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.
Immunomodulatory regimens often have fewer side effects than existing drugs, including less potential for creating resistance when treating microbial disease.
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.
|Interleukins||IL-2, IL-7, IL-12|
|Chemokines||CCL3, CCL26, CXCL7|
|Immunomodulatory imide drugs (IMiDs)||thalidomide and its analogues (lenalidomide, pomalidomide, and apremilast)|
|Other||cytosine phosphate-guanosine, oligodeoxynucleotides, glucans|
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 and its efficacy is enhanced by 20–30% when cell-based immunotherapy is combined with conventional treatment methods.
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. 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.
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. Since then several monoclonal antibodies have been approved for treatment of various hematological malignancies as well as for solid tumors.
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, actinic keratoses, basal cell cancer, vaginal intraepithelial neoplasia, squamous cell cancer, cutaneous lymphoma, and superficial malignant melanoma. Injection immunotherapy ("intralesional" or "intratumoral") uses mumps, candida, the HPV vaccine or trichophytin antigen injections to treat warts (HPV induced tumors).
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.
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.
T-cell adoptive transfer
Adoptive cell transfer in vitro cultivates autologous, extracted T cells for later transfusion.
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. The technique has been tested on refractory stage IV metastatic melanomas and advanced skin cancer.
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. Lymphodepletion may be achieved by myeloablative chemotherapy, to which total body irradiation may be added for greater effect. 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. As of 2012, clinical trials for metastatic melanoma were ongoing at multiple sites. Clinical responses to adoptive transfer of T cells were observed in patients with metastatic melanoma resistant to multiple immunotherapies.
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.
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.
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.
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.
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. The therapy has been tested against Hepatitis C, Chronic fatigue syndrome and HHV6 infection.
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.
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 clones co-ordinating the autoimmune attack.
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. 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.
Creating immune tolerance reduces or eliminates the need for lifelong immunosuppression and attendant side effects. It has been tested on transplantations, rheumatoid arthritis, type 1 diabetes and other autoimmune disorders.
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.
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. 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. Dosages increase over time, as the person becomes desensitized. This technique has been tested on infants to prevent peanut allergies.
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.
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 Crohn's, allergies and asthma. The mechanism of how the helminths modulate the immune response, is unknown. Hypothesized mechanisms include 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.
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.
- "Immunotherapy | Memorial Sloan Kettering Cancer Center". mskcc.org. Retrieved 2017-07-27.
- Syn NL, Teng MW, Mok TS, Soo RA (December 2017). "De-novo and acquired resistance to immune checkpoint targeting". The Lancet. Oncology. 18 (12): e731–e741. doi:10.1016/s1470-2045(17)30607-1. PMID 29208439.
- Conforti L (February 2012). "The ion channel network in T lymphocytes, a target for immunotherapy". Clinical Immunology. 142 (2): 105–6. doi:10.1016/j.clim.2011.11.009. PMID 22189042.
- Masihi KN (July 2001). "Fighting infection using immunomodulatory agents". Expert Opinion on Biological Therapy. 1 (4): 641–53. doi:10.1517/14712518.104.22.1681. PMID 11727500. S2CID 33308465.
- Rizk, J.G., Kalantar-Zadeh, K., Mehra, M.R. et al. Pharmaco-Immunomodulatory Therapy in COVID-19. Drugs 80, 1267–1292 (2020). https://doi.org/10.1007/s40265-020-01367-z
- Fuge O, Vasdev N, Allchorne P, Green JS (2015). "Immunotherapy for bladder cancer". Research and Reports in Urology. 7: 65–79. doi:10.2147/RRU.S63447. PMC 4427258. PMID 26000263.
- Pettenati, Caroline; Ingersoll, Molly A. (October 2018). "Mechanisms of BCG immunotherapy and its outlook for bladder cancer". Nature Reviews Urology. 15 (10): 615–625. doi:10.1038/s41585-018-0055-4. ISSN 1759-4820. PMID 29991725. S2CID 49670901.
- Salles G, Barrett M, Foà R, Maurer J, O'Brien S, Valente N, et al. (October 2017). "Rituximab in B-Cell Hematologic Malignancies: A Review of 20 Years of Clinical Experience". Advances in Therapy. 34 (10): 2232–2273. doi:10.1007/s12325-017-0612-x. PMC 5656728. PMID 28983798.
- Hoos A (April 2016). "Development of immuno-oncology drugs - from CTLA4 to PD1 to the next generations". Nature Reviews. Drug Discovery. 15 (4): 235–47. doi:10.1038/nrd.2015.35. PMID 26965203. S2CID 54550859.
- Pento JT (November 2017). "Monoclonal Antibodies for the Treatment of Cancer". Anticancer Research. 37 (11): 5935–5939. doi:10.21873/anticanres.12040. PMID 29061772.
- Simpson, Richard J. (July 2017). "Mobilizing Immune Cells with Exercise for Cancer Immunotherapy". Exerc Sport Sci Rev. 45 (3): 163–172. doi:10.1249/JES.0000000000000114. PMID 28418996.
- van Seters M, van Beurden M, ten Kate FJ, Beckmann I, Ewing PC, Eijkemans MJ, et al. (April 2008). "Treatment of vulvar intraepithelial neoplasia with topical imiquimod". The New England Journal of Medicine. 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". Journal of Lower Genital Tract Disease. 7 (4): 290–3. doi:10.1097/00128360-200310000-00011. PMID 17051086. S2CID 44649376.
- 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". European Urology. 56 (2): 260–5. doi:10.1016/j.eururo.2009.04.009. PMID 19395154.
- Davidson HC, Leibowitz MS, Lopez-Albaitero A, Ferris RL (September 2009). "Immunotherapy for head and neck cancer". Oral Oncology. 45 (9): 747–51. doi:10.1016/j.oraloncology.2009.02.009. PMID 19442565.
- Dani T, Knobler R (January 2009). "Extracorporeal photoimmunotherapy-photopheresis". Frontiers in Bioscience. 14 (14): 4769–77. doi:10.2741/3566. PMID 19273388.
- Eggermont AM, Schadendorf D (June 2009). "Melanoma and immunotherapy". Hematology/Oncology Clinics of North America. 23 (3): 547–64, ix–x. doi:10.1016/j.hoc.2009.03.009. PMID 19464602.
- 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. doi:10.1186/1423-0127-16-49. PMC 2705346. PMID 19473507.
- Pawlita M, Gissmann L (April 2009). "[Recurrent respiratory papillomatosis: indication for HPV vaccination?]". Deutsche Medizinische Wochenschrift (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, 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. doi:10.4161/cbt.8.16.8950. PMID 19471115.
- Di Lorenzo G, Buonerba C, Kantoff PW (May 2011). "Immunotherapy for the treatment of prostate cancer". Nature Reviews. Clinical Oncology. 8 (9): 551–61. doi:10.1038/nrclinonc.2011.72. PMID 21606971. S2CID 5337484.
- Sabado, Rachel L; Balan, Sreekumar; Bhardwaj, Nina (January 2017). "Dendritic cell-based immunotherapy". Cell Research. 27 (1): 74–95. doi:10.1038/cr.2016.157. ISSN 1001-0602. PMC 5223236. PMID 28025976.
- 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.
- Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, et al. (October 2006). "Cancer regression in patients after transfer of genetically engineered lymphocytes". Science. 314 (5796): 126–9. Bibcode:2006Sci...314..126M. doi:10.1126/science.1129003. PMC 2267026. PMID 16946036.
- Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. (June 2008). "Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1". The New England Journal of Medicine. 358 (25): 2698–703. doi:10.1056/NEJMoa0800251. PMC 3277288. PMID 18565862.
- "2008 Symposium Program & Speakers". Cancer Research Institute. Archived from the original on 2008-10-15.
- Highfield R (18 June 2008). "Cancer patient recovers after injection of immune cells". The Telegraph. Archived from the original on 12 September 2008. Retrieved 22 December 2019.
- Antony PA, Piccirillo CA, Akpinarli A, Finkelstein SE, Speiss PJ, Surman DR, et al. (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. doi:10.4049/jimmunol.174.5.2591. PMC 1403291. PMID 15728465.
- Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, et al. (October 2005). "Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells". The Journal of Experimental Medicine. 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". The Journal of Clinical Investigation. 110 (2): 185–92. doi:10.1172/JCI15175. PMC 151053. PMID 12122110.
- Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, et al. (November 2008). "Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens". Journal of Clinical Oncology. 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, et al. (October 2002). "Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes". Science. 298 (5594): 850–4. Bibcode:2002Sci...298..850D. doi:10.1126/science.1076514. PMC 1764179. PMID 12242449.
- Pilon-Thomas S, Kuhn L, Ellwanger S, Janssen W, Royster E, Marzban S, et al. (October 2012). "Efficacy of adoptive cell transfer of tumor-infiltrating lymphocytes after lymphopenia induction for metastatic melanoma". Journal of Immunotherapy. 35 (8): 615–20. doi:10.1097/CJI.0b013e31826e8f5f. PMC 4467830. PMID 22996367.
- Andersen R, Borch TH, Draghi A, Gokuldass A, Rana MA, Pedersen M, et al. (July 2018). "T cells isolated from patients with checkpoint inhibitor-resistant melanoma are functional and can mediate tumor regression". Annals of Oncology. 29 (7): 1575–1581. doi:10.1093/annonc/mdy139. PMID 29688262.
- Seidel, Judith A.; Otsuka, Atsushi; Kabashima, Kenji (2018-03-28). "Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations". Frontiers in Oncology. 8: 86. doi:10.3389/fonc.2018.00086. ISSN 2234-943X. PMC 5883082. PMID 29644214.
- Haanen, John B. A. G.; Robert, Caroline (2015). "Immune Checkpoint Inhibitors". Immuno-Oncology. Progress in Tumor Research. 42: 55–66. doi:10.1159/000437178. ISBN 978-3-318-05589-4. PMID 26382943.
- "Immune Checkpoint Inhibitors - National Cancer Institute". www.cancer.gov. 2019-09-24. Retrieved 2020-08-24.
- Manjunath SR, Ramanan G, Dedeepiya VD, Terunuma H, Deng X, Baskar S, et al. (January 2012). "Autologous immune enhancement therapy in recurrent ovarian cancer with metastases: a case report". Case Reports in Oncology. 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". Journal of Leukocyte Biology. 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". Journal of Immunotherapy. 34 (2): 129–38. doi:10.1097/CJI.0b013e3182048c4e. PMID 21304407. S2CID 26385818.
- 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". International Reviews of Immunology. 27 (3): 93–110. doi:10.1080/08830180801911743. PMID 18437601. S2CID 27557213.
- See DM, Tilles JG (1996). "alpha-Interferon treatment of patients with chronic fatigue syndrome". Immunological Investigations. 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". Clinical Infectious Diseases. 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". Pediatrics International. 42 (6): 631–6. doi:10.1046/j.1442-200x.2000.01315.x. PMID 11192519.
- Ospina-Quintero, Laura; Jaramillo, Julio C.; Tabares-Guevara, Jorge H.; Ramírez-Pineda, José R. (24 April 2020). "Reformulating Small Molecules for Cardiovascular Disease Immune Intervention: Low-Dose Combined Vitamin D/Dexamethasone Promotes IL-10 Production and Atheroprotection in Dyslipidemic Mice". Frontiers in Immunology. 11: 743. doi:10.3389/fimmu.2020.00743. PMC 7197409. PMID 32395119.
- Rayner, Fiona; Isaacs, John D (2018-12-01). "Therapeutic tolerance in autoimmune disease". Seminars in Arthritis and Rheumatism. 48 (3): 558–562. doi:10.1016/j.semarthrit.2018.09.008. ISSN 0049-0172. PMID 30348449.
- 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. S2CID 30884739.
- Stolp, Jessica; Zaitsu, Masaaki; Wood, Kathryn J. (2019), Boyd, Ashleigh S. (ed.), "Immune Tolerance and Rejection in Organ Transplantation", Immunological Tolerance, New York, NY: Springer New York, 1899, pp. 159–180, doi:10.1007/978-1-4939-8938-6_12, ISBN 978-1-4939-8936-2, PMID 30649772
- McMurchy, Alicia N.; Bushell, Andrew; Levings, Megan K.; Wood, Kathryn J. (2011-08-01). "Moving to tolerance: Clinical application of T regulatory cells". Seminars in Immunology. Advances in Transplantation. 23 (4): 304–313. doi:10.1016/j.smim.2011.04.001. ISSN 1044-5323. PMC 3836227. PMID 21620722.
- Baker, Kenneth F; Isaacs, John D (March 2014). "Prospects for Therapeutic Tolerance in Humans". Current Opinion in Rheumatology. 26 (2): 219–227. doi:10.1097/BOR.0000000000000029. ISSN 1040-8711. PMC 4640179. PMID 24378931.
- Cooles, Faye A. H.; Isaacs, John D. (2010-08-01). "Treating to re-establish tolerance in inflammatory arthritis – lessons from other diseases". Best Practice & Research Clinical Rheumatology. Pharmacotherapy: Concepts of Pathogenesis and Emerging Treatments. 24 (4): 497–511. doi:10.1016/j.berh.2010.01.007. ISSN 1521-6942. PMID 20732648.
- Durham SR, Walker SM, Varga EM, Jacobson MR, O'Brien F, Noble W, et al. (August 1999). "Long-term clinical efficacy of grass-pollen immunotherapy". The New England Journal of Medicine. 341 (7): 468–75. doi:10.1056/NEJM199908123410702. PMID 10441602. S2CID 14629112.
- Jones, Stacie M.; Burks, A. Wesley; Dupont, Christophe (2014-02-01). "State of the art on food allergen immunotherapy: Oral, sublingual, and epicutaneous". Journal of Allergy and Clinical Immunology. 133 (2): 318–323. doi:10.1016/j.jaci.2013.12.1040. ISSN 0091-6749. PMID 24636471.
- MacGinnitie, Andrew J.; Rachid, Rima; Gragg, Hana; Little, Sara V.; Lakin, Paul; Cianferoni, Antonella; Heimall, Jennifer; Makhija, Melanie; Robison, Rachel; Chinthrajah, R. Sharon; Lee, John (2017-03-01). "Omalizumab facilitates rapid oral desensitization for peanut allergy". Journal of Allergy and Clinical Immunology. 139 (3): 873–881.e8. doi:10.1016/j.jaci.2016.08.010. ISSN 0091-6749. PMC 5369605. PMID 27609658. S2CID 3626708.
- "Clinical Trials Search Results - Stanford University School of Medicine". med.stanford.edu. Retrieved 2016-04-03.
- Ring, J.; Gutermuth, J. (2011). "100 years of hyposensitization: history of allergen-specific immunotherapy (ASIT)". Allergy. 66 (6): 713–724. doi:10.1111/j.1398-9995.2010.02541.x. ISSN 1398-9995. PMID 21320133. S2CID 19390006.
- 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. S2CID 1033417.
- 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". Parasitology Research. 104 (2): 217–21. doi:10.1007/s00436-008-1297-5. PMID 19050918. S2CID 19279688.
- Laclotte C, Oussalah A, Rey P, Bensenane M, Pluvinage N, Chevaux JB, et al. (December 2008). "[Helminths and inflammatory bowel diseases]". Gastroenterologie Clinique et Biologique (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 Immunology. 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. 58. pp. 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, et al. (2009). Yazdanbakhsh M (ed.). "Necator americanus infection: a possible cause of altered dendritic cell differentiation and eosinophil profile in chronically infected individuals". PLOS Neglected Tropical Diseases. 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, et al. (June 2009). "Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions". The Journal of Experimental Medicine. 206 (6): 1395–408. doi:10.1084/jem.20082779. PMC 2715056. PMID 19468064.
- Reynolds, Lisa A.; Finlay, B. Brett; Maizels, Rick M. (2015-10-16). "Cohabitation in the Intestine: Interactions among Helminth Parasites, Bacterial Microbiota, and Host Immunity". The Journal of Immunology. 195 (9): 4059–4066. doi:10.4049/jimmunol.1501432. ISSN 0022-1767.
- Hong CH, Tang MR, Hsu SH, Yang CH, Tseng CS, Ko YC, et al. (September 2019). "Enhanced early immune response of leptospiral outer membrane protein LipL32 stimulated by narrow band mid-infrared exposure". Journal of Photochemistry and Photobiology. B, Biology. 198: 111560. doi:10.1016/j.jphotobiol.2019.111560. PMID 31336216.
- Chang HY, Li MH, Huang TC, Hsu CL, Tsai SR, Lee SC, et al. (February 2015). "Quantitative proteomics reveals middle infrared radiation-interfered networks in breast cancer cells". Journal of Proteome Research. 14 (2): 1250–62. doi:10.1021/pr5011873. PMID 25556991.
- Nagaya T, Okuyama S, Ogata F, Maruoka Y, Choyke PL, Kobayashi H (May 2019). "Near infrared photoimmunotherapy using a fiber optic diffuser for treating peritoneal gastric cancer dissemination". Gastric Cancer. 22 (3): 463–472. doi:10.1007/s10120-018-0871-5. PMC 7400986. PMID 30171392.
- Mitsunaga M, Ogawa M, Kosaka N, Rosenblum LT, Choyke PL, Kobayashi H (November 2011). "Cancer cell-selective in vivo near infrared photoimmunotherapy targeting specific membrane molecules". Nature Medicine. 17 (12): 1685–91. doi:10.1038/nm.2554. PMC 3233641. PMID 22057348.
- Sato K, Sato N, Xu B, Nakamura Y, Nagaya T, Choyke PL, et al. (August 2016). "Spatially selective depletion of tumor-associated regulatory T cells with near-infrared photoimmunotherapy". Science Translational Medicine. 8 (352): 352ra110. doi:10.1126/scitranslmed.aaf6843. PMID 27535621.
- Nagaya T, Nakamura Y, Sato K, Harada T, Choyke PL, Kobayashi H (June 2016). "Improved micro-distribution of antibody-photon absorber conjugates after initial near infrared photoimmunotherapy (NIR-PIT)". Journal of Controlled Release. 232: 1–8. doi:10.1016/j.jconrel.2016.04.003. PMC 4893891. PMID 27059723.
- Zhen Z, Tang W, Wang M, Zhou S, Wang H, Wu Z, et al. (February 2017). "Protein Nanocage Mediated Fibroblast-Activation Protein Targeted Photoimmunotherapy To Enhance Cytotoxic T Cell Infiltration and Tumor Control". Nano Letters. 17 (2): 862–869. Bibcode:2017NanoL..17..862Z. doi:10.1021/acs.nanolett.6b04150. PMID 28027646.