Immunotherapies: Types, Interaction with Immune System, and New Developments

This report discusses the concept of immunotherapies, various types of therapies and their interaction with the immune system, and new types of immunotherapies that are under development. It covers activation immunotherapies, immune enhancement therapies, suppression immunotherapies, allergen immunotherapy, and helminthic therapies. It also discusses newer types of immunotherapies in development, such as PD-1 pathway targeting therapy, IgV targeted therapy, DC-based vaccination, and tumor-infiltrating lymphocytes (TILs).

Running Head: IMMUNITY RELATED THERPIES 0
IMMUNOTHERAPIES
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Table of Contents
Introduction.................................................................................................................................................2
Concept of Immunotherapy.........................................................................................................................2
Various Types of Therapies and their Interaction with the Immune System...............................................3
Activation Immunotherapies...................................................................................................................3
Immune enhancement therapies...............................................................................................................4
Helminthic therapies...............................................................................................................................6
Newer Types of Immunotherapies in Development....................................................................................7
PD-1 pathway targeting therapy..............................................................................................................7
IgV targeted therapy................................................................................................................................7
DC-based vaccination..............................................................................................................................7
Tumor-infiltrating lymphocytes (TILs)......................................................................................................8
Conclusion...................................................................................................................................................8
References.................................................................................................................................................10

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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

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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).

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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

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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)

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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).
Example it can be used for Peanut allergies in infants
Helminthic therapies
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

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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.

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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

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pathways targeting therapy, IgV targeting therapy, DC-based vaccination, and tumor-infiltrating
lymphocytes

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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.

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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 PD-L1 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.

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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.

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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.