Immunotherapy

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Immunotherapy

CAR T-cell Therapy.svg

The diagram above represents the process of chimeric antigen receptor T-cell therapy (CAR), this is a
method of immunotherapy, which is a growing practice in the treatment of cancer. The final result
should be a production of equipped T-cells that can recognize and fight the infected cancer cells in the
body.

T-cells (represented by objects labeled as ’t’) are removed from the patient's blood.

Then in a lab setting the gene that encodes for the specific antigen receptors are incorporated into the T-
cells.

Thus producing the CAR receptors (labeled as c) on the surface of the cells.

The newly modified T-cells are then further harvested and grown in the lab.

After a certain time period, the engineered T-cells are infused back into the patient.

MeSH D007167

OPS-301 code 8-03

[edit on Wikidata]

Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the

immune system. Immunotherapies designed to elicit or amplify an immune response are classified as
activation immunotherapies, while immunotherapies that reduce or suppress are classified as
suppression immunotherapies.

In recent years, immunotherapy has become of great interest to researchers, clinicians and
pharmaceutical companies, particularly in its promise to treat various forms of cancer.[1][2][3]

Immunomodulatory regimens often have fewer side effects than existing drugs, including less potential
for creating resistance when treating microbial disease.[4]

Cell-based immunotherapies are effective for some cancers. Immune effector cells such as lymphocytes,
macrophages, dendritic cells, natural killer cells (NK Cell), cytotoxic T lymphocytes (CTL), etc., work
together to defend the body against cancer by targeting abnormal antigens expressed on the surface of
tumor cells.

Therapies such as granulocyte colony-stimulating factor (G-CSF), interferons, imiquimod and cellular
membrane fractions from bacteria are licensed for medical use. Others including IL-2, IL-7, IL-12, various
chemokines, synthetic cytosine phosphate-guanosine (CpG) oligodeoxynucleotides and glucans are
involved in clinical and preclinical studies.

Contents

1 Immunomodulators

2 Activation immunotherapies

2.1 Cancer

3 Immune enhancement therapy

4 Suppression immunotherapies

4.1 Immunosuppressive drugs

4.2 Immune tolerance

4.3 Allergies

5 Helminthic therapies

6 See also

7 References
8 External links

Immunomodulators

Immunomodulators are the active agents of immunotherapy. They are a diverse array of recombinant,
synthetic, and natural preparations.

Class Example agents

Interleukins IL-2, IL-7, IL-12

Cytokines Interferons, G-CSF

Chemokines CCL3, CCL26, CXCL7

Immunomodulatory imide drugs (IMiDs) thalidomide and its analogues (lenalidomide,

pomalidomide, and apremilast)

Other cytosine phosphate-guanosine, oligodeoxynucleotides, glucans

Activation immunotherapies

Cancer

Main article: Cancer immunotherapy

Cancer treatment used to be focused on killing or removing cancer cells and tumors, with chemotherapy
or surgery or radiation. These treatments can be very effective and in many cases are still used. In 2018
the Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo “for their
discovery of cancer therapy by inhibition of negative immune regulation.” Cancer immunotherapy
attempts to stimulate the immune system to destroy tumors. A variety of strategies are in use or are
undergoing research and testing. Randomized controlled studies in different cancers resulting in
significant increase in survival and disease free period have been reported[2] and its efficacy is enhanced
by 20–30% when cell-based immunotherapy is combined with conventional treatment methods.[2]

One of the oldest forms of cancer immunotherapy is the use of BCG vaccine, which was originally to
vaccinate against tuberculosis and later was found to be useful in the treatment of bladder cancer.[5]
BCG immunotherapy induces both local and systemic immune responses. The mechanisms by which BCG
immunotherapy mediates tumour immunity have been widely studied, but they are still not completely
understood.[6]

The use of monoclonal antibodies in cancer therapy was first introduced in 1997 with rituximab, an anti-
CD20 antibody for treatment of B cell lymphoma.[7] Since then several monoclonal antibodies have been
approved for treatment of various hematological malignancies as well as for solid tumors.[8][9]
The extraction of G-CSF lymphocytes from the blood and expanding in vitro against a tumour antigen
before reinjecting the cells with appropriate stimulatory cytokines. The cells then destroy the tumor cells
that express the antigen.[citation needed]Topical immunotherapy utilizes an immune enhancement
cream (imiquimod) which produces interferon, causing the recipient's killer T cells to destroy warts,[10]
actinic keratoses, basal cell cancer, vaginal intraepithelial neoplasia,[11] squamous cell cancer,[12][13]
cutaneous lymphoma,[14] and superficial malignant melanoma.[15] Injection immunotherapy
("intralesional" or "intratumoral") uses mumps, candida, the HPV vaccine[16][17] or trichophytin antigen
injections to treat warts (HPV induced tumors).

Adoptive cell transfer has been tested on lung [18] and other cancers, with greatest success achieved in
melanoma.

Dendritic cell-based pump-priming or vaccination

Dendritic cells (DC) can be stimulated to activate a cytotoxic response towards an antigen. Dendritic
cells, a type of antigen-presenting cell, are harvested from the person needing the immunotherapy.
These cells are then either pulsed with an antigen or tumor lysate or transfected with a viral vector,
causing them to display the antigen. Upon transfusion into the person, these activated cells present the
antigen to the effector lymphocytes (CD4+ helper T cells, cytotoxic CD8+ T cells and B cells). This initiates
a cytotoxic response against tumor cells expressing the antigen (against which the adaptive response has
now been primed). The cancer vaccine Sipuleucel-T is one example of this approach.[19]

The current approaches for DC-based vaccination are mainly based on antigen loading on in vitro-
generated DCs from monocytes or CD34+ cells, activating them with different TLR ligands, cytokine
combinations, and injecting them back to the patients. The in vivo targeting approaches comprise
administering specific cytokines (e.g., Flt3L, GM-CSF) and targeting the DCs with antibodies to C-type
lectin receptors or agonistic antibodies (e.g., anti-CD40) that are conjugated with antigen of interest.
Future approach may target DC subsets based on their specifically expressed C-type lectin receptors or
chemokine receptors. Another potential approach is the generation of genetically engineered DCs from
induced pluripotent stem cells and use of neoantigen-loaded DCs for inducing better clinical outcome.
[20]

T-cell adoptive transfer

Adoptive cell transfer in vitro cultivates autologous, extracted T cells for later transfusion.[21]

Alternatively, Genetically engineered T cells are created by harvesting T cells and then infecting the T
cells with a retrovirus that contains a copy of a T cell receptor (TCR) gene that is specialised to recognise
tumour antigens. The virus integrates the receptor into the T cells' genome. The cells are expanded non-
specifically and/or stimulated. The cells are then reinfused and produce an immune response against the
tumour cells.[22] The technique has been tested on refractory stage IV metastatic melanomas[21] and
advanced skin cancer.[23][24][25]

Whether T cells are genetically engineered or not, before reinfusion, lymphodepletion of the recipient is
required to eliminate regulatory T cells as well as unmodified, endogenous lymphocytes that compete
with the transferred cells for homeostatic cytokines.[21][26][27][28] Lymphodepletion may be achieved
by myeloablative chemotherapy, to which total body irradiation may be added for greater effect.[29]
Transferred cells multiplied in vivo and persisted in peripheral blood in many people, sometimes
representing levels of 75% of all CD8+ T cells at 6–12 months after infusion.[30] As of 2012, clinical trials
for metastatic melanoma were ongoing at multiple sites.[31] Clinical responses to adoptive transfer of T
cells were observed in patients with metastatic melanoma resistant to multiple immunotherapies.[32]

Checkpoint inhibitors

Main article: Checkpoint inhibitor

Anti-PD-1/PD-L1 and anti-CTLA-4 antibodies are the two types of checkpoint inhibitors currently
available to patients.The approval of anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-
programmed cell death protein 1 (PD-1) antibodies for human use has already resulted in significant
improvements in disease outcomes for various cancers.[33]

Although these molecules were originally discovered as molecules playing a role in T cell activation or
apoptosis, subsequent preclinical research showed their important role in the maintenance of peripheral
immune tolerance.[34]

Immune checkpoint inhibitors are approved to treat some patients with a variety of cancer types,
including melanoma, breast cancer, bladder cancer, cervical cancer, colon cancer, head and neck cancer,
or hodgkin lymphoma.[35]

These therapies have revolutionized cancer immunotherapy as they showed for the first time in many
years of research in metastatic melanoma, which is considered one of the most immunogenic human
cancers, an improvement in overall survival, with an increasing group of patients benefitting long-term
from these treatments.[34]

Immune enhancement therapy

Autologous immune enhancement therapy use a person's own peripheral blood-derived natural killer
cells, cytotoxic T lymphocytes, epithelial cells and other relevant immune cells are expanded in vitro and
then reinfused.[36] The therapy has been tested against Hepatitis C,[37][38][39] Chronic fatigue
syndrome[40][41] and HHV6 infection.[42]

Suppression immunotherapies

Immune suppression dampens an abnormal immune response in autoimmune diseases or reduces a

normal immune response to prevent rejection of transplanted organs or cells.

Immunosuppressive drugs

Immunosuppressive drugs help manage organ transplantation and autoimmune disease. Immune
responses depend on lymphocyte proliferation. Cytostatic drugs are immunosuppressive.
Glucocorticoids are somewhat more specific inhibitors of lymphocyte activation, whereas inhibitors of
immunophilins more specifically target T lymphocyte activation. Immunosuppressive antibodies target
steps in the immune response. Other drugs modulate immune responses and can be used to induce
immune regulation. It has been observed in a preclinical trial that regulation of the immune system by
small immunosuppressive molecules such as Vitamin D and Dexamethasone, administered under a low-
dose regimen and subcutaneously, could be helpful in preventing or treating chronic inflammation.[43]

Immune tolerance

The body naturally does not launch an immune system attack on its own tissues. Models generally
identify CD4+ T-cells at the centre of the autoimmune response. Loss of T-cell tolerance then unleashes
B-cells and other immune effector cells on to the target tissue. The ideal tolerogenic therapy would
target the specific T-cell clone(s) co-ordinating the autoimmune attack.[44]

Immune tolerance therapies seek to reset the immune system so that the body stops mistakenly
attacking its own organs or cells in autoimmune disease or accepts foreign tissue in organ
transplantation.[45] A recent therapeutic approach is the infusion of regulatory immune cells into
transplant recipients. The transfer of regulatory immune cells has the potential to inhibit the activity of
effector.[46][47]

Creating immune tolerance reduces or eliminates the need for lifelong immunosuppression and
attendant side effects. It has been tested on transplantations, rehumatoid arthritis, type 1 diabetes and
other autoimmune disorders.

Approaches to therapeutic tolerance induction[44][48][49]

Modality Details

Non-antigen specific • Monoclonal Antibodies Depleting

Anti-CD52

Anti-CD4

Anti-LFA2

Non-depleting

Anti-CD4

Anti-CD3

Anti-LFA-1

CTLA4-Ig

Anti-CD25

• Haematopoietic stem cell transplantation Non-myeloablative Myeloablative

• Mesenchymal stem cell transplantation

• Regulatory T cell therapy Non-antigen specific Antigen-specific

• Low dose IL-2 to expand regulatory T cells

• Microbiome manipulation

Antigen specific• Peptide therapy Subcutaneous, intradermal, Mucosal (oral, inhaled)

Tolerogenic dendritic cells, liposomes and nanoparticles

• Altered peptide ligands

Allergies

Main article: Allergen immunotherapy

Immunotherapy can also be used to treat allergies. While allergy treatments (such as antihistamines or
corticosteroids) treat allergic symptoms, immunotherapy can reduce sensitivity to allergens, lessening its
severity.

Immunotherapy may produce long-term benefits.[50] Immunotherapy is partly effective in some people
and ineffective in others, but it offers allergy sufferers a chance to reduce or stop their symptoms.

The therapy is indicated for people who are extremely allergic or who cannot avoid specific allergens.

IgE-mediated food allergy is a global health problem that affects millions of persons and affects every
aspect of life for the patient.[51] A promising approach to treat food allergies is the use of oral
immunotherapy (OIT). OIT consists in a gradual exposure to increasing amounts of allergen can lead to
the majority of subjects tolerating doses of food sufficient to prevent reaction on accidental exposure.
[52] Dosages increase over time, as the person becomes desensitized. This technique has been tested on
infants to prevent peanut allergies.[53]

Allergen-specific immunotherapy (ASIT) has become the gold standard for the causative treatment for
IgE‐mediated allergic diseases for a large variety of allergens. One may curiously await the new
developments, which will further enhance our understanding of allergy mechanisms and improve ASIT
for the next generations of patients and physicians.[54]

Helminthic therapies

Whipworm ova (Trichuris suis) and Hookworm (Necator americanus) have been tested for immunological
diseases and allergies. Helminthic therapy has been investigated as a treatment for relapsing remitting
multiple sclerosis[55] Crohn's,[56][57][58] allergies and asthma.[59] The mechanism of how the
helminths modulate the immune response, is unknown. Hypothesized mechanisms include re-
polarisation of the Th1 / Th2 response[60] and modulation of dendritic cell function.[61][62] The
helminths down regulate the pro-inflammatory Th1 cytokines, Interleukin-12 (IL-12), Interferon-Gamma
(IFN-γ) and Tumour Necrosis Factor-Alpha (TNF-ά), while promoting the production of regulatory Th2
cytokines such as IL-10, IL-4, IL-5 and IL-13.[60][63]

Co-evolution with helminths has shaped some of the genes associated with Interleukin expression and
immunological disorders, such Crohn's, ulcerative colitis and celiac disease. Helminth's relationship to
humans as hosts should be classified as mutualistic or symbiotic.[citation needed]

See also

Biological response modifier

Sepsivac

Checkpoint inhibitor

Interleukin-2 immunotherapy

Immunostimulant

Microtransplantation

Photoimmunotherapy in vitro or in vivo[64][65][66][67][68][69][70]

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External links

Langreth R (12 February 2009). "Cancer Miracles". Forbes.

International Society for Biological Therapy of Cancer

Cancer Research Institute Annual International Cancer Immunotherapy Symposia Series

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