Immunotherapy is 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.
- 1 Immunomodulators
- 2 Activation immunotherapies
- 3 Suppression immunotherapies
- 4 Other approaches
- 5 See also
- 6 References
- 7 External links
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.
|Interleukins||IL-2, IL-7, IL-12|
|Cytokines||Interferons, G-CSF, Imiquimod|
|Chemokines||CCL3, CCL26, CXCL7|
|Other||cytosine phosphate-guanosine, oligodeoxynucleotides, glucans|
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. Immuno cell therapy for cancer was first introduced by Rosenberg and his colleagues of National Institute of Health USA. In the late 1980s, they published an article in which they reported a low tumor regression rate (2.6–3.3%) in 1205 patients with metastatic cancer 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 1980s 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.
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
Dendritic cell-based immunotherapy
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 vaccine Sipuleucel-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.
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 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. 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 Allergen immunotherapy.
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 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.
- "immunotherapies definition". Dictionary.com. Retrieved 2009-06-02.
- Masihi KN (July 2001). "Fighting infection using immunomodulatory agents". Expert Opin Biol Ther 1 (4): 641–53. doi:10.1517/147125184.108.40.2061. PMID 11727500.
- Rosenberg SA (January 1984). "Adoptive immunotherapy of cancer: accomplishments and prospects". Cancer Treat Rep 68 (1): 233–55. PMID 6362866.
- 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. Cancer 105 (4): 512–9. doi:10.1002/ijc.11119. PMID 12712443.
- Egawa K (2004). "Immuno-cell therapy of cancer in Japan". Anticancer Res. 24 (5C): 3321–6. PMID 15515427.
- 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. PMID 15654904.
- 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. PMID 9816009.
- Kimura H, Yamaguchi Y (July 1997). "A phase III randomized study of interleukin-2 lymphokine-activated killer cell immunotherapy combined with chemotherapy or radiotherapy after curative or noncurative resection of primary lung carcinoma". Cancer 80 (1): 42–9. doi:10.1002/(SICI)1097-0142(19970701)80:1<42::AID-CNCR6>3.0.CO;2-H. PMID 9210707.
- 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". Lancet 356 (9232): 802–7. doi:10.1016/S0140-6736(00)02654-4. PMID 11022927.
- 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. PMID 12060615.
- Järvinen 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. PMID 19395154.
- 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. PMID 18385498.
- Buck HW, Guth KJ (October 2003). "Treatment of vaginal intraepithelial neoplasia (primarily low grade) with imiquimod 5% cream". J Low Genit Tract Dis 7 (4): 290–3. doi:10.1097/00128360-200310000-00011. PMID 17051086.
- Davidson HC, Leibowitz MS, Lopez-Albaitero A, Ferris RL (September 2009). "Immunotherapy for head and neck cancer". Oral Oncol. 45 (9): 747–51. doi:10.1016/j.oraloncology.2009.02.009. PMID 19442565.
- Dani T, Knobler R (2009). "Extracorporeal photoimmunotherapy-photopheresis". Front. Biosci. 14 (14): 4769–77. doi:10.2741/3566. PMID 19273388.
- Eggermont AM, Schadendorf D (June 2009). "Melanoma and immunotherapy". Hematol. Oncol. Clin. North Am. 23 (3): 547–64, ix–x. doi:10.1016/j.hoc.2009.03.009. PMID 19464602.
- Chuang CM, Monie A, Wu A, Hung CF (2009). "Combination of apigenin treatment with therapeutic HPV DNA vaccination generates enhanced therapeutic antitumor effects". J. Biomed. Sci. 16 (1): 49. doi:10.1186/1423-0127-16-49. PMC 2705346. PMID 19473507.
- 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. PMID 19353471.
- 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. PMID 19471115.
- 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. PMID 19483655.
- Di Lorenzo G, Buonerba C, Kantoff PW (September 2011). "Immunotherapy for the treatment of prostate cancer". Nature Reviews Clinical Oncology 8 (9): 551–61. doi:10.1038/nrclinonc.2011.72. PMID 21606971.
- Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME (April 2008). "Adoptive cell transfer: a clinical path to effective cancer immunotherapy". Nature Reviews Cancer 8 (4): 299–308. doi:10.1038/nrc2355. PMC 2553205. PMID 18354418.
- 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. PMID 19482686.
- 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. PMID 19479206.
- 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. 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 (March 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". Journal of Immunology 174 (5): 2591–601. PMC 1403291. PMID 15728465.
- 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 (October 2005). "Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells". J. Exp. Med. 202 (7): 907–12. doi:10.1084/jem.20050732. PMC 1397916. PMID 16203864.
- Dummer W, Niethammer AG, Baccala R, Lawson BR, Wagner N, Reisfeld RA, Theofilopoulos AN (July 2002). "T cell homeostatic proliferation elicits effective antitumor autoimmunity". J. Clin. Invest. 110 (2): 185–92. doi:10.1172/JCI15175. PMC 151053. PMID 12122110.
- 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 (November 2008). "Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens". J. Clin. Oncol. 26 (32): 5233–9. doi:10.1200/JCO.2008.16.5449. PMC 2652090. PMID 18809613.
- 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 (October 2002). "Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes". Science 298 (5594): 850–4. doi:10.1126/science.1076514. PMC 1764179. PMID 12242449.
- Pilon-Thomas S, Kuhn L, Ellwanger S, Janssen W, Royster E, Marzban S, Kudchadkar R, Zager J, Gibney G, Sondak VK, Weber J, Mulé JJ, Sarnaik AA (October 2012). "Efficacy of adoptive cell transfer of tumor-infiltrating lymphocytes after lymphopenia induction for metastatic melanoma". J. Immunother. 35 (8): 615–20. doi:10.1097/CJI.0b013e31826e8f5f. PMID 22996367.
- Manjunath SR, Ramanan G, Dedeepiya VD, Terunuma H, Deng X, Baskar S, Senthilkumar R, Thamaraikannan P, Srinivasan T, Preethy S, Abraham SJ (January 2012). "Autologous immune enhancement therapy in recurrent ovarian cancer with metastases: a case report". Case Rep Oncol 5 (1): 114–8. doi:10.1159/000337319. PMC 3364094. PMID 22666198.
- 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. PMID 15339939.
- 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. PMID 21304407.
- 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. PMID 18437601.
- See DM, Tilles JG (1996). "alpha-Interferon treatment of patients with chronic fatigue syndrome". Immunol. Invest. 25 (1–2): 153–64. doi:10.3109/08820139609059298. PMID 8675231.
- Ojo-Amaize EA, Conley EJ, Peter JB (January 1994). "Decreased natural killer cell activity is associated with severity of chronic fatigue immune dysfunction syndrome". Clin. Infect. Dis. 18 Suppl 1: S157–9. doi:10.1093/clinids/18.Supplement_1.S157. PMID 8148445.
- Kida K, Isozumi R, Ito M (December 2000). "Killing of human Herpes virus 6-infected cells by lymphocytes cultured with interleukin-2 or -12". Pediatr Int 42 (6): 631–6. doi:10.1046/j.1442-200x.2000.01315.x. PMID 11192519.
- 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 (October 2006). "Cancer regression in patients after transfer of genetically engineered lymphocytes". Science 314 (5796): 126–9. doi:10.1126/science.1129003. PMC 2267026. PMID 16946036.
- Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, Jungbluth A, Gnjatic S, Thompson JA, Yee C (June 2008). "Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1". N. Engl. J. Med. 358 (25): 2698–703. doi:10.1056/NEJMoa0800251. PMC 3277288. PMID 18565862.
- "2008 Symposium Program & Speakers". Cancer Research Institute.
- http://www.telegraph.co.uk/earth/main.jhtml?xml=/earth/2008/06/18/scicanc118.xml[full citation needed]
- 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 Immunology 110 (1): 17–23. doi:10.1067/mai.2002.124258. PMID 12110811.
- 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. PMID 10441602.
- Correale J, Farez M (February 2007). "Association between parasite infection and immune responses in multiple sclerosis". Annals of Neurology 61 (2): 97–108. doi:10.1002/ana.21067. PMID 17230481.
- Croese J, O'neil J, Masson J, Cooke S, Melrose W, Pritchard D, Speare R (January 2006). "A proof of concept study establishing Necator americanus in Crohn's patients and reservoir donors". Gut 55 (1): 136–7. doi:10.1136/gut.2005.079129. PMC 1856386. PMID 16344586.
- 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. doi:10.1007/s00436-008-1297-5. PMID 19050918.
- 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. PMID 18619749.
- Zaccone P, Fehervari Z, Phillips JM, Dunne DW, Cooke A (October 2006). "Parasitic worms and inflammatory diseases". Parasite Immunol. 28 (10): 515–23. doi:10.1111/j.1365-3024.2006.00879.x. PMC 1618732. PMID 16965287.
- Brooker S, Bethony J, Hotez PJ (2004). Human Hookworm Infection in the 21st Century. "Advances in Parasitology Volume 58". Advances in parasitology. Advances in Parasitology 58: 197–288. doi:10.1016/S0065-308X(04)58004-1. ISBN 9780120317585. PMC 2268732. PMID 15603764.
- Fujiwara RT, Cançado GG, Freitas PA, Santiago HC, Massara CL, Dos Santos Carvalho O, Corrêa-Oliveira R, Geiger SM, Bethony J (2009). "Necator americanus infection: a possible cause of altered dendritic cell differentiation and eosinophil profile in chronically infected individuals". In Yazdanbakhsh, Maria. PLoS Negl Trop Dis 3 (3): e399. doi:10.1371/journal.pntd.0000399. PMC 2654967. PMID 19308259.
- 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. doi:10.1111/j.1365-2567.2008.03008.x. PMC 2632707. PMID 19120496.
- Fumagalli M, Pozzoli U, Cagliani R, Comi GP, Riva S, Clerici M, Bresolin N, Sironi M (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. doi:10.1084/jem.20082779. PMC 2715056. PMID 19468064.