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Immunotherapy is a medical term defined as "Treatment of disease by inducing, enhancing, or suppressing an immune response".
Immunotherapies designed to elicit or amplify an immune response are classified as Activation Immunotherapies.
Immunotherapies designed to reduce, suppress or more appropriately direct an existing immune response, as in cases of autoimmunity or allergy, are classified as Suppression Immunotherapies.
The active agents of immunotherapy are collectively called immunomodulators or Cytokines. They are a diverse array of recombinant, synthetic and natural preparations. Some of these substances, such as granulocyte colony-stimulating factor (G-CSF), interferons, imiquimod and cellular membrane fractions from bacterial microorganisms are already licensed for use in patients. Others including IL-12, various chemokines, synthetic cytosine phosphate-guanosine (CpG), oligodeoxynucleotides and glucans are being currently investigated extensively in clinical and preclinical studies. Immunomodulatory regimens offer an attractive approach as they often have fewer side effects than existing drugs, including less potential for creating resistance in microbial diseases.
Examples of activation immunotherapiesEdit
Cancer immunotherapy attempts to stimulate the immune system to reject and destroy tumors. BCG immunotherapy  for early stage (non-invasive) bladder cancer utilizes instillation of attenuated live bacteria into the bladder, and is effective in preventing recurrence in up to two thirds of cases. Topical immunotherapy utilizes an immune enhancement cream (imiquimod) which is an interferon producer causing the patients own killer T cells to destroy warts,, actinic keratoses, basal cell cancer, vaginal intraepithelial neoplasia., squamous cell cancer, cutaneous lymphoma, and superficial malignant melanoma. Injection immunotherapy uses mumps, candida the HPV vaccine, or trichophytin antigen injections to treat warts (HPV induced tumors). Lung cancer has been demonstrated to potentially respond to immunotherapy.
In many parts of Asia, Medicinal mushrooms are thought to be able to boost the immune system naturally. Cellular and animal research has shown that Agaricus blazei may stimulate immune system cells and the production of interferons and interleukins (reviewed by G. Hetland). Mushroom isolates like PSK also are used to increase immune system parameters (reviewed by Kobayashi). Used in conjunction with chemotherapy, PSK has increased the survival time of cancer patients in randomized, control studies, with a variety of cancer types.
Dendritic cell based immunotherapyEdit
This utilizes dendritic cells to activate a cytotoxic response towards an antigen. Dendritic cells, an antigen presenting cell, are harvested from a patient. These cells are then either pulsed with an antigen or transfected with a viral vector. The activated dendritic cells are then placed back into the patient; these cells then present the antigens to effector lymphocytes (CD4+ T cells, CD8+ T cells, and in specialized dendritic cells, B cells also). This initiates a cytotoxic response to occur against these antigens and anything that may present these antigens. One use for this therapy is in cancer immunotherapy. Tumor Antigens are presented to dendritic cells, which cause the immune system to target these antigens, which are often expressed on cancerous cells. The Dendreon product candidate Provenge is one example of this approach.
T cell based adoptive immunotherapyEdit
ACT uses T cell-based cytotoxic responses to attack cancer. T cells that have a natural or genetically engineered reactivity to a patient's cancer are expanded, made more effective, in vitro using a variety of means and then adoptively transferred into a cancer patient.
For example, T cells with a naturally occurring reactivity to a patient’s cancer can be found infiltrated in the patient's own tumors. The tumor can be harvested, and these tumor-infiltrating lymphocytes (TIL) can then be expanded, or made more effective, in vitro using high concentrations of interluekin-2 (IL-2), anti-CD3 and allo-reactive feeders. These T cells can then be transferred back into the patient along with exogenous administration of IL-2 to further boost their activity.
The initial studies of ACT using TIL, however, revealed that persistence of the transferred cells in vivo was too short. Before reinfusion, lymphodepletion of the recipient is required to eliminate regulatory T cells as well as normal endogenous lymphocytes that compete with the transferred cells for homeostatic cytokines. Prior lymphodepletion to transfer of the expanded TIL was made by total body irradiation. The trend for increasing survival as a function of increasing lymphodepletion was highly significant (P=0.007). Transferred cells expanded in vivo and persisted in the peripheral blood in many patients, sometimes achieving levels of 75% of all CD8+ T cells at 6-12 months after infusion.
Morgan et al. (2006) demonstrated that the adoptive cell transfer of lymphocytes transduced with retrovirus encoding T cell receptors (TCRs) that recognize a cancer antigen can mediate anti-tumor responses in patients with metastatic melanomas.
In such T cell genetic engineering, TCRs that have been identified to have reactivity against tumor-associated antigens are cloned into a replication-incompetent virus that is capable of genomic integration. A patient's own lymphocytes are exposed to these viruses and then expanded non-specifically or stimulated using the engineered TCR. The cells are then transferred back into the patient. This therapy has been demonstrated to result in objective clinical responses in patients with refractory stage IV cancer. The Surgery Branch of the National Cancer Institute (Bethesda, Maryland) is actively investigating this form of cancer treatment for patients suffering aggressive melanomas.
Combination of ACT with such genetic engineering of T cells has opened possibilities for the extension of ACT immunotherapy to patients with a wide variety of cancer types and is a promising new approach to cancer treatment.
In June 2008, it was announced that US doctors from the Clinical Research Division led by Dr. Cassian Yee at Fred Hutchinson Cancer Research Center in Seattle had successfully treated a patient with advanced skin cancer by injecting the patient with immune cells cloned from his own immune system. The patient was free from tumours within eight weeks of treatment. Dr. Cassian Yee described the research findings at The Cancer Research Institute International 2008 Symposia Series. . Responses, however, were not seen in other patients in this clinical trial.
Examples of Suppression ImmunotherapiesEdit
Immune tolerance is the process by which the body naturally does not launch an immune system attack on its own tissues. Immune tolerance therapies seeks 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. A brief treatment should then reduce or eliminate the need for life-long immunosuppression and the chances of attendant side effects, in the case of transplantation, or preserve the body's own function, at least in part, in cases of type 1 diabetes or other autoimmune disorders.
- Main article: Allergy immunotherapy
Immunotherapy is also used to treat allergies. While other allergy treatments (such as antihistamines or corticosteroids) treat only the symptoms of allergic disease, immunotherapy is the only available treatment that can modify the natural course of the allergic disease, by reducing sensitivity to allergens.
A three-to-five-year individually tailored regimen of injections may result in long-term benefits. Recent research suggests that patients who complete immunotherapy may continue to see benefits for years to come. Immunotherapy does not work for everyone and is only partly effective in some people, but it offers allergy sufferers the chance to eventually reduce or stop symptomatic/rescue medication.
The therapy is indicated for people who are extremely allergic or who cannot avoid specific allergens. For example, they may not be able to live a normal life and completely avoid pollen, dust mites, mold spores, pet dander, insect venom, and certain other common triggers of allergic reactions. Immunotherapy is generally not indicated for food or medicinal allergies. Immunotherapy is typically individually tailored and administered by an allergist (allergologist). Injection schedules are available in some healthcare systems and can be prescribed by family physicians. This therapy is particularly useful for people with allergic rhinitis or asthma.
The therapy is particularly likely to be successful if it begins early in life or soon after the allergy develops for the first time. Immunotherapy involves a series of injections (shots) given regularly for several years by a specialist in a hospital clinic. In the past, this was called a serum, but this is an incorrect name. Most allergists now call this mixture an allergy extract. The first shots contain very tiny amounts of the allergen or antigen to which you are allergic. With progressively increasing dosages over time, your body will adjust to the allergen and become less sensitive to it. This process is called desensitization. A recently approved sublingual tablet (Grazax), containing a grass pollen extract, is similarly effective, with few side effects, and can be self-administered at home, including by those patients who also suffer from allergic asthma, a condition which precludes the use of injection-based desensitization. To read more about this topic, see: allergy and hyposensitization.
Other approaches to immunotherapyEdit
Recent research into the clinical effectiveness of Whipworm ova (Trichuris suis) and Hookworm (Necator americanus) for the treatment of certain immunological diseases and allergies means that these organisms must be classified as Immuno-therapeutic agents. Helminthic therapy is being investigated as a potentially highly effective treatment for the symptoms and or disease process in disorders such as relapsing remitting multiple sclerosis, Crohn’s, allergies and asthma.
The precise mechanism of how the helminths modulate the immune response, ensuring their survival in the host and incidentally effectively modulating autoimmune disease processes, is currently unknown. However, several broad mechanisms have been postulated, such as a re-polarisation of the Th1 / Th2 response, and modulation of dendritic cell function by Fujiwara and Carvalho. That helminths modulate host immune response is proven, as the core assertion of the hygiene hypothesis appears to have been, with the recent publication of a study demonstrating that co-evolution with helminths has shaped at least some of the genes associated with Interleukin expression and immunological disorders, like Crohn's, Ulcerative Colitis and Celiac Disease. Much of the research that has been published now indicates a key role, for what have been traditionally regarded as disease causing organisms, the helminths, in down regulating the pro-inflammatory Th1 cytokines, IL-12 (Interleukin-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.
- ↑ immunotherapies definition | Dictionary.com. URL accessed on 2009-06-02.
- ↑ Expert Opinion on Biological Therapy July 2001, Vol. 1, No. 4, Pages 641-653 , DOI 10.1517/147125184.108.40.2061 Fighting infection using immunomodulatory agents K Noel Masihi http://www.informahealthcare.com/doi/abs/10.1517/147125220.127.116.111
- ↑ 3.0 3.1 Järvinen R, Kaasinen E, Sankila A, Rintala E (April 2009). Long-term Efficacy of Maintenance Bacillus Calmette-Guérin versus Maintenance Mitomycin C Instillation Therapy in Frequently Recurrent TaT1 Tumours without Carcinoma In Situ: A Subgroup Analysis of the Prospective, Randomised FinnBladder I Study with a 20-Year Follow-up. European Urology 56 (2): 260.
- ↑ van Seters M, van Beurden M, ten Kate FJ, et al. (April 2008). Treatment of vulvar intraepithelial neoplasia with topical imiquimod. The New England journal of medicine 358 (14): 1465–73.
- ↑ Buck HW, Guth KJ (October 2003). Treatment of vaginal intraepithelial neoplasia (primarily low grade) with imiquimod 5% cream. Journal of lower genital tract disease 7 (4): 290–3.
- ↑ Davidson HC, Leibowitz MS, Lopez-Albaitero A, Ferris RL (May 2009). Immunotherapy for head and neck cancer. Oral Oncology 45 (9): 747–51.
- ↑ Dani T, Knobler R (2009). Extracorporeal photoimmunotherapy-photopheresis. Frontiers in Bioscience : a Journal and Virtual Library 14: 4769–77.
- ↑ Eggermont AM, Schadendorf D (June 2009). Melanoma and immunotherapy. Hematology/oncology Clinics of North America 23 (3): 547–64, ix–x.
- ↑ Chuang CM, Monie A, Wu A, Hung CF (May 2009). Combination of apigenin treatment with therapeutic HPV DNA vaccination generates enhanced therapeutic antitumor effects. Journal of Biomedical Science 16 (1): 49.
- ↑ Pawlita M, Gissmann L (April 2009). [Recurrent respiratory papillomatosis: indication for HPV vaccination?]. Deutsche Medizinische Wochenschrift (1946) 134 Suppl 2: S100–2.
- ↑ Kang N, Zhou J, Zhang T, et al. (August 2009). Adoptive immunotherapy of lung cancer with immobilized anti-TCRgammadelta antibody-expanded human gammadelta T cells in peripheral blood. Cancer Biology & Therapy 8 (16): 1540–9.
- ↑ Hetland G, Johnson E, Lyberg T, Bernardshaw S, Tryggestad AM, Grinde B (2008). Effects of the medicinal mushroom Agaricus blazei Murill on immunity, infection and cancer.. Scand J Immunol 68 (4): 363–70.
- ↑ Kobayashi H, Matsunaga K, Oguchi Y (1995). Antimetastatic effects of PSK (Krestin), a protein-bound polysaccharide obtained from basidiomycetes: an overview. Cancer Epidemiology, Biomarkers & Prevention 4 (3): 275–81.
- ↑ Overes IM, Fredrix H, Kester MG, et al. (May 2009). Efficient Activation of LRH-1-specific CD8+ T-cell Responses From Transplanted Leukemia Patients by Stimulation With P2X5 mRNA-electroporated Dendritic Cells. Journal of Immunotherapy (Hagerstown, Md. : 1997) 32 (6): 539.
- ↑ 15.0 15.1 15.2 Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME (2008). "Adoptive cell transfer: A clinical path to effective cancer immunotherapy." Nat Rev Cancer 8(4): 299–308, PMID 18354418, Full text at PMC: 2553205
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- ↑ Motohashi S, Nakayama T (2009). Natural killer T cell-mediated immunotherapy for malignant diseases. Frontiers in Bioscience (Scholar Edition) 1: 108–116.
- ↑ Khattar M, Chen W, Stepkowski SM (May 2009). Expanding and converting regulatory T cells: a horizon for immunotherapy. Archivum Immunologiae et Therapiae Experimentalis 57 (3): 199.
- ↑ Rosenberg SA, Aebersold P, Cornetta K, Kasid A, Morgan RA, Moen R, Karson EM, Lotze MT, Yang JC, Topalian SL (1990). "Gene transfer into humans--immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction." N Engl J Med 323(9): 570-578, PMID 2381442.
- ↑ Antony PA, Piccirillo CA, Akpinarli A, Finkelstein SE, Speiss PJ, Surman DR, Palmer DC, Chan CC, Klebanoff CA, Overwijk WW, Rosenberg SA, Restifo NP (2005). "CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells." J Immunol 174(5): 2591-2601, PMID 15728465, Full text at PMC: 1403291 .
- ↑ Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, Hwang LN, Yu Z, Wrzesinski C, Heimann DM, Surh CD, Rosenberg SA, Restifo NP (2005). "Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells." J Exp Med 202(7): 907-912, PMID 16203864, Full text at PMC: 1397916
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- ↑ Dummer W, Niethammer AG, Baccala R, Lawson BR, Wagner N, Reisfeld RA, Theofilopoulos AN (2002). "T cell homeostatic proliferation elicits effective antitumor autoimmunity." J Clin Invest 110(2): 185-192, PMID 12122110, Full text at PMC: 151053
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- ↑ 22.0 22.1 Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, Robbins PF, Huang J, Citrin DE, Leitman SF, Wunderlich J, Restifo NP, Thomasian A, Downey SG, Smith FO, Klapper J, Morton K, Laurencot C, White DE, Rosenberg SA (2008). "Adoptive cell therapy for patients with metastatic melanoma: Evaluation of intensive myeloablative chemoradiation preparative regimens." J Clin Oncol 26(32): 5233–5239, PMID 18809613,
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- ↑ Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry R, Restifo NP, Hubicki AM, Robinson MR, Raffeld M, Duray P, Seipp CA, Rogers-Freezer L, Morton KE, Mavroukakis SA, White DE, Rosenberg SA (2002). "Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes." Science 298(5594): 850–854, PMID 12242449, Full text at PMC: 1764179
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- ↑ Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP, Zheng Z, Nahvi A, de Vries CR, Rogers-Freezer LJ, Mavroukakis SA, Rosenberg SA (2006). "Cancer regression in patients after transfer of genetically engineered lymphocytes." Science 314(5796): 126–129, PMID 16946036, Full text at PMC: 2267026
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- ↑ Hunder N, Wallen H, Cao J, Hendricks D,Reilly J, Rodmyre R, Jungbluth A, Gnjatic S, Thompson J, and Yee C (2008). Treatment of Metastatic Melanoma with Autologous CD4+ T Cells against NY-ESO-1. N. Engl. J. Med. 358 (25): 2698–2703.
- ↑ Rotrosen D, Matthews JB, Bluestone JA (2002). The immune tolerance network: a new paradigm for developing tolerance-inducing therapies. J. Allergy Clin. Immunol. 110 (1): 17–23.
- ↑ Durham SR, Walker SM, Varga EM, et al. (1999). Long-term clinical efficacy of grass-pollen immunotherapy. N. Engl. J. Med. 341 (7): 468–75.
- ↑ Correale J, Farez M (February 2007). Association between parasite infection and immune responses in multiple sclerosis. Ann. Neurol. 61 (2): 97–108.
- ↑ Croese J, O'neil J, Masson J, et al. (January 2006). A proof of concept study establishing Necator americanus in Crohn's patients and reservoir donors. Gut 55 (1): 136–7.
- ↑ Reddy A, Fried B (January 2009). An update on the use of helminths to treat Crohn's and other autoimmunune diseases. Parasitol. Res. 104 (2): 217–21.
- ↑ Laclotte C, Oussalah A, Rey P, et al. (December 2008). [Helminths and inflammatory bowel diseases]. Gastroenterol. Clin. Biol. 32 (12): 1064–74.
- ↑ Zaccone P, Fehervari Z, Phillips JM, Dunne DW, Cooke A (October 2006). Parasitic worms and inflammatory diseases. Parasite Immunol. 28 (10): 515–23.
- ↑ 33.0 33.1 Brooker S, Bethony J, Hotez PJ (2004). Human hookworm infection in the 21st century. Adv. Parasitol. 58: 197–288.
- ↑ Fujiwara RT, Cançado GG, Freitas PA, et al. (2009). Necator americanus Infection: A Possible Cause of Altered Dendritic Cell Differentiation and Eosinophil Profile in Chronically Infected Individuals. PLoS Negl Trop Dis 3 (3): e399.
- ↑ Carvalho L, Sun J, Kane C, Marshall F, Krawczyk C, Pearce EJ (January 2009). Review series on helminths, immune modulation and the hygiene hypothesis: mechanisms underlying helminth modulation of dendritic cell function. Immunology 126 (1): 28–34.
- ↑ Fumagalli M, Pozzoli U, Cagliani R, et al. (June 2009). Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions. J. Exp. Med. 206 (6): 1395–408.
- International Society for Biological Therapy of Cancer
- Cancer Research Institute Annual International Cancer Immunotherapy Symposia Series
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