Immunotherapy is a medical term defined as the "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, while immunotherapies that reduce or suppress are classified as suppression immunotherapies.
The active agents of immunotherapy are collectively called immunomodulators. They are a diverse array of recombinant, synthetic and natural preparations, often cytokines. Some of these substances, such as granulocyte colony-stimulating factor (G-CSF), interferons, imiquimod and cellular membrane fractions from bacteria are already licensed for use in patients. Others including IL-2, IL-7, IL-12, various chemokines, synthetic cytosine phosphate-guanosine (CpG) oligodeoxynucleotides and glucans are currently being 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.
Cell based Immunotherapies are proven to be 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 the tumor due to mutation.
Cancer immunotherapy attempts to stimulate the immune system to reject and destroy tumors. Dr William Coley used Coley's Toxins in the late 1800s as crude immunotherapy with some success. Immuno cell therapy for cancer was first introduced by Rosenberg and his colleagues of National Institute of Health USA. In the late 80s, they published an article in which they reported a low tumorregression rate (2.6–3.3%) in 1205 patients with metastaticcancer who underwent different types of active specific immunotherapy (ASI), and suggested that immuno cell therapy along with specific chemotherapy is the future of cancer immunotherapy. Initially Immunotherapy treatments involved administration of cytokines such as Interleukin. Thereafter the adverse effects of such intravenously administered cytokines lead to the extraction of the lymphocytes from the blood and expanding in vitro against tumour antigen before injecting the cells with appropriate stimulatory cytokines. The cells will then specifically target and destroy the tumor expressing antigen against which they have been raised.
The concept of this treatment started in the US in 80s and fully fledged clinical treatments on a routine basis have been in practice in Japan since 1990. Randomized controlled studies in different cancers resulting in significant increase in survival and disease free period have been reported and its efficacy is enhanced by 20–30% when cell-based immunotherapy is combined with other conventional treatment methods.
Dendritic cells can be stimulated to activate a cytotoxic response towards an antigen. Dendritic cells, a type of antigen presenting cell, are harvested from a patient. These cells are then either pulsed with an antigen or transfected with a viral vector. Upon transfusion back into the patient these activated cells present tumour antigen to effector lymphocytes (CD4+ T cells, CD8+ T cells, and B cells). This initiates a cytotoxic response to occur against cells expressing tumour antigens (against which the adaptive response has now been primed). The cancer vaccineSipuleucel-T is one example of this approach.
T-cell adoptive transfer
Adoptive cell transfer uses T cell-based cytotoxic responses to attack cancer cells. T cells that have a natural or genetically engineered reactivity to a patient's cancer are generated in vitro and then transferred back into the cancer patient. One study using autologous tumor-infiltrating lymphocytes was an effective treatment for patients with metastatic melanoma;. This can be achieved by taking T cells that are found with the tumor of the patient, which are trained to attack the cancerous cells. These T cells are referred to as tumor-infiltrating lymphocytes (TIL) are then encouraged to multiply in vitro using high concentrations of IL-2, anti-CD3 and allo-reactive feeder cells. These T cells are then transferred back into the patient along with exogenous administration of IL-2 to further boost their anti-cancer activity.
Thus far, a 51% objective response rate has been observed; and in some patients, tumors shrank to undetectable size.
The initial studies of adoptive cell transfer 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. Lymphodepletion was made by total body irradiation prior to transfer of the expanded TIL. 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. Clinical trials based on adoptive cell transfer of TILs for patients with metastatic melanoma are currently ongoing at the National Cancer Institute (Bethesda,MD,USA), Moffitt Cancer Center (Tampa,FL,USA), MD Anderson Cancer Center (Houston,TX,USA), Sheba Medical Center (Tel Hashomer,Israel), Herlev University Hospital (Herlev,Denmark) and NKI Antonie van Leeuwenhoek (Amsterdam, Netherlands).
Autologous Immune Enhancement Therapy
The Autologous immune enhancement therapy (AIET) is an autologous immune cell based therapy wherein the patient's own peripheral blood-derived NK cells Cytotoxic T Lymphocytes and other relevant immune cells are expanded in vitro and then reinfused to tackle cancer. There are also studies proving their efficacy against Hepatitis C Viral infection, Chronic fatigue Syndrome and HHV6 infection.
Genetically engineered T cells
Genetically engineered T cells are created by infecting patient's cells with a virus that contain a copy of a T cell receptor (TCR) gene that is specialised to recognise tumour antigens. The virus is not able to reproduce within the cell however integrates into the human genome. This is beneficial as new TCR gene remains stable in the T-cell. A patient's own T cells are exposed to these viruses and then expanded non-specifically or stimulated using the genetically engineered TCR. The cells are then transferred back into the patient and ready to have an immune response against the tumour. Morgan et al. (2006) demonstrated that the adoptive cell transfer of lymphocytes transduced with retrovirus encoding TCRs that recognize a cancer antigen are able to mediate anti-tumour responses in patients with metastatic melanomas. 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. The use of adoptive cell transfer with genetically engineered T cells is a promising new approach to the treatment of a variety of cancers.
In one case study, United States 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 cellscloned 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. Larger trials are now under way.
The potential use of immunotherapy is to restore the immune system of patients with immune deficiencies as result of infection or chemotherapy. For example, cytokines have been tested in clinical trials. Interleukin-7 has been in clinical trials for HIV and cancer patients. Interleukin-2 has also been tested in HIV patients.
Immunosuppressive drugs are important tools in the management of organ transplantation and autoimmune disease. Immune responses depend on lymphocyte proliferation, and 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 an increasingly-broad array of steps in the immune response, and there are still other drugs that modulate immune responses.
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 lifelong 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.
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 one-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) or through specialized physician offices. 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 one is allergic. With progressively increasing dosages over time, one's body adjusts to the allergen and becomes less sensitive to it, in a process known as 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.
Recent research into the clinical effectiveness of Whipwormova (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 sclerosisCrohn’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 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.
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, so that their relationship to humans as hosts should not be classified as parasitic, rather as mutualistic, symbionts.
^Rosenberg SA (January 1984). "Adoptive immunotherapy of cancer: accomplishments and prospects". Cancer Treat Rep68 (1): 233–55. PMID6362866.
^Yang Q, Hokland ME, Bryant JL, Zhang Y, Nannmark U, Watkins SC, Goldfarb RH, Herberman RB, Basse PH (July 2003). "Tumor-localization by adoptively transferred, interleukin-2-activated NK cells leads to destruction of well-established lung metastases". Int. J. Cancer105 (4): 512–9. doi:10.1002/ijc.11119. PMID12712443.
^Egawa K (2004). "Immuno-cell therapy of cancer in Japan". Anticancer Res.24 (5C): 3321–6. PMID15515427.
^Li K, Li CK, Chuen CK, Tsang KS, Fok TF, James AE, Lee SM, Shing MM, Chik KW, Yuen PM (February 2005). "Preclinical ex vivo expansion of G-CSF-mobilized peripheral blood stem cells: effects of serum-free media, cytokine combinations and chemotherapy". Eur. J. Haematol.74 (2): 128–35. doi:10.1111/j.1600-0609.2004.00343.x. PMID15654904.
^Fujita K, Ikarashi H, Takakuwa K, Kodama S, Tokunaga A, Takahashi T, Tanaka K (May 1995). "Prolonged disease-free period in patients with advanced epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes". Clin. Cancer Res.1 (5): 501–7. PMID9816009.
^Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, Shimada K, Sakamoto M, Hirohashi S, Ohashi Y, Kakizoe T (September 2000). "Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial". Lancet356 (9232): 802–7. doi:10.1016/S0140-6736(00)02654-4. PMID11022927.
^Kono K, Takahashi A, Ichihara F, Amemiya H, Iizuka H, Fujii H, Sekikawa T, Matsumoto Y (June 2002). "Prognostic significance of adoptive immunotherapy with tumor-associated lymphocytes in patients with advanced gastric cancer: a randomized trial". Clin. Cancer Res.8 (6): 1767–71. PMID12060615.
^ abJärvinen R, Kaasinen E, Sankila A, Rintala E (August 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". Eur. Urol.56 (2): 260–5. doi:10.1016/j.eururo.2009.04.009. PMID19395154.
^van Seters M, van Beurden M, ten Kate FJ, Beckmann I, Ewing PC, Eijkemans MJ, Kagie MJ, Meijer CJ, Aaronson NK, Kleinjan A, Heijmans-Antonissen C, Zijlstra FJ, Burger MP, Helmerhorst TJ (April 2008). "Treatment of vulvar intraepithelial neoplasia with topical imiquimod". N. Engl. J. Med.358 (14): 1465–73. doi:10.1056/NEJMoa072685. PMID18385498.
^Pawlita M, Gissmann L (April 2009). "[Recurrent respiratory papillomatosis: indication for HPV vaccination?]". Dtsch. Med. Wochenschr. (in German). 134 Suppl 2: S100–2. doi:10.1055/s-0029-1220219. PMID19353471.
^Kang N, Zhou J, Zhang T, Wang L, Lu F, Cui Y, Cui L, He W (August 2009). "Adoptive immunotherapy of lung cancer with immobilized anti-TCRgammadelta antibody-expanded human gammadelta T-cells in peripheral blood". Cancer Biol. Ther.8 (16): 1540–9. doi:10.4161/cbt.8.16.8950. PMID19471115.
^Overes IM, Fredrix H, Kester MG, Falkenburg JH, van der Voort R, de Witte TM, Dolstra H (2009). "Efficient activation of LRH-1-specific CD8+ T-cell responses from transplanted leukemia patients by stimulation with P2X5 mRNA-electroporated dendritic cells". J. Immunother.32 (6): 539–51. doi:10.1097/CJI.0b013e3181987c22. PMID19483655.
^Motohashi S, Nakayama T (2009). "Natural killer T cell-mediated immunotherapy for malignant diseases". Front Biosci (Schol Ed)1: 108–16. doi:10.2741/S10. PMID19482686.
^Khattar M, Chen W, Stepkowski SM (2009). "Expanding and converting regulatory T cells: a horizon for immunotherapy". Arch. Immunol. Ther. Exp. (Warsz.)57 (3): 199–204. doi:10.1007/s00005-009-0021-1. PMID19479206.
^Rosenberg SA, Aebersold P, Cornetta K, Kasid A, Morgan RA, Moen R, Karson EM, Lotze MT, Yang JC, Topalian SL (August 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): 570–8. doi:10.1056/NEJM199008303230904. PMID2381442.
^Li Y, Zhang T, Ho C, Orange JS, Douglas SD, Ho WZ (December 2004). "Natural killer cells inhibit hepatitis C virus expression". J. Leukoc. Biol.76 (6): 1171–9. doi:10.1189/jlb.0604372. PMID15339939.
^Doskali M, Tanaka Y, Ohira M, Ishiyama K, Tashiro H, Chayama K, Ohdan H (March 2011). "Possibility of adoptive immunotherapy with peripheral blood-derived CD3⁻CD56+ and CD3+CD56+ cells for inducing antihepatocellular carcinoma and antihepatitis C virus activity". J. Immunother.34 (2): 129–38. doi:10.1097/CJI.0b013e3182048c4e. PMID21304407.
^Terunuma H, Deng X, Dewan Z, Fujimoto S, Yamamoto N (2008). "Potential role of NK cells in the induction of immune responses: implications for NK cell-based immunotherapy for cancers and viral infections". Int. Rev. Immunol.27 (3): 93–110. doi:10.1080/08830180801911743. PMID18437601.
^Rotrosen D, Matthews JB, Bluestone JA (July 2002). "The immune tolerance network: a new paradigm for developing tolerance-inducing therapies". The Journal of Allergy and Clinical Immunology110 (1): 17–23. doi:10.1067/mai.2002.124258. PMID12110811.
^Durham SR, Walker SM, Varga EM, Jacobson MR, O'Brien F, Noble W, Till SJ, Hamid QA, Nouri-Aria KT (August 1999). "Long-term clinical efficacy of grass-pollen immunotherapy". N. Engl. J. Med.341 (7): 468–75. doi:10.1056/NEJM199908123410702. PMID10441602.
^Correale J, Farez M (February 2007). "Association between parasite infection and immune responses in multiple sclerosis". Annals of Neurology61 (2): 97–108. doi:10.1002/ana.21067. PMID17230481.
^Laclotte C, Oussalah A, Rey P, Bensenane M, Pluvinage N, Chevaux JB, Trouilloud I, Serre AA, Boucekkine T, Bigard MA, Peyrin-Biroulet L (December 2008). "[Helminths and inflammatory bowel diseases]". Gastroenterol. Clin. Biol. (in French) 32 (12): 1064–74. doi:10.1016/j.gcb.2008.04.030. PMID18619749.