Immune Modulation Therapy

Immuno modulation 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.

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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]

Immunomodulatory regimens often have fewer side effects than existing drugs, including less potential for creating resistance when treating microbial disease.[3]

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.

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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

Cancer Activation immunotherapies

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.[4]

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.

Topical immunotherapy utilizes an immune enhancement cream (imiquimod) which produces interferon, causing the recipient’s killer T cells to destroy warts,[5] actinic keratoses, basal cell cancer, vaginal intraepithelial neoplasia,[6] squamous cell cancer,[7][8] cutaneous lymphoma,[9] and superficial malignant melanoma.[10]

Injection immunotherapy (“intralesional” or “intratumoral”) uses mumps, candida, the HPV vaccine[11][12] or trichophytin antigen injections to treat warts (HPV induced tumors).

Adoptive cell transfer has been tested on lung [13] and other cancers, with greatest success achieved in melanoma.

Dendritic cell-based pump-priming

Dendritic cells 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.[14]

T-cell adoptive transfer

Adoptive cell transfer in vitro cultivates autologous, extracted T cells for later transfusion.[15] 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.[16] The technique has been tested on refractory stage IV metastatic melanomas[15] and advanced skin cancer[17][18][19]

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.[15][20][21][22] Lymphodepletion can be achieved by total body irradiation.[23] 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.[24] As of 2012, clinical trials for metastatic melanoma were ongoing at multiple sites.[25] Clinical responses to adoptive transfer of T cells were observed in patients with metastatic melanoma resistant to multiple immunotherapies.[26]

Immune enhancement therapy

Autologous immune enhancement therapy use a person’s own peripheral blood-derived natural killer cells, cytotoxic T lymphocytes and other relevant immune cells are expanded in vitro and then reinfused.[27] The therapy has been tested against Hepatitis C,[28][29][30] Chronic fatigue syndrome[31][32] and HHV6 infection.[33]

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.

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.

1T-cells (represented by objects labeled as ’t’) are removed from the patient’s blood.

2Then in a lab setting the gene that encodes for the specific antigen receptors are incorporated into the T-cells.

3Thus producing the CAR receptors (labeled as c) on the surface of the cells.

4The newly modified T-cells are then further harvested and grown in the lab.

5After a certain time period, the engineered T-cells are infused back into the patient.

References

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In this Page, first explanation what is the immune system (Section A) and follow up on different modalities to regulate it (Section B)

 

The human immune system is a complex and powerful defense

mechanism.

The primary function of the immune system is to defend the body from pathogens, which are disease-causing organisms such as viruses and bacteria. Tissues, cells, and proteins in the immune system work together to achieve this function.

How Immunity Works

 

Screen Shot 2017-11-16 at 10.23.22 PM

 

To fight infections, the immune system must be able to identify pathogens. Pathogens have molecules called antigens on their surface. Antigens provide a unique signature for the pathogen that enables immune system cells to recognize different pathogens and distinguish pathogens from the body’s own cells and tissues. When a pathogen gets into the body, the immune system reacts in 2 ways.

•The innate immune response is a rapid reaction. Innate immune cells recognize certain molecules found on many pathogens. These cells also react to signaling molecules released by the body in response to infection. Through these actions, innate immune cells quickly begin fighting an infection. This response results in inflammation. The cells involved in this reaction can kill pathogens and can also help activate cells involved in adaptive immunity.

•The adaptive immune response is slower than the innate response but is better able to target specific pathogens. There are 2 main cell types involved in this response: T cells and B cells. Some T cells kill pathogens and infected cells. Other T cells help control the adaptive immune response. The main function of B cells is to make antibodies against specific antigens. Antibodies, also known as immunoglobulins, are proteins that attach themselves to pathogens. This signals immune cells to destroy the pathogen.

It takes time for T and B cells to respond to the new antigens when a pathogen causes an infection. Once exposed to the pathogen, these cells develop a memory for the pathogen so that they are ready for the next infection. As part of the adaptive immune response, some T and B cells change into memory cells. Memory cells mostly stay in the lymph nodes and the spleen and “remember” particular antigens. If a person becomes infected with the same pathogen again, these cells are able to quickly and vigorously begin fighting the infection.

Disorders of the Immune System

Immunodeficiency results when the body does not have enough of certain kinds of immune cells or the cells do not function properly. When that happens, a person is more vulnerable to infections. Immunodeficiency can be primary (genetic) or secondary (due to other conditions). Secondary immunodeficiency can be caused by

•Medications: steroids, chemotherapy drugs, other drugs that suppress the immune system

•Medical conditions: diabetes, kidney disease, liver disease

•Infection: HIV, which can lead to AIDS

•Other conditions: malnutrition, surgery, trauma, extremes of age (newborn and elderly)

Autoimmune disease occurs when the immune system overreacts against the body’s own cells and tissues. Lupus, multiple sclerosis, rheumatoid arthritis, and celiac disease are all types of autoimmune disease.

 

Section B

Holistic Regulation of the Immune System

 

 

Sources:

Chinen J, Shearer WT. Secondary immunodeficiencies, including HIV infection. J Allergy Clin Immunol. 2010;125(2)(suppl 2):S195-S203.

Haynes BF, Soderberg KA, Fauci AS. Introduction to the immune system. In: Longo DL, Fauci AS, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 18th ed. New York, NY: McGraw-Hill; 2012:2650-2685.

 

•  Autologous Dendritic Cell Cancer Vaccine. Dendritic cells are key regulators of immune responses and orchestrate innate and adaptive immunities. They are the most potent antigen-presenting cells and have the potential to invoke an anti-tumor immune response. The vaccine is cultured from the patient’s own peripheral monocytes in the presence of a recombinant growth factor, special cytokines and the patient’s own tumor antigens. These items are then fractionated into peptides in order to achieve a more specific immune response.

•  Prostate Cancer Vaccine. This vaccine is designed to stimulate a patient’s immune system to target prostate cancer cells. The preparation of the vaccine involves culturing the patient’s peripheral monocytes in vitro in the presence of a recombinant growth factor, special cytokines and their own prostate-specific antigen.

•  Lymphokine-Activated Killer Cells – Also known as LAK Cells. These cells are autologous lymphocytes, (T-cells) that in the presence of Interleukin-2 are expanded and activated to destroy cancer cells.

•  Activated Natural Killer Cells – Also known as NK Cells. NK Cells are autologous natural killer cells, a type of lymphocytes of the innate immune system that in the presence of Interleukin-21 and special cytokines are expanded and activated to destroy cancer cells.

•  Coley’s Mixed Bacterial Vaccine. Use of the vaccine opens blockades in the body matrix (all solid, semi-solid and fluid connective tissues), stimulates the production of the body’s own interferons, interleukins, colony stimulating factors, tumor necrosis factor and other potent disease fighters.

•  Autologous Cytokines to continue boosting the immune system during the home care program.

•  Extracorporeal Photopheresis (FDA-approved for cutaneous T-Cell lymphoma based on research by Richard L. Edelson, Carole L. Berger, et al., Yale University, USA) to provide immunomodulatory properties.

•  Systemic Hyperthermia. Systemic Hyperthermia enhances immune functions.

The Issels® Integrative Immunotherapy for Cancer

The Issels® Integrative Immunotherapy is a highly personalized, proprietary blend of research-based non-toxic therapies that focus with equal importance on the elimination of both the cancer tumor and the underlying causes for the immune suppression leading to the tumor.

This comprehensive integrative strategy provides for the basis of long-term remission and healing. It has been shown to enhance the effectiveness of the vaccine and cell therapies, of the gene-targeted cancer treatments, as well as of standard treatments, and helps to reduce the latter’s toxic side effects.

* * * * * * *

A retrospective analysis of Natural Killer Cells (NKC) counts included 129 cancer patients who underwent the Issels Treatment® program at the Issels Medical Center in Santa Barbara, California. KC response to the Issels Immunotherapy protocol revealed an average 48% increase in absolute NKC levels per patient in approximately 3 weeks.

Advanced Gene-Targeted Cancer Therapies

Depending on the individual patient’s needs, we also integrate gene-targeted cancer therapies into the immunobiologic core treatment program. Targeted cancer therapies are medications that block the growth and spread of cancer cells by interfering with specific molecules needed for tumor growth. Although chemical drugs in nature, they are not only less harmful to normal cells and less toxic than traditional chemotherapy, but they have also been shown to improve outcomes in patients who have qualified for this treatment.

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