is activated towards an antigen through the stimulation of dendritic cells. Dendritic cells are a kind of an antigen presenting cell that are collected from the person requiring immunotherapy. Such cells are then either pulsed with tumor lysate or antigen or transfected with a type of viral vector leading them to show the antigen. Upon transfusion into an individual, the antigen is presented by the activated cells to the effector lymphocytes. This, in turn, initiates the cytotoxic response against the tumor cells that expressing the antigen. One of the examples of this approach is cancer vaccine Sipuleucel- T (Ribas, 2015).

T- Cell Adoptive Transfer- autologous is cultivated by adoptive transfer of cell in vitro which is the extracted T cells for the purpose of later transfusion. The creation of genetically engineered T cells is ensured by the way of harvesting and then infecting such T cells with the retrovirus containing T cell receptor gene copy which is customized for recognizing tumor antigens. The receptor is integrated by the virus into the T cells’ genome. The expansion of cells is stimulated and or non- specifically. The cells are then further reinfused and trigger the immune response in order to fight with tumor cells. This approach has been tested on the refractory stage 4 metastatic melanomas and new skin Cancers. Before the infusion lymph depletion of the recipient is needed for the elimination of the regulatory t cells and the endogenous lymphocytes. Total body irradiation may also help to achieve lypho depletion. The transferred cells persisted and multiplied in vivo in the peripheral blood in various people, in some cases representing levels of on nearly 75 percent of all the CD8 plus t cells at six to twelve months after the infusion (Rosenberg, and Restifo, 2015).

 

Immune enhancement therapies 

One of the example this therapy is autologous immune enhancement therapy (AIET) which uses an individual’s own peripheral blood-derived NKC (natural killer cells), the cytotoxic T lymphocytes and various other immune cells are multiplied and in vivo and further leads to reinfusion. This therapy can be used against hepatitis c, HHV6 infections and chronic fatigue symptoms (Manjunath et al., 2012).

IN this therapy NK cells and the t lymphocytes are collected from the patient's blood and expended to 30 folds and activated. These activated cells are then re-infused in the patient's circulation. These cells now act against the malignant cells in an effective way and the provide energy to the immune system. It is estimated that each NK cell us able to kill nearly 27 cancerous cells within its life cycle (Terunuma et al., 2013).

Suppression immunotherapy- This type of immune therapy weakens an impaired immune response in an autoimmune system or decreases the normal response of immune system to stop the rejection of transplanted cells or organs (Stewart, and Smyth, 2011).

Immune-suppressive Drugs- The immunosuppressive medicines help to manage autoimmune disease and organ transplantation. Normally the immune response is depending on the proliferation of the lymphocytes. Drugs like glucocorticoids are more unique or specific to inhibit lymphocyte activation.  Autoimmune disorder and act like immune-suppressor. On the other hand, the inhibitors of the immunophilins particularly target the T lymphocyte activation. The immunosuppressive abs (antibodies) attack steps immune response (Egli, et al., 2009) 

Immune tolerance- In these type therapies, the immune system has been reset in order to stop the body mistakenly targeting its own cells and organs in an autoimmune disease or accepting the foreign tissues in transplantation of organs. Producing immunity decreases or reduces the need for lifelong immunosuppression and related adverse reactions. This method has been examined in transplantation, and diabetes type two (Makkouk, and Weiner, 2015).

Allergen immunotherapy- Immunotherapies that are used to deal with allergies can decrease the sensitivity to different allergens and reducing the severity of these allergies. This therapy is not effective for all people; it is effective in some cases and ineffective in others. However, t proved a chance for the people with allergies to reduce the issues or symptoms caused by the foreign invader. This therapy is recommended for the people who are highly allergic or cannot avoid some type of allergens. It is not used in food and medicinal allergies (Pajno et al., 2018)

This therapy works by reducing the allergen’s tendency to induce the IgE formation.  The main objective of this therapy is to direct body’s immune response away from the humoral immunity and towards the cellular immunity. Further, it induces the body to form less IgE antibodies and high amount of CD4+ T regulatory cells that are usually secret IL-10 and TGF – beta which monitor the response in order to keep it away from IgE formation (Cox et al., 2011).

This therapy includes the use of whipworm and hookworm to treat allergies and immunological disease. This therapy has been tested as the treatment for issues like multiple sclerosis Crohn’s, asthma, and allergies (Erb, 2009). The procedure of modulation of helminths on the immune response is still unknown. Some of the studies hypothesizes that this immune therapy includes re-polarization of Th1 or th2 response and direct function of the dendritic cells.  The helminths down are able to regulate the TH1 (pro-inflammatory) cytokines, IL2-12, IL-gamma, and TNF- alpha (Wammes et al., 2014).

 

Newer Types of Immunotherapies in Development 

PD-1 pathway targeting therapy 

This immunotherapy is the new generation therapy that targets the PD-1 pathway of cells. PD-1 is the protein present on the surface of the cells and act as a regulating factor of immune system response by downregulating the immune system (Topalian, Drake, and Pardoll, 2012). The impaired protein leads to the alteration in programmed cell death and causing abnormal cell proliferation or cell division (Chinai, et al., 2015). The ligands for the B7 family attaches to the receptor of T cell, responsible for the dysfunction of these receptors in cancer and other infectious diseases (Munn, 2018). Some recent ongoing and completed trails that target PD-1 molecules have provided evidence of remarkable success in the cancer patient by generating a durable clinical response. In chronic viral infections, the pre-clinical information reveals that targeting these molecules and their ligands are able to improve the response of the T cells and clearance of virus (Chinai et al., 2015) 

IgV targeted therapy

Zang and Xingxing have developed new maBs (monoclonal antibodies) to the IgV domain as a new cancer immunotherapy that targets B7x members of a B7 family which inhibit the T cell functioning. They have also developed the IgV domain of B7-H3 and underdeveloped immunotherapy that work in B7-H3 molecules (Zang, 2017)

DC-based vaccination

Dendritic cells based vaccination have specific capabilities like an innate and adaptive response of an immune system, revealed that they are the ideal APC to enhance the antitumor attacks (Lee, Lee, and Rhee, 2018). In various clinical trials, it has been found that this therapy is safe and effective in the cancer immunotherapy. In this therapy, the dendritic cells are loaded with tumor antigens and activation of DCs is the crucial step. Using micro bubbles combined with the Ultrasound irradiation to transfer antigen into DC of the mouse model demonstrated significant suppression of the melanoma lung metastases (Tu, et al., 2018)

 

Tumor-infiltrating lymphocytes (TILs)

TIL therapies are the type of adoptive cell transfer immunotherapy that includes growing T cells and expending from the resected metastatic tumor deposits. One of the articles published in Onclive by Subramanian reported that in colorectal cancers type and density of TILs can be a strong factor that may improve the prognostication which is based on the pathological criteria. Further, it was revealed that in triple negative breast cancer increases the stromal TILs correlated with lowering the risk of death and overall mortality (Subramanian, 2018). The fundamental protocol for the therapy named ACT-TIL developed for metastatic melanoma. It was consist of metastasectomy and fragmentation of resected lesion and micro-culture to expand the TIL production in the presence of IL-2 (Boxberg et al., 2018). This therapy is durable and has increased complete response rate than other immunotherapies (Saltz et al, 2018). In the recent clinical trials of this therapy show good results when a patient with chemo-refractory hormone positive breast cancer has been cured with ACT with TIL reactive against the mutant versions of 4 different protein: SLC3A2, CADPS2, CTSB, and KIAA0368 ((Subramanian, 2018).

Conclusion

Immunotherapy is the clinical approach that is used to treat disease like cancer by suppressing or activating the immune system of the body. The immune system works like a self-defense against the diseases or infection caused by the foreign invaders. When the body’s immune system failed to treat a disorder or infection and in case of autoimmunity immunotherapy is used to alter the condition. These therapies are emerging day by day and gaining the interest of various researchers, pharmaceutical companies and clinicians for dealing with various types of the health condition like multiple myelomas and hepatitis. Various companies are now adopting this therapy to develop advanced drugs. There are various immunotherapies such as Activation immunotherapies (it includes dendritic cell-based pump priming and the T cell adoptive transfer), immune enhancement therapies (Autologous immune enhancement therapy, suppression immunotherapy, immune suppressive drugs, immune tolerance, allergen immunotherapy), and helminthic therapies. There are various latest or advanced therapies are in developing or newly developed.  Some of the newer therapies in developing phase include PD-1 pathways targeting therapy, IgV targeting therapy, DC-based vaccination, and tumor-infiltrating lymphocytes.

 

References

Boxberg, M., Steiger, K., Lenze, U., Rechl, H., von Eisenhart-Rothe, R., Wörtler, K., Weichert, W., Langer, R. and Specht, K., 2018. PD-L1 and PD-1 and characterization of tumor-infiltrating lymphocytes in high grade sarcomas of soft tissue–prognostic implications and rationale for immunotherapy. OncoImmunology, 7(3), p.e1389366.

Chinai, J.M., Janakiram, M., Chen, F., Chen, W., Kaplan, M. and Zang, X., 2015. New immunotherapies targeting the PD-1 pathway. Trends in pharmacological sciences, 36(9), pp.587-595.

Cox, L., Nelson, H., Lockey, R., Calabria, C., Chacko, T., Finegold, I., Nelson, M., Weber, R., Bernstein, D.I., Blessing-Moore, J. and Khan, D.A., 2011. Allergen immunotherapy: a practice parameter third update. Journal of Allergy and Clinical Immunology, 127(1), pp.S1-S55.

Eggermont, A.M., Kroemer, G. and Zitvogel, L., 2013. Immunotherapy and the concept of a clinical cure. European journal of cancer, 49(14), pp.2965-2967.

Egli, A., Köhli, S., Dickenmann, M. and Hirsch, H.H., 2009. Inhibition of polyomavirus BK-specific T-Cell responses by immunosuppressive drugs. Transplantation, 88(10), pp.1161-1168.

Erb, K.J., 2009. Can helminths or helminth-derived products be used in humans to prevent or treat allergic diseases?. Trends in Immunology, 30(2), pp.75-82.

Gorelik, M., Narisety, S.D., Guerrerio, A.L., Chichester, K.L., Keet, C.A., Bieneman, A.P., Hamilton, R.G., Wood, R.A., Schroeder, J.T. and Frischmeyer-Guerrerio, P.A., 2015. Suppression of the immunologic response to peanut during immunotherapy is often transient. Journal of Allergy and Clinical Immunology, 135(5), pp.1283-1292.

Lee, C., Lee, M. and Rhee, I., 2018. Distinct features of dendritic cell-based immunotherapy as cancer vaccines. Clinical and experimental vaccine research, 7(1), pp.16-23.

Makkouk, A. and Weiner, G.J., 2015. Cancer immunotherapy and breaking immune tolerance: new approaches to an old challenge. Cancer research, 75(1), pp.5-10.

Manjunath, S.R., Ramanan, G., Dedeepiya, V.D., Terunuma, H., Deng, X., Baskar, S., Senthilkumar, R., Thamaraikannan, P., Srinivasan, T., Preethy, S. and Abraham, S.J., 2012. Autologous immune enhancement therapy in recurrent ovarian cancer with metastases: a case report. Case reports in oncology, 5(1), pp.114-118.

Munn, D.H., 2018. The host protecting the tumor from the host—targeting PDL1 expressed by host cells. Journal of Clinical Investigation, 128(2), pp.570-572.

Pajno, G.B., Fernandez?Rivas, M., Arasi, S., Roberts, G., Akdis, C.A., Alvaro?Lozano, M., Beyer, K., Bindslev?Jensen, C., Burks, W., Ebisawa, M. and Eigenmann, P., 2018. EAACI Guidelines on allergen immunotherapy: IgE?mediated food allergy. Allergy, 73(4), pp.799-815.

Ribas, A., 2015. Releasing the brakes on cancer immunotherapy. New England Journal of Medicine, 373(16), pp.1490-1492.

Rosenberg, S.A. and Restifo, N.P., 2015. Adoptive cell transfer as personalized immunotherapy for human cancer. Science, 348(6230), pp.62-68.

Rosenberg, S.A. and Restifo, N.P., 2015. Adoptive cell transfer as personalized immunotherapy for human cancer. Science, 348(6230), pp.62-68.

Salama, A.K., Postow, M.A. and Salama, J.K., 2016. Irradiation and immunotherapy: from concept to the clinic. Cancer, 122(11), pp.1659-1671.

Saltz, J., Gupta, R., Hou, L., Kurc, T., Singh, P., Nguyen, V., Samaras, D., Shroyer, K.R., Zhao, T., Batiste, R. and Van Arnam, J., 2018. Spatial organization and molecular correlation of tumor-infiltrating lymphocytes using deep learning on pathology images. Cell Reports, 23(1), p.181.

Stewart, T.J. and Smyth, M.J., 2011. Improving cancer immunotherapy by targeting tumor-induced immune suppression. Cancer and Metastasis Reviews, 30(1), pp.125-140.

Subramanian, K. (2018). TILs show growing potential as novel immunotherapy. Available from https://www.onclive.com/publications/oncology-live/2017/vol-19-no-19/tils-show-growing-potential-as-novel-immunotherapy 9 Accessed on 07 October 2018.

Terunuma, H., Deng, X., Nishino, N. and Watanabe, K., 2013. NK cell-based autologous immune enhancement therapy (AIET) for cancer. Journal of stem cells & regenerative medicine, 9(1), p.9.

Topalian, S.L., Drake, C.G. and Pardoll, D.M., 2012. Targeting the PD-1/B7-H1 (PD-L1) pathway to activate anti-tumor immunity. Current opinion in immunology, 24(2), pp.207-212.

Tu, J., Zhang, H., Yu, J., Liufu, C. and Chen, Z., 2018. Ultrasound-mediated microbubble destruction: a new method in cancer immunotherapy. OncoTargets and therapy, 11, p.5763.

Wammes, L.J., Mpairwe, H., Elliott, A.M. and Yazdanbakhsh, M., 2014. Helminth therapy or elimination: epidemiological, immunological, and clinical considerations. The Lancet infectious diseases, 14(11), pp.1150-1162.

Zang, X., 2017. Targeting B7x and B7-H3 as New Immunotherapies for Prostate Cancer. Albert Einstein College of Medicine, Inc Bronx United States.

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