Immunotherapy

{{Short description|Activation or suppression of the immune system to treat disease}} {{About|immunotherapy in general|the specific use in oncology|Cancer immunotherapy|the academic journal|Immunotherapy (journal)}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{more medical citations needed|date=April 2018}}

{{Infobox medical intervention | Name = Immunotherapy | Image = CAR T-cell Therapy.svg| | Caption =The diagram above represents the process of chimeric antigen receptor T-cell therapy (CAR), this is a method of immunotherapy, which is a growing practice in the treatment of cancer. The final result should be a production of equipped T-cells that can recognize and fight the infected cancer cells in the body. {{ordered list |1=T-cells (represented by objects labeled as 't') are removed from the patient's blood. |2=Then in a lab setting the gene that encodes for the specific antigen receptors are incorporated into the T-cells. |3=Thus producing the CAR receptors (labeled as c) on the surface of the cells. |4=The newly modified T-cells are then further harvested and grown in the lab. |5=After a certain time period, the engineered T-cells are infused back into the patient. }} | ICD10 = | ICD9unlinked = | MeshID = D007167 | OPS301 = {{OPS301|8-03}} | OtherCodes = }}

'''Immunotherapy''', also known as '''biological therapy''' or '''biotherapy''', encompasses a diverse set of therapeutic strategies that harness or modify the immune system to prevent, control, or eliminate disease. In its narrowest definition, immunotherapy refers to treatments designed to stimulate or guide the immune system to recognize and fight cancer, often by enhancing or restoring immune responses to eradicate malignant cells while sparing healthy tissue.<ref name="cancer.org">{{cite web |last= |date=7 August 2025 |title=What Is Immunotherapy? |url=https://www.cancer.org/cancer/managing-cancer/treatment-types/immunotherapy.html |access-date=5 October 2025 |work=American Cancer Society |language=en}}</ref><ref name="NCI">{{cite web |last= |date=24 September 2019 |title=Immunotherapy to Treat Cancer |url=https://www.cancer.gov/about-cancer/treatment/types/immunotherapy |access-date=5 October 2025 |work=National Cancer Institute (NCI) |publisher=U.S. Department of Health and Human Services |language=en}}</ref><ref name="cancerresearch.org">{{cite web |last= |date=15 August 2025  |title=What Is Immunotherapy? |url=https://www.cancerresearch.org/what-is-immunotherapy |access-date=5 October 2025 |work=Cancer Research Institute}}</ref>

A broader definition of immunotherapy applies beyond oncology, including strategies to stimulate or suppress immune activity against other diseases such as autoimmune disorders, infectious diseases, and allergies. These approaches may involve vaccines, immune modulators, or monoclonal antibodies designed to alter immune responses, either to boost protection against pathogens or to reduce damaging inflammation.<ref>{{cite web |last= |date= |title=Diseases We Treat With Immunotherapy |url=https://www.moffitt.org/treatments/immunotherapy/diseases-treated-with-immunotherapy/ |access-date=5 October 2025 |work=Immunotherapy |publisher=Moffitt Cancer Center |language=en}}</ref><ref>{{cite web |last= |date=2 February 2011  |title=Definition of immunotherapy |url=https://www.cancer.gov/publications/dictionaries/cancer-terms/def/immunotherapy |access-date=5 October 2025 |work=NCI Dictionary of Cancer Terms |publisher=National Cancer Institute |language=en}}</ref>

Immunotherapy includes both passive methods, like monoclonal antibodies that mark abnormal cells for immune destruction, and active methods, such as cancer vaccines, immune checkpoint inhibitors, adoptive cell transfer, and cytokine therapies. Advances in immunotherapy have transformed the treatment landscape for cancer and are increasingly applied to a wider range of conditions, improving outcomes for many patients, though responses can vary depending on disease type, genetic background, and environmental factors.<ref name="NCI" /><ref name="cancerresearch.org" /><ref name="Spranger_2016">{{cite book |title=Tumor Immunology |vauthors=Spranger S, Sivan A, Corrales L, Gajewski TF |date=2016 |publisher=Elsevier |isbn=978-0-12-805156-6 |veditors=Schreiber RD |series=Advances in Immunology |volume=130 |pages=75–93 |chapter=Chapter Three — Tumor and Host Factors Controlling Antitumor Immunity and Efficacy of Cancer Immunotherapy |doi=10.1016/bs.ai.2015.12.003 |pmc=4864964 |pmid=26923000}}</ref><ref name="Gunjur_2022">{{cite journal |vauthors=Gunjur A, Manrique-Rincón AJ, Klein O, Behren A, Lawley TD, Welsh SJ, Adams DJ |date=8 April 2022  |title='Know thyself' - host factors influencing cancer response to immune checkpoint inhibitors |journal=The Journal of Pathology |type=Invited review |volume=257 |issue=4 |pages=513–525 |doi=10.1002/path.5907 |pmc=9320825 |pmid=35394069}}</ref><ref name="Baci_2022">{{cite journal |vauthors=Baci D, Cekani E, Imperatori A, Ribatti D, Mortara L |date=5 July 2022  |title=Host-Related Factors as Targetable Drivers of Immunotherapy Response in Non-Small Cell Lung Cancer Patients |journal=Frontiers in Immunology |type=Review article |volume=13 |doi=10.3389/fimmu.2022.914890 |pmc=9298844 |pmid=35874749 |doi-access=free |article-number=914890}}</ref>

Cell-based immunotherapies are effective for some cancers.<ref>{{cite journal |vauthors=Riley RS, June CH, Langer R, Mitchell MJ |date=March 2019 |title=Delivery technologies for cancer immunotherapy |journal=Nature Reviews Drug Discovery |type=Review article |volume=18 |issue=3 |pages=175–196 |doi=10.1038/s41573-018-0006-z |pmc=6410566 |pmid=30622344}}</ref><ref>{{Cite journal |vauthors=Li Y, McBride DW, Tang Y, Doycheva D, Zhang JH, Tang Z |date=16 February 2023  |title=Immunotherapy as a treatment for Stroke: Utilizing regulatory T cells |journal=Brain Hemorrhages |type=Review article |publisher=KeAi Communications Co., Ltd. |publication-place=Beijing, China |volume=4 |issue=3 |pages=147–153 |doi=10.1016/j.hest.2023.02.003 |doi-access=free}}</ref> Immune effector cells such as lymphocytes, macrophages, dendritic cells, natural killer cells, and cytotoxic T lymphocytes work together to defend the body against cancer by targeting abnormal antigens expressed on the surface of tumor cells. Vaccine-induced immunity to COVID-19 relies mostly on an immunomodulatory T-cell response.<ref name="Geers_2021">{{cite journal |vauthors=Geers D, Shamier MC, Bogers S, den Hartog G, Gommers L, Nieuwkoop NN, Schmitz KS, Rijsbergen LC, van Osch JA, Dijkhuizen E, Smits G, Comvalius A, van Mourik D, Caniels TG, van Gils MJ, Sanders RW, Oude Munnink BB, Molenkamp R, de Jager HJ, Haagmans BL, de Swart RL, Koopmans MP, van Binnendijk RS, de Vries RD, GeurtsvanKessel CH |date=28 May 2021 |title=SARS-CoV-2 variants of concern partially escape humoral but not T-cell responses in COVID-19 convalescent donors and vaccinees |journal=Science Immunology |type=Research article |volume=6 |issue=59 |doi=10.1126/sciimmunol.abj1750 |pmc=9268159 |pmid=34035118 |doi-access=free |article-number=eabj1750}}</ref>

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. {{toclimit|3}}

==Immunomodulators== Immunomodulators are the active agents of immunotherapy. They are a diverse array of recombinant, synthetic, and natural preparations.<ref>{{cite journal |vauthors=Rizk JG, Kalantar-Zadeh K, Mehra MR, Lavie CJ, Rizk Y, Forthal DN |date=21 July 2020  |title=Pharmaco-Immunomodulatory Therapy in COVID-19 |journal=Drugs |type=Leading article (topic overview) |volume=80 |issue=13 |pages=1267–1292 |doi=10.1007/s40265-020-01367-z |pmc=7372203 |pmid=32696108 |doi-access=free}}</ref> {| class="wikitable sortable" style="text-align:center" ! Class !! Example agents |- | Interleukins || IL-2, IL-7, IL-12 |- | Cytokines || Interferons, G-CSF |- | Chemokines || CCL3, CCL26, CXCL7 |- Antimicrobial peptides || | Immunomodulatory imide drugs (IMiDs) || thalidomide and its analogues (lenalidomide, pomalidomide, and apremilast), BCG vaccine,<ref>{{Cite web |last= |date=7 July 2025  |title=Immunomodulators and Their Side Effects |url=https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/immunomodulators.html |url-status=live |archive-url=https://web.archive.org/web/20250716000310/https://www.cancer.org/cancer/managing-cancer/treatment-types/immunotherapy/immunomodulators.html |archive-date=16 July 2025 |access-date=5 October 2025 |website=Immunotherapy |publisher=American Cancer Society}}</ref><ref>{{cite journal |vauthors=Martino A, Casetti R, Poccia F |date=22 January 2007  |title=Enhancement of BCG-induced Th1 immune response through Vgamma9Vdelta2 T cell activation with non-peptidic drugs |journal=Vaccine |volume=25 |issue=6 |pages=1023–1029 |doi=10.1016/j.vaccine.2006.09.070 |pmid=17118497 }}</ref> & Covid vaccines<ref>{{cite journal |vauthors=Sahin U, Muik A, Derhovanessian E, Vogler I, Kranz LM, Vormehr M, Baum A, Pascal K, Quandt J, Maurus D, Brachtendorf S, Lörks V, Sikorski J, Hilker R, Becker D, Eller AK, Grützner J, Boesler C, Rosenbaum C, Kühnle MC, Luxemburger U, Kemmer-Brück A, Langer D, Bexon M, Bolte S, Karikó K, Palanche T, Fischer B, Schultz A, Shi PY, Fontes-Garfias C, Perez JL, Swanson KA, Loschko J, Scully IL, Cutler M, Kalina W, Kyratsous CA, Cooper D, Dormitzer PR, Jansen KU, Türeci Ö |date=30 September 2020  |title=COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses |journal=Nature |type=Article |volume=586 |issue=7830 |pages=594–599 |bibcode=2020Natur.586..594S |doi=10.1038/s41586-020-2814-7 |pmid=32998157 |doi-access=free}}</ref><ref>{{cite journal |vauthors=Woldemeskel BA, Garliss CC, Blankson JN |date=6 April 2021  |title=SARS-CoV-2 mRNA vaccines induce broad CD4+ T cell responses that recognize SARS-CoV-2 variants and HCoV-NL63 |journal=The Journal of Clinical Investigation |type=Concise communication |volume=131 |issue=10 |doi=10.1172/JCI149335 |pmc=8121504 |pmid=33822770 |article-number=e149335}}</ref><ref name="Geers_2021" /> {{dubious|reason=COVID-19 and BCG vaccines are not chemically classified as IMiDs; clarification needed.|date=May 2025}} |- | Other || cytosine phosphate-guanosine, oligodeoxynucleotides, glucans |}

==Activation immunotherapies==

===Cancer=== {{main|Cancer immunotherapy}}

Cancer treatment used to be focused on killing or removing cancer cells and tumours, with chemotherapy or surgery or radiation. 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 tumours. 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<ref name="Syn_2017">{{Cite journal |vauthors=Syn NL, Teng MW, Mok TS, Soo RA |date=December 2017 |title=De-novo and acquired resistance to immune checkpoint targeting |journal=The Lancet Oncology |type=Review |publisher=Elsevier |volume=18 |issue=12 |pages=e731–e741 |doi=10.1016/s1470-2045(17)30607-1 |pmid=29208439}}</ref> and its efficacy is enhanced by 20–30% when cell-based immunotherapy is combined with conventional treatment methods.<ref name="Syn_2017" />

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.<ref>{{cite journal |vauthors=Fuge O, Vasdev N, Allchorne P, Green JS |date=2015 |title=Immunotherapy for bladder cancer |journal=Research and Reports in Urology |type=Review |volume=7 |pages=65–79 |doi=10.2147/RRU.S63447 |pmc=4427258 |pmid=26000263 |doi-access=free}}</ref> BCG immunotherapy induces both local and systemic immune responses. The mechanisms by which BCG immunotherapy mediates tumor immunity have been widely studied, but they are still not completely understood.<ref>{{cite journal |vauthors=Pettenati C, Ingersoll MA |date=10 July 2018 |title=Mechanisms of BCG immunotherapy and its outlook for bladder cancer |journal=Nature Reviews Urology |type=Review article |volume=15 |issue=10 |pages=615–625 |doi=10.1038/s41585-018-0055-4 |pmid=29991725}}</ref>

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.<ref>{{cite journal |vauthors=Salles G, Barrett M, Foà R, Maurer J, O'Brien S, Valente N, Wenger M, Maloney DG |date=5 October 2017 |title=Rituximab in B-Cell Hematologic Malignancies: A Review of 20 Years of Clinical Experience |journal=Advances in Therapy |type=Review |volume=34 |issue=10 |pages=2232–2273 |doi=10.1007/s12325-017-0612-x |pmc=5656728 |pmid=28983798 |doi-access=free}}</ref> Since then several monoclonal antibodies have been approved for treatment of various haematological malignancies as well as for solid tumours.<ref>{{cite journal |vauthors=Hoos A |date=11 March 2016 |title=Development of immuno-oncology drugs - from CTLA4 to PD1 to the next generations |journal=Nature Reviews Drug Discovery |type=Outlook |volume=15 |issue=4 |pages=235–247 |doi=10.1038/nrd.2015.35 |pmid=26965203}}</ref><ref>{{cite journal |vauthors=Pento JT |date=November 2017 |title=Monoclonal Antibodies for the Treatment of Cancer |journal=Anticancer Research |type=Review article |volume=37 |issue=11 |pages=5935–5939 |doi=10.21873/anticanres.12040 |pmc=3288558 |pmid=29061772 |doi-access=free}}</ref>

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 tumour cells that express the antigen.<ref>{{cite journal |vauthors=Simpson RJ, Bigley AB, Agha N, Hanley PJ, Bollard CM |date=July 2017 |title=Mobilizing Immune Cells With Exercise for Cancer Immunotherapy |journal=Exercise and Sport Sciences Reviews |type=Article |volume=45 |issue=3 |pages=163–172 |doi=10.1249/JES.0000000000000114 |pmc=6814300 |pmid=28418996}}</ref> Topical immunotherapy utilizes an immune enhancement cream (imiquimod) which produces interferon, causing the recipient's killer T cells to destroy warts,<ref name="van_Seters_2008">{{cite journal |vauthors=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 |date=3 April 2008 |title=Treatment of vulvar intraepithelial neoplasia with topical imiquimod |journal=The New England Journal of Medicine |type=Original article |volume=358 |issue=14 |pages=1465–1473 |doi=10.1056/NEJMoa072685 |hdl=1765/32485 |pmid=18385498 |doi-access=free |hdl-access=free}}</ref> actinic keratoses, basal cell cancer, vaginal intraepithelial neoplasia,<ref name="Buck_2003">{{cite journal |vauthors=Buck HW, Guth KJ |date=October 2003 |title=Treatment of vaginal intraepithelial neoplasia (primarily low grade) with imiquimod 5% cream |journal=Journal of Lower Genital Tract Disease |type=Original article |publisher=Lippincott Williams & Wilkins |publication-place=United States |volume=7 |issue=4 |pages=290–293 |doi=10.1097/00128360-200310000-00011 |pmid=17051086 }}</ref> squamous cell cancer,<ref name="Jarvinen_2009">{{cite journal |vauthors=Järvinen R, Kaasinen E, Sankila A, Rintala E |date=August 2009 |orig-date=available online 16 April 2009 |title=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 |journal=European Urology |type=Research article |volume=56 |issue=2 |pages=260–265 |doi=10.1016/j.eururo.2009.04.009 |pmid=19395154 }}</ref><ref name="Davidson_2009">{{cite journal |vauthors=Davidson HC, Leibowitz MS, Lopez-Albaitero A, Ferris RL |date=September 2009 |orig-date=Available online 12 May 2009 |title=Immunotherapy for head and neck cancer |journal=Oral Oncology |type=Review |volume=45 |issue=9 |pages=747–751 |doi=10.1016/j.oraloncology.2009.02.009 |pmc=8978306 |pmid=19442565 |doi-access=free}}</ref> cutaneous lymphoma,<ref name="Dani_2009">{{cite journal |vauthors=Dani T, Knobler R |date=1 January 2009 |title=Extracorporeal photoimmunotherapy-photopheresis |journal=Frontiers in Bioscience |type=Article |volume=14 |issue=12 |pages=4769–4777 |doi=10.2741/3566 |pmid=19273388 |doi-access=free}}</ref> and superficial melanoma.<ref name="Eggermont_2009">{{cite journal |vauthors=Eggermont AM, Schadendorf D |title=Melanoma and Immunotherapy |journal=Hematology/Oncology Clinics of North America |type=Review |date=June 2009 |volume=23 |issue=3 |pages=547–564 |doi=10.1016/j.hoc.2009.03.009 |pmid=19464602 }}</ref> Injection immunotherapy ("intralesional" or "intratumoural") uses mumps, candida, the HPV vaccine<ref name="Chuang_2009">{{cite journal | vauthors = Chuang CM, Monie A, Wu A, Hung CF | title = Combination of apigenin treatment with therapeutic HPV DNA vaccination generates enhanced therapeutic antitumor effects | journal = Journal of Biomedical Science | volume = 16 | issue = 1 | page = 49 | date = May 2009 | pmid = 19473507 | pmc = 2705346 | doi = 10.1186/1423-0127-16-49 | doi-access = free }}</ref><ref name="Pawlita_2009">{{cite journal | vauthors = Pawlita M, Gissmann L | title = Rekurrierende respiratorische Papillomatose: Indikation für HPV-Vakzination? | journal = Deutsche Medizinische Wochenschrift | volume = 134 | issue = Suppl 2 | pages = S100–S102 | date = April 2009 | pmid = 19353471 | doi = 10.1055/s-0029-1220219 | language = de | trans-title = Recurrent respiratory papillomatosis: indication for HPV vaccination? }}</ref> or trichophytin antigen injections to treat warts (HPV induced tumours).

Adoptive cell transfer has been tested on lung<ref name="Kang_2009">{{cite journal | vauthors = Kang N, Zhou J, Zhang T, Wang L, Lu F, Cui Y, Cui L, He W | title = Adoptive immunotherapy of lung cancer with immobilized anti-TCRgammadelta antibody-expanded human gammadelta T-cells in peripheral blood | journal = Cancer Biology & Therapy | volume = 8 | issue = 16 | pages = 1540–1549 | date = August 2009 | pmid = 19471115 | doi = 10.4161/cbt.8.16.8950 }}</ref> and other cancers, with greatest success achieved in melanoma.

====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 tumour 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 tumour cells expressing the antigen (against which the adaptive response has now been primed). The first FDA-approved cell-based immunotherapy,<ref>{{cite journal | vauthors = Cheever MA, Higano CS | title = PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine | journal = Clinical Cancer Research | volume = 17 | issue = 11 | pages = 3520–3526 | date = June 2011 | pmid = 21471425 | doi = 10.1158/1078-0432.CCR-10-3126 | doi-access = free }}</ref> the cancer vaccine Sipuleucel-T is one example of this approach.<ref name="Di_Lorenzo_2011">{{cite journal | vauthors = Di Lorenzo G, Buonerba C, Kantoff PW | title = Immunotherapy for the treatment of prostate cancer | journal = Nature Reviews. Clinical Oncology | volume = 8 | issue = 9 | pages = 551–561 | date = May 2011 | pmid = 21606971 | doi = 10.1038/nrclinonc.2011.72 }}</ref> The Immune Response Corporation<ref>{{cite journal | title = Sipuleucel-T: APC 8015, APC-8015, prostate cancer vaccine--Dendreon | journal = Drugs in R&D | volume = 7 | issue = 3 | pages = 197–201 | date = 2006 | pmid = 16752945 | doi = 10.2165/00126839-200607030-00006 }}</ref> (IRC) developed this immunotherapy and licensed the technology to Dendreon, which obtained FDA clearance.

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. Multiple, next-generation anti-CD40 platforms are being actively developed.<ref>{{cite journal | vauthors = Andersson H, Nyesiga B, Hermodsson T, Enell Smith K, Hägerbrand K, Lindstedt M, Ellmark P | title = Next-generation CD40 agonists for cancer immunotherapy | journal = Expert Opinion on Biological Therapy | volume = 24 | issue = 5 | pages = 351–363 | date = May 2024 | pmid = 38764393 | doi = 10.1080/14712598.2024.2357714 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Sabado RL, Balan S, Bhardwaj N | title = Dendritic cell-based immunotherapy | journal = Cell Research | volume = 27 | issue = 1 | pages = 74–95 | date = January 2017 | pmid = 28025976 | pmc = 5223236 | doi = 10.1038/cr.2016.157 }}</ref>

====Adoptive cell therapy==== Adoptive cell therapy encompasses three main approaches: (1) TIL therapy, (2) T cell receptor-engineered T cells (TCR-T cells), and (3) chimeric antigen receptor T cells (CAR-T cells), with newer adaptations including CAR-NK cells and CAR-macrophages under early investigation.

The first proof-of-concept for ACT was demonstrated by Steven Rosenberg and colleagues in 1988, when they showed that TILs expanded ex vivo and reinfused into patients, together with high-dose interleukin-2, could mediate tumor regression in patients with metastatic melanoma.<ref>{{cite journal | vauthors = Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST, Simon P, Lotze MT, Yang JC, Seipp CA | title = Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report | journal = The New England Journal of Medicine | volume = 319 | issue = 25 | pages = 1676–1680 | date = December 1988 | pmid = 3264384 | doi = 10.1056/NEJM198812223192527 }}</ref> In 2024, FDA has granted an accelerated approval for lifileucel, a TIL-based therapy for metastatic melanoma.<ref>{{cite journal | vauthors = Chesney J, Lewis KD, Kluger H, Hamid O, Whitman E, Thomas S, Wermke M, Cusnir M, Domingo-Musibay E, Phan GQ, Kirkwood JM, Hassel JC, Orloff M, Larkin J, Weber J, Furness AJ, Khushalani NI, Medina T, Egger ME, Graf Finckenstein F, Jagasia M, Hari P, Sulur G, Shi W, Wu X, Sarnaik A | title = Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study | journal = Journal for Immunotherapy of Cancer | volume = 10 | issue = 12 | article-number = e005755 | date = December 2022 | pmid = 36600653 | pmc = 9748991 | doi = 10.1136/jitc-2022-005755 }}</ref>

Adoptive cell transfer ''in vitro'' cultivates autologous, extracted T cells for later transfusion.<ref name="Rosenberg_2008">{{cite journal | vauthors = Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME | title = Adoptive cell transfer: a clinical path to effective cancer immunotherapy | journal = Nature Reviews. Cancer | volume = 8 | issue = 4 | pages = 299–308 | date = April 2008 | pmid = 18354418 | pmc = 2553205 | doi = 10.1038/nrc2355 }}</ref>

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.<ref name="Morgan_2006">{{cite journal | vauthors = 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 | title = Cancer regression in patients after transfer of genetically engineered lymphocytes | journal = Science | volume = 314 | issue = 5796 | pages = 126–129 | date = October 2006 | pmid = 16946036 | pmc = 2267026 | doi = 10.1126/science.1129003 | bibcode = 2006Sci...314..126M }}</ref> The technique has been tested on refractory stage IV metastatic melanomas<ref name="Rosenberg_2008" /> and advanced skin cancer.<ref name="Hunder_2008">{{cite journal | vauthors = Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, Jungbluth A, Gnjatic S, Thompson JA, Yee C | title = Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1 | journal = The New England Journal of Medicine | volume = 358 | issue = 25 | pages = 2698–2703 | date = June 2008 | pmid = 18565862 | pmc = 3277288 | doi = 10.1056/NEJMoa0800251 }}</ref><ref name="urlCancer Research Institute - 2008 Symposium Program & Speakers">{{Cite web | title = 2008 Symposium Program & Speakers | url = http://www.cancerresearch.org/events/symposium/cancer-immunology-immunotherapy-2008/program-speakers.html | archive-url = https://web.archive.org/web/20081015045915/http://www.cancerresearch.org/events/symposium/cancer-immunology-immunotherapy-2008/program-speakers.html | archive-date = 2008-10-15 | publisher = Cancer Research Institute }}</ref><ref>{{Cite news | vauthors = Highfield R | title = Cancer patient recovers after injection of immune cells | date = 18 June 2008 | url = https://www.telegraph.co.uk/earth/main.jhtml?xml=/earth/2008/06/18/scicanc118.xml | archive-url = https://web.archive.org/web/20080912063314/http://www.telegraph.co.uk/earth/main.jhtml?xml=%2Fearth%2F2008%2F06%2F18%2Fscicanc118.xml | archive-date = 12 September 2008 | access-date = 22 December 2019 | work = The Telegraph }}</ref> In 2024, the FDA granted accelerated approval to afamitresgene autoleucel (TECELTA, Adaptimmune LLC), the first TCR-T therapy for solid tumors.<ref>{{cite journal | vauthors = D'Angelo SP, Araujo DM, Abdul Razak AR, Agulnik M, Attia S, Blay JY, Carrasco Garcia I, Charlson JA, Choy E, Demetri GD, Druta M, Forcade E, Ganjoo KN, Glod J, Keedy VL, Le Cesne A, Liebner DA, Moreno V, Pollack SM, Schuetze SM, Schwartz GK, Strauss SJ, Tap WD, Thistlethwaite F, Valverde Morales CM, Wagner MJ, Wilky BA, McAlpine C, Hudson L, Navenot JM, Wang T, Bai J, Rafail S, Wang R, Sun A, Fernandes L, Van Winkle E, Elefant E, Lunt C, Norry E, Williams D, Biswas S, Van Tine BA | title = Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial | journal = Lancet | volume = 403 | issue = 10435 | pages = 1460–1471 | date = April 2024 | pmid = 38554725 | pmc = 11419333 | doi = 10.1016/S0140-6736(24)00319-2 }}</ref>

CAR-T therapy uses peripheral blood T cells that are genetically engineered ex vivo to express synthetic receptors targeting specific tumor antigens. To date, the FDA has approved several CAR-T cell therapies for hematological malignancies, including B-cell acute lymphoblastic leukemia, B-cell lymphoma, and multiple myeloma.<ref name="auto">{{cite journal | vauthors = Albelda SM | title = CAR T cell therapy for patients with solid tumours: key lessons to learn and unlearn | journal = Nature Reviews. Clinical Oncology | volume = 21 | issue = 1 | pages = 47–66 | date = January 2024 | pmid = 37904019 | doi = 10.1038/s41571-023-00832-4 }}</ref> The first FDA-approved CAR-T therapy, Kymriah, used this approach. To obtain the clinical and commercial supply of this CAR-T, Novartis purchased the manufacturing plant, the distribution system and hired the production team that produced Sipuleucel-T developed by Dendreon and the Immune Response Corporation.<ref>{{Cite news | title = Updated: Novartis buys Dendreon New Jersey plant | date = 20 December 2012 | url = https://www.fiercepharma.com/supply-chain/updated-novartis-buys-dendreon-new-jersey-plant | url-status = live | archive-url = https://web.archive.org/web/20230607102450/https://www.fiercepharma.com/supply-chain/updated-novartis-buys-dendreon-new-jersey-plant | archive-date = 2023-06-07 | access-date = 2021-12-09 | work = Fierce Pharma | language = en }}</ref>

Whether T cells are genetically engineered or not, before re-infusion, lympho-depletion 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.<ref name="Rosenberg_2008" /><ref name="Antony_2005">{{cite journal | vauthors = Antony PA, Piccirillo CA, Akpinarli A, Finkelstein SE, Speiss PJ, Surman DR, Palmer DC, Chan CC, Klebanoff CA, Overwijk WW, Rosenberg SA, Restifo NP | title = 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 = Journal of Immunology | volume = 174 | issue = 5 | pages = 2591–2601 | date = March 2005 | pmid = 15728465 | pmc = 1403291 | doi = 10.4049/jimmunol.174.5.2591 }}</ref><ref name="Gattinoni_2005">{{cite journal | vauthors = 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 | title = Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells | journal = The Journal of Experimental Medicine | volume = 202 | issue = 7 | pages = 907–912 | date = October 2005 | pmid = 16203864 | pmc = 1397916 | doi = 10.1084/jem.20050732 }}</ref><ref name="Dummer_2002">{{cite journal | vauthors = Dummer W, Niethammer AG, Baccala R, Lawson BR, Wagner N, Reisfeld RA, Theofilopoulos AN | title = T cell homeostatic proliferation elicits effective antitumor autoimmunity | journal = The Journal of Clinical Investigation | volume = 110 | issue = 2 | pages = 185–192 | date = July 2002 | pmid = 12122110 | pmc = 151053 | doi = 10.1172/JCI15175 }}</ref> Lymphodepletion may be achieved by myeloablative chemotherapy, to which total body irradiation may be added for greater effect.<ref name="Dudley_2008">{{cite journal | vauthors = 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 | title = Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens | journal = Journal of Clinical Oncology | volume = 26 | issue = 32 | pages = 5233–5239 | date = November 2008 | pmid = 18809613 | pmc = 2652090 | doi = 10.1200/JCO.2008.16.5449 }}</ref> 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.<ref name="Dudley_2002">{{cite journal | vauthors = 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 | title = Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes | journal = Science | volume = 298 | issue = 5594 | pages = 850–854 | date = October 2002 | pmid = 12242449 | pmc = 1764179 | doi = 10.1126/science.1076514 | bibcode = 2002Sci...298..850D }}</ref> {{As of|2012}}, clinical trials for metastatic melanoma were ongoing at multiple sites.<ref name="PilonThomas_2012">{{cite journal | vauthors = 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 | title = Efficacy of adoptive cell transfer of tumor-infiltrating lymphocytes after lymphopenia induction for metastatic melanoma | journal = Journal of Immunotherapy | volume = 35 | issue = 8 | pages = 615–620 | date = October 2012 | pmid = 22996367 | pmc = 4467830 | doi = 10.1097/CJI.0b013e31826e8f5f }}</ref> Clinical responses to adoptive transfer of T cells were observed in patients with metastatic melanoma resistant to multiple immunotherapies.<ref name="Andersen_2018">{{cite journal | vauthors = Andersen R, Borch TH, Draghi A, Gokuldass A, Rana MA, Pedersen M, Nielsen M, Kongsted P, Kjeldsen JW, Westergaard MC, Radic HD, Chamberlain CA, Hölmich LR, Hendel HW, Larsen MS, Met Ö, Svane IM, Donia M | title = T cells isolated from patients with checkpoint inhibitor-resistant melanoma are functional and can mediate tumor regression | journal = Annals of Oncology | volume = 29 | issue = 7 | pages = 1575–1581 | date = July 2018 | pmid = 29688262 | doi = 10.1093/annonc/mdy139 | doi-access = free }}</ref> Although CAR-T cell therapies have shown significant success in hematological malignancies, their application in solid tumors remains limited. Several recent reviews discussed emerging strategies for solid tumor CAR-T cell therapy, and highlighted novel targets that may help overcome current challenges in antigen specificity and tumor infiltration.<ref name="auto"/><ref>{{cite journal | vauthors = Ouladan S, Orouji E | title = Chimeric Antigen Receptor-T Cells in Colorectal Cancer: Pioneering New Avenues in Solid Tumor Immunotherapy | journal = Journal of Clinical Oncology | volume = 43 | issue = 8 | pages = 994–1005 | date = March 2025 | pmid = 39805063 | pmc = 11895826 | doi = 10.1200/JCO-24-02081 }}</ref><ref>{{cite journal | vauthors = Uslu U, June CH | title = Beyond the blood: expanding CAR T cell therapy to solid tumors | journal = Nature Biotechnology | volume = 43 | issue = 4 | pages = 506–515 | date = April 2025 | pmid = 39533105 | doi = 10.1038/s41587-024-02446-2 }}</ref>

==== Checkpoint inhibitors ==== {{Main|Checkpoint inhibitor}} 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.<ref>{{cite journal | vauthors = Seidel JA, Otsuka A, Kabashima K | title = Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations | journal = Frontiers in Oncology | volume = 8 | article-number = 86 | date = 2018-03-28 | pmid = 29644214 | pmc = 5883082 | doi = 10.3389/fonc.2018.00086 | doi-access = free }}</ref>

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.<ref name="Haanen_2015">{{cite book | vauthors = Haanen JB, Robert C | chapter = Immune Checkpoint Inhibitors | title = ImmunoOncology | volume = 42 | pages = 55–66 | date = 2015 | pmid = 26382943 | doi = 10.1159/000437178 | series = Progress in Tumor Research | isbn = 978-3-318-05589-4 }}</ref>

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, lung cancer head and neck cancer, or Hodgkin lymphoma.<ref>{{Cite web | title = Immune Checkpoint Inhibitors - National Cancer Institute | date = 2019-09-24 | url = https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/checkpoint-inhibitors | url-status = live | archive-url = https://web.archive.org/web/20231022075124/https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/checkpoint-inhibitors | archive-date = 2023-10-22 | access-date = 2020-08-24 | website = National Cancer Institute }}</ref><ref>{{Cite web | title = Immunotherapy By Cancer Type | url = https://www.cancerresearch.org/immunotherapy-by-cancer-type | website = Cancer Research Institute }}</ref>

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 benefiting long-term from these treatments, although caution remains needed for specific subgroups.<ref name="Haanen_2015" /><ref name="Queirolo_2019">{{cite journal | vauthors = Queirolo P, Boutros A, Tanda E, Spagnolo F, Quaglino P | title = Immune-checkpoint inhibitors for the treatment of metastatic melanoma: a model of cancer immunotherapy | journal = Seminars in Cancer Biology | volume = 59 | pages = 290–297 | date = December 2019 | pmid = 31430555 | doi = 10.1016/j.semcancer.2019.08.001 | hdl-access = free | hdl = 2318/1717353 }}</ref><ref name="Moyers_2021">{{Cite book | vauthors = Moyers JT, Glitza Oliva IC | chapter = Immunotherapy for Melanoma | title = Immunotherapy | volume = 1342 | pages = 81–111 | date = 2021 | pmid = 34972963 | doi = 10.1007/978-3-030-79308-1_3 | isbn = 978-3-030-79307-4 | series = Advances in Experimental Medicine and Biology }}</ref>

The next generation of checkpoint inhibitors targets other receptors such as lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT). Antibodies against these receptors have been evaluated in clinical studies, but have not yet been approved for widespread use.<ref>{{cite journal | vauthors = Cai L, Li Y, Tan J, Xu L, Li Y | title = Targeting LAG-3, TIM-3, and TIGIT for cancer immunotherapy | journal = Journal of Hematology & Oncology | volume = 16 | issue = 1 | page = 101 | date = September 2023 | pmid = 37670328 | pmc = 10478462 | doi = 10.1186/s13045-023-01499-1 | doi-access = free | article-number = 101 }}</ref>

==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 re-infused.<ref name="Manjunath_2012">{{cite journal | vauthors = Manjunath SR, Ramanan G, Dedeepiya VD, Terunuma H, Deng X, Baskar S, Senthilkumar R, Thamaraikannan P, Srinivasan T, Preethy S, Abraham SJ | title = Autologous immune enhancement therapy in recurrent ovarian cancer with metastases: a case report | journal = Case Reports in Oncology | volume = 5 | issue = 1 | pages = 114–118 | date = January 2012 | pmid = 22666198 | pmc = 3364094 | doi = 10.1159/000337319 }}</ref> The therapy has been tested against hepatitis C,<ref name="Doskali_2004">{{cite journal | vauthors = Li Y, Zhang T, Ho C, Orange JS, Douglas SD, Ho WZ | title = Natural killer cells inhibit hepatitis C virus expression | journal = Journal of Leukocyte Biology | volume = 76 | issue = 6 | pages = 1171–1179 | date = December 2004 | pmid = 15339939 | doi = 10.1189/jlb.0604372 | doi-access = free }}</ref><ref name="Li_2011">{{cite journal | vauthors = Doskali M, Tanaka Y, Ohira M, Ishiyama K, Tashiro H, Chayama K, Ohdan H | title = Possibility of adoptive immunotherapy with peripheral blood-derived CD3⁻CD56+ and CD3+CD56+ cells for inducing antihepatocellular carcinoma and antihepatitis C virus activity | journal = Journal of Immunotherapy | volume = 34 | issue = 2 | pages = 129–138 | date = March 2011 | pmid = 21304407 | doi = 10.1097/CJI.0b013e3182048c4e }}</ref><ref name="Terunuma_2008">{{cite journal | vauthors = Terunuma H, Deng X, Dewan Z, Fujimoto S, Yamamoto N | title = Potential role of NK cells in the induction of immune responses: implications for NK cell-based immunotherapy for cancers and viral infections | journal = International Reviews of Immunology | volume = 27 | issue = 3 | pages = 93–110 | year = 2008 | pmid = 18437601 | doi = 10.1080/08830180801911743 }}</ref> chronic fatigue syndrome<ref name="See_1996">{{cite journal | vauthors = See DM, Tilles JG | title = alpha-Interferon treatment of patients with chronic fatigue syndrome | journal = Immunological Investigations | volume = 25 | issue = 1–2 | pages = 153–164 | year = 1996 | pmid = 8675231 | doi = 10.3109/08820139609059298 }}</ref><ref name="Ojo-Amaize_1994">{{cite journal | vauthors = Ojo-Amaize EA, Conley EJ, Peter JB | title = Decreased natural killer cell activity is associated with severity of chronic fatigue immune dysfunction syndrome | journal = Clinical Infectious Diseases | volume = 18 | issue = Suppl 1 | pages = S157–S159 | date = January 1994 | pmid = 8148445 | doi = 10.1093/clinids/18.Supplement_1.S157 }}</ref> and HHV6 infection.<ref name="Kida_2000">{{cite journal | vauthors = Kida K, Isozumi R, Ito M | title = Killing of human Herpes virus 6-infected cells by lymphocytes cultured with interleukin-2 or -12 | journal = Pediatrics International | volume = 42 | issue = 6 | pages = 631–636 | date = December 2000 | pmid = 11192519 | doi = 10.1046/j.1442-200x.2000.01315.x }}</ref>

==Suppression immunotherapies==

Immune suppression dampens an abnormal immune response in autoimmune diseases or reduces a normal immune response to prevent rejection of transplanted organs or cells.

===Immunosuppressive drugs=== Immunosuppressive drugs can be used to control the immune system with organ transplantation and with autoimmune disease. Immune responses depend on lymphocyte proliferation. Lymphocyte proliferation is the multiplication of lymphocyte cells used to fight and remember foreign invaders.{{citation needed|date=July 2025}} Cytostatic drugs are a type of immunosuppressive drug that aids in slowing down the growth of rapidly dividing cells. Another example of an immunosuppressive drug is Glucocorticoids which are more specific inhibitors of lymphocyte activation. Glucocorticoids work by emulating actions of natural actions of the body's adrenal glands to help suppress the immune system, which is helpful with autoimmune diseases.{{citation needed|date=July 2025}} Alternatively, inhibitors of immunophilins more specifically target T lymphocyte activation, the process by which T-lymphocytes stimulate and begin to respond to a specific antigen,<ref>{{Cite book | vauthors = Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P | title = Molecular Biology of the Cell | date = 2007-12-31 | doi = 10.1201/9780203833445 | isbn = 978-0-203-83344-5 }}</ref> There is also Immunosuppressive antibodies which target steps in the immune response to prevent the body from attacking its tissues, which is a problem with autoimmune diseases,<ref>{{Cite journal | vauthors = Qian Y, Dupps WJ, Meisler DM, Jeng BH | title = Epithelial Debridement for Epithelial Basement Membrane Abnormalities Associated with Endothelial Disorders | journal = European Ophthalmic Review | volume = 04 | issue = 1 | page = 70 | date = 2010 | doi = 10.17925/eor.2010.04.01.70 }}</ref> There are various other drugs that modulate immune responses and can be used to induce immune regulation. It was observed in a preclinical trial that regulation of the immune system by small immunosuppressive molecules such as vitamin D, dexamethasone, and curcumin could be helpful in preventing or treating chronic inflation. Given that the molecules are administered under a low-dose regimen and subcutaneously. A study provides a promising preclinical demonstration of the effectiveness and ease of preparation of Valrubicin-loaded immunoliposomes (Val-ILs) as a novel nanoparticle technology to target immunosuppressive cells. Val-ILs have the potential to be used as a precise and effective therapy based on targeted vesicle-mediated cell death of immunosuppressive cells.<ref name="Georgievski_2024">{{cite journal | vauthors = Georgievski A, Bellaye PS, Tournier B, Choubley H, Pais de Barros JP, Herbst M, Béduneau A, Callier P, Collin B, Végran F, Ballerini P, Garrido C, Quéré R | title = Valrubicin-loaded immunoliposomes for specific vesicle-mediated cell death in the treatment of hematological cancers | journal = Cell Death & Disease | volume = 15 | issue = 5 | page = 328 | date = May 2024 | pmid = 38734740 | pmc = 11088660 | doi = 10.1038/s41419-024-06715-5 | article-number = 328 }}</ref>

===Immune tolerance===

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.<ref name="Rayner Isaacs Therapeutic tolerance">{{cite journal | vauthors = Rayner F, Isaacs JD | title = Therapeutic tolerance in autoimmune disease | journal = Seminars in Arthritis and Rheumatism | volume = 48 | issue = 3 | pages = 558–562 | date = December 2018 | pmid = 30348449 | doi = 10.1016/j.semarthrit.2018.09.008 }}</ref>

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.<ref name="Rotrosen_2002">{{cite journal | vauthors = Rotrosen D, Matthews JB, Bluestone JA | title = The immune tolerance network: a new paradigm for developing tolerance-inducing therapies | journal = The Journal of Allergy and Clinical Immunology | volume = 110 | issue = 1 | pages = 17–23 | date = July 2002 | pmid = 12110811 | doi = 10.1067/mai.2002.124258 | doi-access = free }}</ref> A recent{{when|date=June 2021}} 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.<ref>{{Cite book | vauthors = Stolp J, Zaitsu M, Wood KJ | chapter = Immune Tolerance and Rejection in Organ Transplantation | title = Immunological Tolerance | volume = 1899 | pages = 159–180 | date = 2019 | pmid = 30649772 | doi = 10.1007/978-1-4939-8938-6_12 | isbn = 978-1-4939-8936-2 | series = Methods in Molecular Biology }}</ref><ref>{{cite journal | vauthors = McMurchy AN, Bushell A, Levings MK, Wood KJ | title = Moving to tolerance: clinical application of T regulatory cells | journal = Seminars in Immunology | volume = 23 | issue = 4 | pages = 304–313 | date = August 2011 | pmid = 21620722 | pmc = 3836227 | doi = 10.1016/j.smim.2011.04.001 | series = Advances in Transplantation }}</ref>

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. {| class="wikitable" |+Approaches to therapeutic tolerance induction<ref name="Rayner Isaacs Therapeutic tolerance" /><ref>{{cite journal | vauthors = Baker KF, Isaacs JD | title = Prospects for therapeutic tolerance in humans | journal = Current Opinion in Rheumatology | volume = 26 | issue = 2 | pages = 219–227 | date = March 2014 | pmid = 24378931 | pmc = 4640179 | doi = 10.1097/BOR.0000000000000029 }}</ref><ref>{{cite journal | vauthors = Cooles FA, Isaacs JD | title = Treating to re-establish tolerance in inflammatory arthritis - lessons from other diseases | journal = Best Practice & Research. Clinical Rheumatology | volume = 24 | issue = 4 | pages = 497–511 | date = August 2010 | pmid = 20732648 | doi = 10.1016/j.berh.2010.01.007 | series = Pharmacotherapy: Concepts of Pathogenesis and Emerging Treatments }}</ref> ! !'''Modality''' !'''Details''' ! |- |'''Non-antigen specific''' |Monoclonal Antibodies | Depleting: * Anti-CD52 * Anti-CD4 * Anti-LFA-2 | Non-depleting: * Anti-CD4 * Anti-CD3 * Anti-LFA-1 * CTLA4-Ig * Anti-CD25 |- | |Haematopoietic stem cell transplantation |Non-myeloablative |Myeloablative |- | |Mesenchymal stem cell transplantation | colspan="2" | |- | |Regulatory T cell therapy |Non-antigen specific |Antigen-specific |- | |Low dose IL-2 to expand regulatory T cells | colspan="2" | |- | |Microbiome manipulation | colspan="2" | |- |'''Antigen specific''' |Peptide therapy | colspan="2" |Subcutaneous, intradermal, transmucosal (oral, inhaled)

Tolerogenic dendritic cells, liposomes and nanoparticles |- | |Altered peptide ligands | | |}

=== Allergen immunotherapy === {{main|Allergen immunotherapy}}

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. Allergen immunotherapy can also be referred to as allergen desensitization or hypo-sensitization.<ref name="Persaud_2024">{{Cite book | vauthors = Persaud Y, Memon RJ, Savliwala MN | chapter = Allergy Immunotherapy | title = StatPearls | location = Treasure Island (FL) | date = 2024 | pmid = 30570988 | publisher = StatPearls Publishing | access-date = 2024-05-10 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK535367/ }}</ref> Immunotherapy may produce long-term benefits.<ref name="Durham_1999">{{cite journal | vauthors = Durham SR, Walker SM, Varga EM, Jacobson MR, O'Brien F, Noble W, Till SJ, Hamid QA, Nouri-Aria KT | title = Long-term clinical efficacy of grass-pollen immunotherapy | journal = The New England Journal of Medicine | volume = 341 | issue = 7 | pages = 468–475 | date = August 1999 | pmid = 10441602 | doi = 10.1056/NEJM199908123410702 | doi-access = free }}</ref> Immunotherapy is partly effective in some people and ineffective in others, but it offers people with allergies a chance to reduce or stop their symptoms.{{citation needed|date=June 2021}}

Subcutaneous allergen immunotherapy was first introduced in 1911 through the hypothesis that people with hay fever were sensitive to pollen from grass. A process was developed to create an extract by drawing out timothy pollen in distilled water and then boiling it. This was injected into patients in increasing doses to help alleviate symptoms.<ref>{{cite journal | vauthors = James C, Bernstein DI | title = Allergen immunotherapy: an updated review of safety | journal = Current Opinion in Allergy and Clinical Immunology | volume = 17 | issue = 1 | pages = 55–59 | date = February 2017 | pmid = 27906697 | pmc = 5644500 | doi = 10.1097/ACI.0000000000000335 }}</ref>

Allergen Immunotherapy is indicated for people who are extremely allergic or who cannot avoid specific allergens and when there is evidence of an IgE-mediated reaction that correlates with allergen symptoms. These IgE-mediated reactions can be identified via a blood IgE test or skin testing. If a specific IgE antibody is negative, there is no evidence that allergen immunotherapy will be effective for that patient.

However, there are risks associated with allergen immunotherapy as it is the administration of an agent the patient is known to be highly allergic to. Patients are at increased risk of fatal anaphylaxis, local reaction at the site of injection, or life-threatening systemic allergic reactions.<ref name="Persaud_2024" />

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.<ref>{{cite journal | vauthors = MacGinnitie AJ, Rachid R, Gragg H, Little SV, Lakin P, Cianferoni A, Heimall J, Makhija M, Robison R, Chinthrajah RS, Lee J, Lebovidge J, Dominguez T, Rooney C, Lewis MO, Koss J, Burke-Roberts E, Chin K, Logvinenko T, Pongracic JA, Umetsu DT, Spergel J, Nadeau KC, Schneider LC | title = Omalizumab facilitates rapid oral desensitization for peanut allergy | journal = The Journal of Allergy and Clinical Immunology | volume = 139 | issue = 3 | pages = 873–881.e8 | date = March 2017 | pmid = 27609658 | pmc = 5369605 | doi = 10.1016/j.jaci.2016.08.010 | doi-access = free }}</ref> Dosages increase over time, as the person becomes desensitized. This technique has been tested on infants to prevent peanut allergies.<ref>{{cite press release | title = Oral immunotherapy for peanut allergy in young children | date = 8 February 2022 | url = https://www.nih.gov/news-events/nih-research-matters/oral-immunotherapy-peanut-allergy-young-children | publisher = National Institutes of Health }}</ref>

==Helminthic therapies==

Whipworm ova (''Trichuris suis'') and hookworm (''Necator americanus'') have been tested for immunological diseases and allergies, and have proved beneficial on multiple fronts, yet it is not entirely understood. Scientists have found that the immune response triggered by the burrowing of hookworm larvae to pass through the lungs and blood so the production of mast cells and specific antibodies are now present. They also reduce inflammation or responses ties to autoimmune diseases, but despite this, the hookworm's effects are considered to be negative typically.<ref name="Loukas_2001">{{cite journal | vauthors = Loukas A, Prociv P | title = Immune responses in hookworm infections | journal = Clinical Microbiology Reviews | volume = 14 | issue = 4 | pages = 689–703, table of contents | date = October 2001 | pmid = 11585781 | pmc = 89000 | doi = 10.1128/CMR.14.4.689-703.2001 }}</ref> Helminthic therapy has been investigated as a treatment for relapsing remitting multiple sclerosis,<ref name="Correale_2007">{{cite journal | vauthors = Correale J, Farez M | title = Association between parasite infection and immune responses in multiple sclerosis | journal = Annals of Neurology | volume = 61 | issue = 2 | pages = 97–108 | date = February 2007 | pmid = 17230481 | doi = 10.1002/ana.21067 }}</ref> Crohn's disease,<ref name="Croese_2006">{{cite journal | vauthors = Croese J, O'neil J, Masson J, Cooke S, Melrose W, Pritchard D, Speare R | title = A proof of concept study establishing Necator americanus in Crohn's patients and reservoir donors | journal = Gut | volume = 55 | issue = 1 | pages = 136–137 | date = January 2006 | pmid = 16344586 | pmc = 1856386 | doi = 10.1136/gut.2005.079129 }}</ref><ref name="Reddy_2009">{{cite journal | vauthors = Reddy A, Fried B | title = An update on the use of helminths to treat Crohn's and other autoimmunune diseases | journal = Parasitology Research | volume = 104 | issue = 2 | pages = 217–221 | date = January 2009 | pmid = 19050918 | doi = 10.1007/s00436-008-1297-5 }}</ref><ref name="Laclotte_2008">{{cite journal | vauthors = Laclotte C, Oussalah A, Rey P, Bensenane M, Pluvinage N, Chevaux JB, Trouilloud I, Serre AA, Boucekkine T, Bigard MA, Peyrin-Biroulet L | title = Helminthes et maladies inflammatoires chroniques intestinales | journal = Gastroenterologie Clinique et Biologique | volume = 32 | issue = 12 | pages = 1064–1074 | date = December 2008 | pmid = 18619749 | doi = 10.1016/j.gcb.2008.04.030 | language = fr | trans-title = Helminths and inflammatory bowel diseases }}</ref> allergies and asthma.<ref name="Zaccone_2006">{{cite journal | vauthors = Zaccone P, Fehervari Z, Phillips JM, Dunne DW, Cooke A | title = Parasitic worms and inflammatory diseases | journal = Parasite Immunology | volume = 28 | issue = 10 | pages = 515–523 | date = October 2006 | pmid = 16965287 | pmc = 1618732 | doi = 10.1111/j.1365-3024.2006.00879.x }}</ref> While there is much to be learned about this, many researchers think that the change in the immune response is thanks to the parasites shifting to a more anti-inflammatory or regulatory system, which would in turn decrease inflammation and self inflicted immune damage as seen in Crohn's and multiple sclerosis. Specifically, MS patients saw lower relapse rates and calmer symptoms in some cases when experimenting with helminthic therapy.<ref name="Donkers_2020">{{cite journal | vauthors = Donkers SJ, Kirkland MC, Charabati M, Osborne LC | title = Perspectives of People with Multiple Sclerosis About Helminth Immunotherapy | journal = International Journal of MS Care | volume = 22 | issue = 1 | pages = 43–51 | date = 2020 | pmid = 32123528 | pmc = 7041615 | doi = 10.7224/1537-2073.2019-044 }}</ref> Hypothesized mechanisms include re-polarisation of the Th1 / Th2 response<ref name="Brooker_2004">{{cite book | vauthors = Brooker S, Bethony J, Hotez PJ | title = Human Hookworm Infection in the 21st Century | volume = 58 | pages = 197–288 | date = 2004 | pmid = 15603764 | pmc = 2268732 | doi = 10.1016/S0065-308X(04)58004-1 | series = Advances in Parasitology | isbn = 978-0-12-031758-5 }}</ref> and modulation of dendritic cell function.<ref name="Fujiwara_2009">{{cite journal | vauthors = Fujiwara RT, Cançado GG, Freitas PA, Santiago HC, Massara CL, Dos Santos Carvalho O, Corrêa-Oliveira R, Geiger SM, Bethony J | title = Necator americanus infection: a possible cause of altered dendritic cell differentiation and eosinophil profile in chronically infected individuals | journal = PLOS Neglected Tropical Diseases | volume = 3 | issue = 3 | article-number = e399 | year = 2009 | pmid = 19308259 | pmc = 2654967 | doi = 10.1371/journal.pntd.0000399 | doi-access = free }}</ref><ref name="Carvalho_2009">{{cite journal | vauthors = Carvalho L, Sun J, Kane C, Marshall F, Krawczyk C, Pearce EJ | title = Review series on helminths, immune modulation and the hygiene hypothesis: mechanisms underlying helminth modulation of dendritic cell function | journal = Immunology | volume = 126 | issue = 1 | pages = 28–34 | date = January 2009 | pmid = 19120496 | pmc = 2632707 | doi = 10.1111/j.1365-2567.2008.03008.x }}</ref> The helminths downregulate the pro-inflammatory Th1 cytokines, interleukin-12 (IL-12), interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), while promoting the production of regulatory Th2 cytokines such as IL-10, IL-4, IL-5 and IL-13.<ref name="Brooker_2004" /><ref name="Fumagalli_2009">{{cite journal | vauthors = Fumagalli M, Pozzoli U, Cagliani R, Comi GP, Riva S, Clerici M, Bresolin N, Sironi M | title = Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions | journal = The Journal of Experimental Medicine | volume = 206 | issue = 6 | pages = 1395–1408 | date = June 2009 | pmid = 19468064 | pmc = 2715056 | doi = 10.1084/jem.20082779 }}</ref>

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. Helminths' relationship to humans as hosts should be classified as mutualistic or symbiotic.<ref>{{cite journal | vauthors = Reynolds LA, Finlay BB, Maizels RM | title = Cohabitation in the Intestine: Interactions among Helminth Parasites, Bacterial Microbiota, and Host Immunity | journal = Journal of Immunology | volume = 195 | issue = 9 | pages = 4059–4066 | date = November 2015 | pmid = 26477048 | pmc = 4617609 | doi = 10.4049/jimmunol.1501432 }}</ref> In some ways, the relationship is symbiotic because the worms themselves need the host (humans) for survival, because this body supplies them with nutrients and a home. From another perspective, it could be reasoned that it is mutualistic, being that the above information about benefits in autoimmune disorders continues to remain true and supported. Also, some say that the worms can regulate gut bacteria.<ref name="Loke_2015">{{cite journal | vauthors = Loke P, Lim YA | title = Helminths and the microbiota: parts of the hygiene hypothesis | journal = Parasite Immunology | volume = 37 | issue = 6 | pages = 314–323 | date = June 2015 | pmid = 25869420 | pmc = 4428757 | doi = 10.1111/pim.12193 }}</ref> Another possibility is one of this being a parasitic relationship, arguing that the possible risks of anemia and other disorders outweighs the benefits, yet this is significantly less supported, with the research alluding to the mutualistic and symbiotic approach being much more likely.

== See also == * Biological response modifier * Sepsivac * Checkpoint inhibitor * Interleukin-2 immunotherapy * Immunostimulant * Microtransplantation * Photoimmunotherapy ''in vitro'' or ''in vivo''<ref>{{cite journal | vauthors = Hong CH, Tang MR, Hsu SH, Yang CH, Tseng CS, Ko YC, Guo CS, Yang CW, Lee SC | title = Enhanced early immune response of leptospiral outer membrane protein LipL32 stimulated by narrow band mid-infrared exposure | journal = Journal of Photochemistry and Photobiology B: Biology | volume = 198 | page = 111560 | date = September 2019 | pmid = 31336216 | doi = 10.1016/j.jphotobiol.2019.111560 | bibcode = 2019JPPB..19811560H | article-number = 111560 }}</ref><ref>{{cite journal | vauthors = Chang HY, Li MH, Huang TC, Hsu CL, Tsai SR, Lee SC, Huang HC, Juan HF | title = Quantitative proteomics reveals middle infrared radiation-interfered networks in breast cancer cells | journal = Journal of Proteome Research | volume = 14 | issue = 2 | pages = 1250–1262 | date = February 2015 | pmid = 25556991 | doi = 10.1021/pr5011873 }}</ref><ref>{{cite journal | vauthors = Nagaya T, Okuyama S, Ogata F, Maruoka Y, Choyke PL, Kobayashi H | title = Near infrared photoimmunotherapy using a fiber optic diffuser for treating peritoneal gastric cancer dissemination | journal = Gastric Cancer | volume = 22 | issue = 3 | pages = 463–472 | date = May 2019 | pmid = 30171392 | pmc = 7400986 | doi = 10.1007/s10120-018-0871-5 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Mitsunaga M, Ogawa M, Kosaka N, Rosenblum LT, Choyke PL, Kobayashi H | title = Cancer cell-selective in vivo near infrared photoimmunotherapy targeting specific membrane molecules | journal = Nature Medicine | volume = 17 | issue = 12 | pages = 1685–1691 | date = November 2011 | pmid = 22057348 | pmc = 3233641 | doi = 10.1038/nm.2554 }}</ref><ref>{{cite journal | vauthors = Sato K, Sato N, Xu B, Nakamura Y, Nagaya T, Choyke PL, Hasegawa Y, Kobayashi H | title = Spatially selective depletion of tumor-associated regulatory T cells with near-infrared photoimmunotherapy | journal = Science Translational Medicine | volume = 8 | issue = 352 | pages = 352ra110 | date = August 2016 | pmid = 27535621 | pmc = 7780242 | doi = 10.1126/scitranslmed.aaf6843 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Nagaya T, Nakamura Y, Sato K, Harada T, Choyke PL, Kobayashi H | title = Improved micro-distribution of antibody-photon absorber conjugates after initial near infrared photoimmunotherapy (NIR-PIT) | journal = Journal of Controlled Release | volume = 232 | pages = 1–8 | date = June 2016 | pmid = 27059723 | pmc = 4893891 | doi = 10.1016/j.jconrel.2016.04.003 }}</ref><ref>{{cite journal | vauthors = Zhen Z, Tang W, Wang M, Zhou S, Wang H, Wu Z, Hao Z, Li Z, Liu L, Xie J | title = Protein Nanocage Mediated Fibroblast-Activation Protein Targeted Photoimmunotherapy To Enhance Cytotoxic T Cell Infiltration and Tumor Control | journal = Nano Letters | volume = 17 | issue = 2 | pages = 862–869 | date = February 2017 | pmid = 28027646 | doi = 10.1021/acs.nanolett.6b04150 | bibcode = 2017NanoL..17..862Z }}</ref>

== References == {{reflist}}

== External links == {{Commons category}}

Category:Immunotherapy Category:Virotherapy